Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1.

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Hinrichsen, Inga; Ernst, Benjamin Philipp; Nuber, Franziska; Passmann, Sandra; Schäfer, Dieter; Steinke, Verena; Friedrichs, Nicolaus; Plotz, Guido; Zeuzem, Stefan; Brieger, Angela

2014-01-24

Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.

Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae.

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Christopher S Campbell

2014-05-01

Full Text Available In Saccharomyces cerevisiae, the essential mismatch repair (MMR endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci. Mlh1-Mlh2 foci were similar to Mlh1-Pms1 foci: they required mispair recognition by Msh2-Msh6, increased in response to increased mispairs or downstream defects in MMR, and formed after induction of DNA damage by phleomycin but not double-stranded breaks by I-SceI. Mlh1-Mlh2 could be recruited to mispair-containing DNA in vitro by either Msh2-Msh6 or Msh2-Msh3. Deletion of MLH2 caused a synergistic increase in mutation rate in combination with deletion of MSH6 or reduced expression of Pms1. Phylogenetic analysis demonstrated that the S. cerevisiae Mlh2 protein and the mammalian PMS1 protein are homologs. These results support a hypothesis that Mlh1-Mlh2 is a non-essential accessory factor that acts to enhance the activity of Mlh1-Pms1.

MLH1-93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation.

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Fennell, Lochlan J; Jamieson, Saara; McKeone, Diane; Corish, Tracie; Rohdmann, Megan; Furner, Tori; Bettington, Mark; Liu, Cheng; Kawamata, Futoshi; Bond, Catherine; Van De Pols, Jolieke; Leggett, Barbara; Whitehall, Vicki

2018-01-05

Sessile serrated adenomas with BRAF mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene MLH1, develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and BRAF mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the MLH1-93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to MLH1 promoter hypermethylation. We performed genotyping for the MLH1-93 polymorphism, quantitative methylation specific PCR, and MLH1 immunohistochemistry on 124 SSAD, 128 TSA, 203 BRAF mutant CRCs and 147 control subjects with normal colonoscopy. The minor A allele was significantly associated with a dose dependent increase in methylation at the MLH1 promoter in SSADs (p = 0.022). The AA genotype was only observed in SSADs with MLH1 loss. The A allele was also overrepresented in BRAF mutant cancers with MLH1 loss. Only one of the TSAs showed loss of MLH1 and the overall genotype distribution in TSAs did not differ from controls. The MLH1-93 AA genotype is significantly associated with promoter hypermethylation and MLH1 loss in the context of SSADs. BRAF mutant microsatellite stable colorectal cancers with the AA genotype most likely arise in TSAs since the A allele does not predispose to methylation in this context.

DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells.

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Fukuhara, Shinichiro; Chang, Inik; Mitsui, Yozo; Chiyomaru, Takeshi; Yamamura, Soichiro; Majid, Shahana; Saini, Sharanjot; Hirata, Hiroshi; Deng, Guoren; Gill, Ankurpreet; Wong, Darryn K; Shiina, Hiroaki; Nonomura, Norio; Dahiya, Rajvir; Tanaka, Yuichiro

2014-11-30

Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer (PCa). MMR can influence the regulation of tumor development in various cancers but their role on PCa has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of PCa cells. The DU145 cell line has been established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 protein expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal PWR-1E and RWPE-1 prostatic cells. MLH1-expressing stable transfectant DU145 cells were then created to characterize the effects this MMR gene has on various growth properties. Expression of MLH1 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth in vivo also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c-Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with STI571 also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against PCa development by inducing c-Abl-mediated apoptosis.

Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation.

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Leclerc, Julie; Flament, Cathy; Lovecchio, Tonio; Delattre, Lucie; Ait Yahya, Emilie; Baert-Desurmont, Stéphanie; Burnichon, Nelly; Bronner, Myriam; Cabaret, Odile; Lejeune, Sophie; Guimbaud, Rosine; Morin, Gilles; Mauillon, Jacques; Jonveaux, Philippe; Laurent-Puig, Pierre; Frébourg, Thierry; Porchet, Nicole; Buisine, Marie-Pierre

2018-04-12

PurposeConstitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far.MethodsWe designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations.ResultsThis strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5'-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription.ConclusionThis is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.GENETICS in MEDICINE advance online publication, 12 April 2018; doi:10.1038/gim.2018.47.

mlh3 mutations in baker's yeast alter meiotic recombination outcomes by increasing noncrossover events genome-wide.

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Najla Al-Sweel

2017-08-01

Full Text Available Mlh1-Mlh3 is an endonuclease hypothesized to act in meiosis to resolve double Holliday junctions into crossovers. It also plays a minor role in eukaryotic DNA mismatch repair (MMR. To understand how Mlh1-Mlh3 functions in both meiosis and MMR, we analyzed in baker's yeast 60 new mlh3 alleles. Five alleles specifically disrupted MMR, whereas one (mlh3-32 specifically disrupted meiotic crossing over. Mlh1-mlh3 representatives for each class were purified and characterized. Both Mlh1-mlh3-32 (MMR+, crossover- and Mlh1-mlh3-45 (MMR-, crossover+ displayed wild-type endonuclease activities in vitro. Msh2-Msh3, an MSH complex that acts with Mlh1-Mlh3 in MMR, stimulated the endonuclease activity of Mlh1-mlh3-32 but not Mlh1-mlh3-45, suggesting that Mlh1-mlh3-45 is defective in MSH interactions. Whole genome recombination maps were constructed for wild-type and MMR+ crossover-, MMR- crossover+, endonuclease defective and null mlh3 mutants in an S288c/YJM789 hybrid background. Compared to wild-type, all of the mlh3 mutants showed increases in the number of noncrossover events, consistent with recombination intermediates being resolved through alternative recombination pathways. Our observations provide a structure-function map for Mlh3 that reveals the importance of protein-protein interactions in regulating Mlh1-Mlh3's enzymatic activity. They also illustrate how defective meiotic components can alter the fate of meiotic recombination intermediates, providing new insights for how meiotic recombination pathways are regulated.

Expression and promoter DNA methylation of MLH1 in colorectal cancer and lung cancer.

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Ma, Yunxia; Chen, Yuan; Petersen, Iver

2017-04-01

Aberrant DNA methylation is a common molecular feature in human cancer. The aims of this study were to analyze the methylation status of MLH1, one of the DNA mismatch repair (MMR) genes, in human colorectal and lung cancer and to evaluate its clinical relevance. The expression of MLH1 was analyzed in 8 colorectal cancer (CRC) and 8 lung cancer cell lines by real-time RT-PCR and western blotting. The MLH1 protein expression was evaluated by immunohistochemistry on tissue microarrays including 121 primary CRC and 90 lung cancer patient samples. In cancer cell lines, the methylation status of MLH1 promoter and exon 2 was investigated by bisulfite sequencing (BS). Methylation-specific-PCR (MSP) was used to evaluate methylation status of MLH1. The expression of MLH1 mRNA was detected in 8 CRC cell lines as well as normal colonic fibroblast cells CCD-33Co. At protein levels, MLH1 was lost in one CRC cell line HCT-116 and normal cells CCD-33Co. No methylation was found in the promoter and exon 2 of MLH1 in CRC cell lines. MLH1 was expressed in 8 lung cancer cell lines at both mRNA and protein levels. Compared to cancer cells, normal bronchial epithelial cells (HBEC) had lower expression of MLH1 protein. In primary CRC, 54.5% of cases exhibited positive staining, while 47.8% of lung tumors were positive for MLH1 protein. MSP analysis showed that 58 out of 92 (63.0%) CRC and 41 out of 73 (56.2%) lung cancer exhibited MLH1 methylation. In CRC, the MLH1 methylation was significantly associated with tumor invasion in veins (P=0.012). However, no significant links were found between MLH1 expression and promoter methylation in both tumor entities. MLH1 methylation is a frequent molecular event in CRC and lung cancer patients. In CRC, methylation of MLH1 could be linked to vascular invasiveness. Copyright © 2017 Elsevier GmbH. All rights reserved.

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.

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Kwok, Chau-To; Vogelaar, Ingrid P; van Zelst-Stams, Wendy A; Mensenkamp, Arjen R; Ligtenberg, Marjolijn J; Rapkins, Robert W; Ward, Robyn L; Chun, Nicolette; Ford, James M; Ladabaum, Uri; McKinnon, Wendy C; Greenblatt, Marc S; Hitchins, Megan P

2014-05-01

Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.

Loss of MLH1 sensitizes colon cancer cells to DNA-PKcs inhibitor KU60648.

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Hinrichsen, Inga; Ackermann, Anne; Düding, Tonja; Graband, Annika; Filmann, Natalie; Plotz, Guido; Zeuzem, Stefan; Brieger, Angela

2017-07-01

Germline mutations of MLH1 are responsible for tumor generation in nearly 50% of patients with Lynch Syndrome, and around 15% of sporadic colorectal cancers show MLH1-deficiency due to promotor hypermethylation. Although these tumors are of lower aggressiveness the benefit for these patients from standard chemotherapy is still under discussion. Recently, it was shown that the sensitivity to the DNA-PKcs inhibitor KU60648 is linked to loss of the MMR protein MSH3. However, loss of MSH3 is rather secondary, as a consequence of MMR-deficiency, and frequently detectable in MLH1-deficient tumors. Therefore, we examined the expression of MLH1, MSH2, MSH6, and MSH3 in different MMR-deficient and proficient cell lines and determined their sensitivity to KU60648 by analyzing cell viability and survival. MLH1-dependent ability of double strand break (DSB) repair was monitored after irradiation via γH2AX detection. A panel of 12 colon cancer cell lines, two pairs of cells, where MLH1 knock down was compared to controls with the same genetic background, and one MLH1-deficient cell line where MLH1 was overexpressed, were included. In summary, we found that MLH1 and/or MSH3-deficient cells exhibited a significantly higher sensitivity to KU60648 than MMR-proficient cells and that overexpression of MLH1 in MLH1-deficient cells resulted in a decrease of cell sensitivity. KU60648 efficiency seems to be associated with reduced DSB repair capacity. Since the molecular testing of colon tumors for MLH1 expression is a clinical standard we believe that MLH1 is a much better marker and a greater number of patients would benefit from KU60648 treatment. © 2017 Wiley Periodicals, Inc.

Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

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Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla

2017-03-01

Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors.

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Levine, A Joan; Phipps, Amanda I; Baron, John A; Buchanan, Daniel D; Ahnen, Dennis J; Cohen, Stacey A; Lindor, Noralane M; Newcomb, Polly A; Rosty, Christophe; Haile, Robert W; Laird, Peter W; Weisenberger, Daniel J

2016-01-01

The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82). These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. MLH1 DNA methylation status should be taken into account in etiologic studies. ©2015 American Association for Cancer Research.

Clinicopathological risk factor distributions for MLH1 promoter region methylation in CIMP positive tumors

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Levine, A. Joan; Phipps, Amanda I.; Baron, John A.; Buchanan, Daniel D.; Ahnen, Dennis J.; Cohen, Stacey A.; Lindor, Noralane M.; Newcomb, Polly A.; Rosty, Christophe; Haile, Robert W.; Laird, Peter W.; Weisenberger, Daniel J.

2015-01-01

Background The CpG Island Methylator Phenotype (CIMP) is a major molecular pathway in colorectal cancer (CRC). Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. Methods We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations and family CRC history with MLH1 methylation status in a large population-based sample of CIMP-positive CRCs defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Results Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR=0.50; 95% Confidence Interval (0.31, 0.82)). Conclusions These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. Impact MLH1 DNA methylation status should be taken into account in etiologic studies. PMID:26512054

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

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Morak, Monika; Ibisler, Ayseguel; Keller, Gisela; Jessen, Ellen; Laner, Andreas; Gonzales-Fassrainer, Daniela; Locher, Melanie; Massdorf, Trisari; Nissen, Anke M; Benet-Pagès, Anna; Holinski-Feder, Elke

2018-04-01

Germline defects in MLH1 , MSH2 , MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1 (CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression. We analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results. We detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients' cDNA. We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols

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Seppälä, Toni; Pylvänäinen, Kirsi; Evans, Dafydd Gareth

2017-01-01

We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy.......We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy....

The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations

International Nuclear Information System (INIS)

Flores-Rozas, H.; Kolodner, R.D.

1998-01-01

The Saccharomyces cerevisiae genome encodes four MutL homologs. Of these, MLH1 and PMS1 are known to act in the MSH2-dependent pathway that repairs DNA mismatches. We have investigated the role of NLH3 in mismatch repair. Mutations in MLH3 increased the rate of reversion of the hom3-10 allele by increasing the rate of deletion of a single T in a run of 7 Ts. Combination of mutations in MLH3 and MSH6 caused a synergistic increase in the hom3-10 reversion rate, whereas the hom3-10 reversion rate in an mlh3 msh3 double mutant was the same as in the respective single mutants. Similar results were observed when the accumulation of mutations at frameshift hot spots in the LYS2 gene was analyzed, although mutation of MLH3 did not cause the same extent of affect at every LYS2 frameshift hot spot. MLH3 interacted with MLH1 in a two-hybrid system. These data are consistent with the idea that a proportion of the repair of specific insertion/deletion mispairs by the MSH3-dependent mismatch repair pathway uses a heterodimeric MLH1-MLH3 complex in place of the MLH1-PMS1 complex

Association between MLH1 -93G>a polymorphism and risk of colorectal cancer.

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Ting Wang

Full Text Available The -93G>A (rs1800734 polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC risk. However, the results remain conflicting rather than conclusive.The aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.To derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls was performed. Odds ratios (ORs and 95% confidence intervals (CIs were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.The overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01-1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01-1.11. This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94-3.28; AG versus GG: OR = 1.29, 95% CI = 1.10-1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24-1.68; AA versusOR = 2.29, 95% CI = 1.78-2.96. Egger's test did not show any evidence of publication bias.Our results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.

Molecular analysis of MLH1 variants in Chinese sporadic colorectal cancer patients.

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Peng, H X; Xu, X; Yang, R; Chu, Y M; Yang, D M; Xu, Y; Zhou, F L; Ma, W Z; Zhang, X J; Guan, M; Yang, Z H; Jin, Z D

2016-04-26

Single nucleotide polymorphisms (SNPs) in mismatch repair genes, especially in the MLH1 gene, are closely associated with susceptibility to hereditary nonpolyposis colorectal cancer. However, few relevant findings are available regarding the association between sporadic colorectal cancer (SCRC) and SNPs of MLH1 in Chinese patients. Therefore, the present study aimed to describe the pathogenic association between three important MLH1 polymorphisms and SCRC in the Chinese population. Peripheral blood samples from 156 SCRC patients and 311 healthy controls were collected. DNA was purified from peripheral blood, and the V384D, R217C, and I219V polymorphisms were evaluated using high-resolution melting analysis and direct sequencing. The association between the three important MLH1 polymorphisms and clinical pathological features of the SCRC patients was analyzed. In addition, PMS2-MLH1 protein interactions were determined by co-immunoprecipitation (Co-IP) to determine the protein functional alteration induced by these SNPs. Among the three polymorphisms, V384D was significantly associated with the risk of SCRC (OR = 31.36, P MLH1 R217C, V384D, and I219V variants had relative binding abilities with PMS2 of 0.59, 0.70, and 0.80, respectively, compared with the wild-type. These findings suggest that MLH1 V384D could be a promising genetic marker for susceptibility to SCRC.

A role for MLH3 in hereditary nonpolyposis colorectal cancer

NARCIS (Netherlands)

Wu, Y; Berends, MJW; Sijmons, RH; Mensink, RGJ; Verlind, E; Kooi, KA; van der Sluis, T; Kempinga, C; van der Zee, AGJ; Hollema, H; Buys, CHCM; Kleibeuker, JH; Hofstra, RMW

2001-01-01

We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC. We identified ten different germline MLH3 variants, one frameshift and nine missense mutations,

High Mutation Levels are Compatible with Normal Embryonic Development in Mlh1-Deficient Mice.

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Fan, Xiaoyan; Li, Yan; Zhang, Yulong; Sang, Meixiang; Cai, Jianhui; Li, Qiaoxia; Ozaki, Toshinori; Ono, Tetsuya; He, Dongwei

2016-10-01

To elucidate the role of the mismatch repair gene Mlh1 in genome instability during the fetal stage, spontaneous mutations were studied in Mlh1-deficient lacZ-transgenic mouse fetuses. Mutation levels were high at 9.5 days post coitum (dpc) and gradually increased during the embryonic stage, after which they remained unchanged. In addition, mutations that were found in brain, liver, spleen, small intestine and thymus showed similar levels and no statistically significant difference was found. The molecular nature of mutations at 12.5 dpc in fetuses of Mlh1 +/+ and Mlh1 -/- mice showed their own unique spectra, suggesting that deletion mutations were the main causes in the deficiency of the Mlh1 gene. Of note, fetuses of irradiated mice exhibited marked differences such as post-implantation loss and Mendelian distribution. Collectively, these results strongly suggest that high mutation ofMlh1 -/- -deficient fetuses has little effect on the fetuses during their early developmental stages, whereas Mlh1 -/- -deficient fetuses from X-ray irradiated mothers are clearly effected.

Disruption of a -35kb enhancer impairs CTCF binding and MLH1 expression in colorectal cells.

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Liu, Qing; Thoms, Julie A; Nunez, Andrea C; Huang, Yizhou; Knezevic, Kathy; Packham, Deborah; Poulos, Rebecca C; Williams, Rachel; Beck, Dominik; Hawkins, Nicholas J; Ward, Robyn L; Wong, Jason W H; Hesson, Luke B; Sloane, Mathew A; Pimanda, John

2018-06-13

MLH1 is a major tumour suppressor gene involved in the pathogenesis of Lynch syndrome and various sporadic cancers. Despite their potential pathogenic importance, genomic regions capable of regulating MLH1 expression over long distances have yet to be identified. Here we use chromosome conformation capture (3C) to screen a 650-kb region flanking the MLH1 locus to identify interactions between the MLH1 promoter and distal regions in MLH1 expressing and non-expressing cells. Putative enhancers were functionally validated using luciferase reporter assays, chromatin immunoprecipitation and CRISPR-Cas9 mediated deletion of endogenous regions. To evaluate whether germline variants in the enhancer might contribute to impaired MLH1 expression in patients with suspected Lynch syndrome, we also screened germline DNA from a cohort of 74 patients with no known coding mutations or epimutations at the MLH1 promoter. A 1.8kb DNA fragment, 35kb upstream of the MLH1 transcription start site enhances MLH1 gene expression in colorectal cells. The enhancer was bound by CTCF and CRISPR-Cas9 mediated deletion of a core binding region impairs endogenous MLH1 expression. 5.4% of suspected Lynch syndrome patients have a rare single nucleotide variant (G>A; rs143969848; 2.5% in gnomAD European, non-Finnish) within a highly conserved CTCF binding motif, which disrupts enhancer activity in SW620 colorectal carcinoma cells. A CTCF bound region within the MLH1 -35 enhancer regulates MLH1 expression in colorectal cells and is worthy of scrutiny in future genetic screening strategies for suspected Lynch syndrome associated with loss of MLH1 expression. Copyright ©2018, American Association for Cancer Research.

Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation.

Science.gov (United States)

Hitchins, Megan P

2016-07-01

Constitutional epimutation of the DNA mismatch repair gene, MLH1, represents a minor cause of Lynch syndrome. MLH1 epimutations are characterized by the soma-wide distribution of methylation of a single allele of the MLH1 promoter accompanied by constitutive allelic loss of transcription. 'Primary' MLH1 epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. 'Secondary' MLH1 epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of MLH1. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for MLH1 epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting MLH1 epimutation testing; overlapping molecular pathology features of MLH1 methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of MLH1 epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of MLH1 epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting MLH1 epimutation testing could provide a cost-effective means of diagnosing these cases.

MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults.

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Alvarez, Marisa C; Santos, Juliana C; Maniezzo, Nathália; Ladeira, Marcelo S; da Silva, Artur L C; Scaletsky, Isabel C A; Pedrazzoli, José; Ribeiro, Marcelo L

2013-05-28

To evaluate the association between Helicobacter pylori (H. pylori) infection and MLH1 and MGMT methylation and its relationship with microsatellite instability (MSI). The methylation status of the MLH1 and MGMT promoter region was analysed by methylation specific methylation-polymerase chain reaction (MSP-PCR) in gastric biopsy samples from uninfected or H. pylori-infected children (n = 50), from adults with chronic gastritis (n = 97) and from adults with gastric cancer (n = 92). MLH1 and MGMT mRNA expression were measured by real-time PCR and normalised to a constitutive gene (β actin). MSI analysis was performed by screening MSI markers at 4 loci (Bat-25, Bat-26, D17S250 and D2S123) with PCR; PCR products were analysed by single strand conformation polymorphism followed by silver staining. Statistical analyses were performed with either the χ(2) test with Yates continuity correction or Fisher's exact test, and statistical significance for expression analysis was assessed using an unpaired Student's t-test. Methylation was not detected in the promoter regions of MLH1 and MGMT in gastric biopsy samples from children, regardless of H. pylori infection status. The MGMT promoter was methylated in 51% of chronic gastritis adult patients and was associated with H. pylori infection (P MLH1 methylation frequencies among H. pylori-infected and non-infected chronic gastritis adult patients were 13% and 7%, respectively. We observed methylation of the MLH1 promoter (39%) and increased MSI levels (68%) in samples from gastric cancer patients in comparison to samples from H. pylori-infected adult chronic gastritis patients (P MLH1 and MGMT mRNA were significantly reduced in chronic gastritis samples that were also hypermethylated (P MLH1 methylation did not occur in earlier-stage H. pylori infections and thus might depend on the duration of infection.

Development of a method for RIA of MLH

International Nuclear Information System (INIS)

Zhang Haoyi; Jin Lichun

2002-01-01

Objective: To develop a method of RIA for MLH to measure the serum level of LH in Rhesus Monkey for animal experiment in reproductive medicine. Methods: 125 I-MLH was prepared with chloramine T-Iodogen method. Rabbit anti-MLH was used as first antibody and sheep anti-rabbit IgG was used as separating agent. RIA was performed with liquid phase competitive radioassay. Results: The specific radioactivity of labelled antigen was 67 μg/mCi; antibody affinity constant was Ka = 3.44 x 10 -9 mol/L the shape of the standard curve was good. r = 0.991, intra-assay error CV = 3.49%, inter-assay error CV = 4.65%. The minimal detectable concentration was 0.42 μg/ml. Mean value of 30 normal Rhesus Monkey serum specimens was 1.17 +- 1.30 μg/ml. Conclusion: The developed method was simple reliable and sensitive. It would be of use in study of contraceptive and sex-physiology drugs

Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family.

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Cini, Giulia; Carnevali, Ileana; Quaia, Michele; Chiaravalli, Anna Maria; Sala, Paola; Giacomini, Elisa; Maestro, Roberta; Tibiletti, Maria Grazia; Viel, Alessandra

2015-04-01

Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The MLH1 ATPase domain is needed for suppressing aberrant formation of interstitial telomeric sequences.

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Jia, Pingping; Chai, Weihang

2018-05-01

Genome instability gives rise to cancer. MLH1, commonly known for its important role in mismatch repair (MMR), DNA damage signaling and double-strand break (DSB) repair, safeguards genome stability. Recently we have reported a novel role of MLH1 in preventing aberrant formation of interstitial telomeric sequences (ITSs) at intra-chromosomal regions. Deficiency in MLH1, in particular its N-terminus, leads to an increase of ITSs. Here, we identify that the ATPase activity in the MLH1 N-terminal domain is important for suppressing the formation of ITSs. The ATPase activity is also needed for recruiting MLH1 to DSBs. Moreover, defective ATPase activity of MLH1 causes an increase in micronuclei formation. Our results highlight the crucial role of MLH1's ATPase domain in preventing the aberrant formation of telomeric sequences at the intra-chromosomal regions and preserving genome stability. Copyright © 2018 Elsevier B.V. All rights reserved.

Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance.

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Li, Jinyun; Ye, Dong; Wang, Lei; Peng, Yingying; Li, Qun; Deng, Hongxia; Zhou, Chongchang

2018-01-01

The mutL homolog-1 ( MLH1 ) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma.

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Wu, Dongping; Chen, Xiaoying; Xu, Yan; Wang, Haiyong; Yu, Guangmao; Jiang, Luping; Hong, Qingxiao; Duan, Shiwei

2017-04-01

The DNA mismatch repair (MMR) gene MutL homolog 1 ( MLH1 ) is critical for the maintenance of genomic integrity. Methylation of the MLH1 gene promoter was identified as a prognostic marker for numerous types of cancer including glioblastoma, colorectal, ovarian and gastric cancer. The present study aimed to determine whether MLH1 promoter methylation was associated with survival in male patients with esophageal squamous cell carcinoma (ESCC). Formalin-fixed, paraffin-embedded ESCC tissues were collected from 87 male patients. MLH1 promoter methylation was assessed using the methylation-specific polymerase chain reaction approach. Kaplan-Meier survival curves and log-rank tests were used to evaluate the association between MLH1 promoter methylation and overall survival (OS) in patients with ESCC. Cox regression analysis was used to obtain crude and multivariate hazard ratios (HR), and 95% confidence intervals (CI). The present study revealed that MLH1 promoter methylation was observed in 53/87 (60.9%) of male patients with ESCC. Kaplan-Meier survival analysis demonstrated that MLH1 promoter hypermethylation was significantly associated with poorer prognosis in patients with ESCC (P=0.048). Multivariate survival analysis revealed that MLH1 promoter hypermethylation was an independent predictor of poor OS in male patients with ESCC (HR=1.716; 95% CI=1.008-2.921). Therefore, MLH1 promoter hypermethylation may be a predictor of prognosis in male patients with ESCC.

Autophagy influences the low-dose hyper-radiosensitivity of human lung adenocarcinoma cells by regulating MLH1.

Science.gov (United States)

Wang, Qiong; Xiao, Zhuya; Lin, Zhenyu; Zhou, Jie; Chen, Weihong; Jie, Wuyun; Cao, Xing; Yin, Zhongyuan; Cheng, Jing

2017-06-01

To investigate the impact of autophagy on the low-dose hyper-radiosensitivity (HRS) of human lung adenocarcinoma cells via MLH1 regulation. Immunofluorescent staining, Western blotting, and electron microscopy were utilized to detect autophagy in A549 and H460 cells. shRNA was used to silence MLH1 expression. The levels of MLH1, mTOR, p-mTOR, BNIP3, and Beclin-1 were measured by real-time polymerase chain reaction (PCR) and Western blotting. A549 cells, which have low levels of MLH1 expression, displayed HRS/induced radioresistance (IRR). Conversely, the radiosensitivity of H460 cells, which express high levels of MLH1, conformed to the linear-quadratic (LQ) model. After down-regulating MLH1 expression, A549 cells showed increased HRS and inhibition of autophagy, whereas H460 cells exhibited HRS/IRR. The levels of mTOR, p-mTOR, and BNIP3 were reduced in cells harboring MLH1 shRNA, and the changes in the mTOR/p-mTOR ratio mirrored those in MLH1 expression. Low MLH1-expressing A549 cells may exhibit HRS. Both the mTOR/p-mTOR and BNIP3/Beclin-1 signaling pathways were found to be related to HRS, but only mTOR/p-mTOR is involved in the regulation of HRS via MLH1 and autophagy.

Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β.

Science.gov (United States)

Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

2017-06-13

Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ.

Effect of MLH1 -93G>A on gene expression in patients with colorectal cancer.

Science.gov (United States)

Funck, Alexandre; Santos, Juliana C; Silva-Fernandes, Isabelle J L; Rabenhorst, Silvia H B; Martinez, Carlos A R; Ribeiro, Marcelo L

2014-09-01

The DNA repair machinery plays a key role in maintaining genomic stability by preventing the emergence of mutations. Furthermore, the -93G>A polymorphism in the MLH1 gene has been associated with an increased risk of developing colorectal cancer. Therefore, the aim of this study was to examine the expression pattern and effect of this polymorphism in normal and tumour samples from patients with colorectal cancer. The MLH1 -93G>A (rs1800734) polymorphism was detected by PCR-RFLP in 49 cases of colorectal cancer. MLH1 expression was investigated using real-time quantitative PCR. The results indicate a significant decrease in MLH1 expression in tumour samples compared to their normal counterparts. The MLH1 gene was also significantly repressed in samples from patients who had some degree of tumour invasion into other organs. Similarly, those patients who were in a more advanced tumour stage (TNM III and IV) exhibited a significant reduction in MLH1 gene expression. Finally, the mutant genotype AA of MLH1 was associated with a significant decrease in the expression of this gene. This finding suggests that this polymorphism could increase the risk of developing colorectal cancer by a defective mismatch repair system, particularly through the loss of MLH1 expression in an allele-specific manner.

Characterization of a Highly Conserved Binding Site of Mlh1 Required for Exonuclease I-Dependent Mismatch Repair

DEFF Research Database (Denmark)

Dherin, Claudine; Gueneau, Emeric; Francin, Mathilde

2009-01-01

Mlh1 is an essential factor of mismatch repair (MMR) and meiotic recombination. It interacts through its C-terminal region with MutL homologs and proteins involved in DNA repair and replication. In this study, we identified the site of yeast Mlh1 critical for the interaction with Exo1, Ntg2......, and Sgs1 proteins, designated as site S2 by reference to the Mlh1/Pms1 heterodimerization site S1. We show that site S2 is also involved in the interaction between human MLH1 and EXO1 or BLM. Binding at this site involves a common motif on Mlh1 partners that we called the MIP-box for the Mlh1 interacting...... protein box. Direct and specific interactions between yeast Mlh1 and peptides derived from Exo1, Ntg2, and Sgs1 and between human MLH1 and peptide derived from EXO1 and BLM were measured with K(d) values ranging from 8.1 to 17.4 microM. In Saccharomyces cerevisiae, a mutant of Mlh1 targeted at site S2...

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

International Nuclear Information System (INIS)

Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram; Kerr, Iain D.; Min, Jinrong

2015-01-01

The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

Energy Technology Data Exchange (ETDEWEB)

Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); Kerr, Iain D., E-mail: ikerr@myriad.com [Myriad Genetic Laboratories Inc., 320 Wakara Way, Salt Lake City, UT 84108 (United States); Min, Jinrong, E-mail: ikerr@myriad.com [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); University of Toronto, Toronto, ON M5G 1L7 (Canada)

2015-07-28

The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.

MLH1 promoter methylation frequency in colorectal cancer patients and related clinicopathological and molecular features.

Directory of Open Access Journals (Sweden)

Xia Li

Full Text Available To describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC; to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis.A literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR and 95% confidence intervals (95% CI were calculated.The pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8-24.1%. They were 18.7% (95% CI: 14.7-23.6% and 16.4% (95% CI: 11.9-22.0% in sporadic and Lynch syndrome (LS CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215-2.215; P = 0.001, tumor location (pooled OR = 3.804, 95% CI: 2.715-5.329; P<0.001, tumor differentiation (pooled OR = 2.131, 95% CI: 1.464-3.102; P<0.001, MSI (OR: 27.096, 95% CI: 13.717-53.526; P<0.001. Significant associations were also observed between MLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427-34.631; P<0.001 and 9.419 (95% CI: 2.613-33.953; P = 0.001, respectively.The frequency of MLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation.

Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome.

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Kidambi, Trilokesh D; Blanco, Amie; Van Ziffle, Jessica; Terdiman, Jonathan P

2016-04-01

At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.

Differential expression of hMLH1 in sporadic human colorectal cancer tumors and distant metastases

DEFF Research Database (Denmark)

Larsen, Nicolai Balle; Heiberg Engel, Peter Johan; Rasmussen, Merete

2009-01-01

in expression between the tumor transition zone and the invasive front. Expression of hMSH2, hMLH1, and hPMS2 was screened immunohistochemically in 92 stage IV tumors and derived liver metastases. In cases with loss of mismatch repair protein expression, lymph node metastases were also examined....... Clinicopathological parameters and Ki-67 staining indexes were evaluated and compared. Four tumors displayed a complete loss of hMLH1/hPMS2 expression at the transition zone; however, three of these expressed both proteins at the invasive front and in liver and lymph node metastases. A further four were predominantly...... hMLH1/hPMS2 negative at the transition zone, but with distinct subclones of hMLH1/hPMS2-expressing cells at the transition zone. All of these tumors expressed hMLH1/hPMS2 at the invasive front and in liver metastases, with three also expressing hMLH/hPMS2 in lymph node metastases. No significant...

Expression of MLH1 and MSH2 in urothelial carcinoma of the renal pelvis.

Science.gov (United States)

Ehsani, Laleh; Osunkoya, Adeboye O

2014-09-01

In this study, we investigated microsatellite instability in urothelial carcinoma of the renal pelvis by lack of immunohistochemical staining for MLH1 and MSH2. The study included 44 cases of urothelial carcinoma of the renal pelvis obtained from radical nephroureterectomy specimens at our institution. We evaluated the loss of nuclear immunohistochemical staining of MLH1 and MSH2. Eight of 44 (18 %) patients had negative MLH1 expression and 25/44 (57 %) patients had negative MSH2 expression. Six of 8 (75 %) patients with negative MLH1 expression were male and 2/8 (25 %) patients were female. Nineteen of 25 (75 %) patients with negative MSH2 expression were male, and 6/25 (24 %) patients were female. Seven of 8 (88 %) cases with negative MLH1 expression were high-grade urothelial carcinoma, and 21/25 (84 %) cases with negative MSH2 expression were high-grade urothelial carcinoma. Twenty-one of 44 (48 %) cases had an inverted growth pattern, of which 3/21 (14 %) cases had negative MLH1 expression and 14/21 (67 %) cases had negative MSH2 expression. Our study showed that microsatellite instability based on negative expression of MLH1 and MSH2 was more common in male patients with high-grade urothelial carcinoma. There is a strong correlation between inverted growth pattern and negative MSH2 expression. Microsatellite instability testing should be performed in patients with upper urinary tract carcinoma and may have prognostic value.

Activation of Saccharomyces cerevisiae Mlh1-Pms1 Endonuclease in a Reconstituted Mismatch Repair System*

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Smith, Catherine E.; Bowen, Nikki; Graham, William J.; Goellner, Eva M.; Srivatsan, Anjana; Kolodner, Richard D.

2015-01-01

Previous studies reported the reconstitution of an Mlh1-Pms1-independent 5′ nick-directed mismatch repair (MMR) reaction using Saccharomyces cerevisiae proteins. Here we describe the reconstitution of a mispair-dependent Mlh1-Pms1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) and a reconstituted Mlh1-Pms1-dependent 3′ nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA), RFC, PCNA, and DNA polymerase δ. Both reactions required Mg2+ and Mn2+ for optimal activity. The MMR reaction also required two reaction stages in which the first stage required incubation of Mlh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of the substrate, followed by a second stage in which other proteins were added. Analysis of different mutant proteins demonstrated that both reactions required a functional Mlh1-Pms1 endonuclease active site, as well as mispair recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation. Mutant Mlh1-Pms1 and PCNA proteins that were defective for Exo1-independent but not Exo1-dependent MMR in vivo were partially defective in the Mlh1-Pms1 endonuclease and MMR reactions, suggesting that both reactions reflect the activation of Mlh1-Pms1 seen in Exo1-independent MMR in vivo. The availability of this reconstituted MMR reaction should now make it possible to better study both Exo1-independent and Exo1-dependent MMR. PMID:26170454

Activation of Saccharomyces cerevisiae Mlh1-Pms1 Endonuclease in a Reconstituted Mismatch Repair System.

Science.gov (United States)

Smith, Catherine E; Bowen, Nikki; Graham, William J; Goellner, Eva M; Srivatsan, Anjana; Kolodner, Richard D

2015-08-28

Previous studies reported the reconstitution of an Mlh1-Pms1-independent 5' nick-directed mismatch repair (MMR) reaction using Saccharomyces cerevisiae proteins. Here we describe the reconstitution of a mispair-dependent Mlh1-Pms1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) and a reconstituted Mlh1-Pms1-dependent 3' nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA), RFC, PCNA, and DNA polymerase δ. Both reactions required Mg(2+) and Mn(2+) for optimal activity. The MMR reaction also required two reaction stages in which the first stage required incubation of Mlh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of the substrate, followed by a second stage in which other proteins were added. Analysis of different mutant proteins demonstrated that both reactions required a functional Mlh1-Pms1 endonuclease active site, as well as mispair recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation. Mutant Mlh1-Pms1 and PCNA proteins that were defective for Exo1-independent but not Exo1-dependent MMR in vivo were partially defective in the Mlh1-Pms1 endonuclease and MMR reactions, suggesting that both reactions reflect the activation of Mlh1-Pms1 seen in Exo1-independent MMR in vivo. The availability of this reconstituted MMR reaction should now make it possible to better study both Exo1-independent and Exo1-dependent MMR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The unstructured linker arms of Mlh1-Pms1 are important for interactions with DNA during mismatch repair

Science.gov (United States)

Plys, Aaron J.; Rogacheva, Maria V.; Greene, Eric C.; Alani, Eric

2012-01-01

DNA mismatch repair (MMR) models have proposed that MSH proteins identify DNA polymerase errors while interacting with the DNA replication fork. MLH proteins (primarily Mlh1-Pms1 in baker’s yeast) then survey the genome for lesion-bound MSH proteins. The resulting MSH-MLH complex formed at a DNA lesion initiates downstream steps in repair. MLH proteins act as dimers and contain long (20 – 30 nanometers) unstructured arms that connect two terminal globular domains. These arms can vary between 100 to 300 amino acids in length, are highly divergent between organisms, and are resistant to amino acid substitutions. To test the roles of the linker arms in MMR, we engineered a protease cleavage site into the Mlh1 linker arm domain of baker’s yeast Mlh1-Pms1. Cleavage of the Mlh1 linker arm in vitro resulted in a defect in Mlh1-Pms1 DNA binding activity, and in vivo proteolytic cleavage resulted in a complete defect in MMR. We then generated a series of truncation mutants bearing Mlh1 and Pms1 linker arms of varying lengths. This work revealed that MMR is greatly compromised when portions of the Mlh1 linker are removed, whereas repair is less sensitive to truncation of the Pms1 linker arm. Purified complexes containing truncations in Mlh1 and Pms1 linker arms were analyzed and found to have differential defects in DNA binding that also correlated with the ability to form a ternary complex with Msh2-Msh6 and mismatch DNA. These observations are consistent with the unstructured linker domains of MLH proteins providing distinct interactions with DNA during MMR. PMID:22659005

Predictive value of CHFR and MLH1 methylation in human gastric cancer.

Science.gov (United States)

Li, Yazhuo; Yang, Yunsheng; Lu, Youyong; Herman, James G; Brock, Malcolm V; Zhao, Po; Guo, Mingzhou

2015-04-01

Gastric carcinoma (GC) has one of the highest mortality rates of cancer diseases and has a high incidence rate in China. Palliative chemotherapy is the main treatment for advanced gastric cancer. It is necessary to compare the effectiveness and toxicities of different regimens. This study explores the possibility of methylation of DNA damage repair genes serving as a prognostic and chemo-sensitive marker in human gastric cancer. The methylation status of five DNA damage repair genes (CHFR, FANCF, MGMT, MLH1, and RASSF1A) was detected by nested methylation-specific PCR in 102 paraffin-embedded gastric cancer samples. Chi-square or Fisher's exact tests were used to evaluate the association of methylation status and clinic-pathological factors. The Kaplan-Meier method and Cox proportional hazards models were employed to analyze the association of methylation status and chemo-sensitivity. The results indicate that CHFR, MLH1, RASSF1A, MGMT, and FANCF were methylated in 34.3% (35/102), 21.6% (22/102), 12.7% (13/102), 9.8% (10/102), and 0% (0/102) of samples, respectively. No association was found between methylation of CHFR, MLH1, RASSF1A, MGMT, or FANCF with gender, age, tumor size, tumor differentiation, lymph node metastasis, and TNM stage. In docetaxel-treated gastric cancer patients, resistance to docetaxel was found in CHFR unmethylated patients by Cox proportional hazards model (HR 0.243, 95% CI, 0.069-0.859, p = 0.028), and overall survival is longer in the CHFR methylated group compared with the CHFR unmethylated group (log-rank, p = 0.036). In oxaliplatin-treated gastric cancer patients, resistance to oxaliplatin was found in MLH1 methylated patients (HR 2.988, 95% CI, 1.064-8.394, p = 0.038), and overall survival was longer in the MLH1 unmethylated group compared with the MLH1 methylated group (log-rank, p = 0.046). CHFR is frequently methylated in human gastric cancer, and CHFR methylation may serve as a docetaxel-sensitive marker. MLH1 methylation was

MLH1 Promoter Methylation Frequency in Colorectal Cancer Patients and Related Clinicopathological and Molecular Features

Science.gov (United States)

Li, Xia; Yao, Xiaoping; Wang, Yibaina; Hu, Fulan; Wang, Fan; Jiang, Liying; Liu, Yupeng; Wang, Da; Sun, Guizhi; Zhao, Yashuang

2013-01-01

Purpose To describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC); to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis. Methods A literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. Results The pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8–24.1%). They were 18.7% (95% CI: 14.7–23.6%) and 16.4% (95% CI: 11.9–22.0%) in sporadic and Lynch syndrome (LS) CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215–2.215; P = 0.001), tumor location (pooled OR = 3.804, 95% CI: 2.715–5.329; PMLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427–34.631; PMLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation. PMID:23555617

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status.

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Kim, Jung H; Rhee, Ye-Y; Bae, Jeong-M; Kwon, Hyeong-J; Cho, Nam-Y; Kim, Mi J; Kang, Gyeong H

2013-07-01

Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n=220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m+), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m+, and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m+ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m+, were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m+ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m+ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features

Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.

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Liu, Cheng; Walker, Neal I; Leggett, Barbara A; Whitehall, Vicki Lj; Bettington, Mark L; Rosty, Christophe

2017-12-01

Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an

Promoter hypermethylation of mismatch repair gene hMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea.

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Fukushima, Takao; Katayama, Yoichi; Watanabe, Takao; Yoshino, Atsuo; Ogino, Akiyoshi; Ohta, Takashi; Komine, Chiaki

2005-02-15

In certain types of human cancers, transcriptional inactivation of hMLH1 by promoter hypermethylation plays a causal role in the loss of mismatch repair functions that modulate cytotoxic pathways in response to DNA-damaging agents. The aim of the present study was to investigate the role of promoter methylation of the hMLH1 gene in malignant astrocytomas. We examined the hMLH1 promoter methylation in a homogeneous cohort of patients with 41 malignant astrocytomas treated by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea chemotherapy in combination with radiation and interferon therapy, and assessed the correlation of such methylation with clinical outcome. hMLH1 promoter methylation was found in 6 (15%) of the 41 newly diagnosed malignant astrocytomas. Hypermethylation of the hMLH1 promoter corresponded closely with a loss of immunohistochemical staining for hMLH1 protein (P = 0.0013). Patients with hMLH1-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with hMLH1-unmethylated tumors (P = 0.0150). The presence of hMLH1 hypermethylation was significantly associated with a longer progression-free survival on both univariate analysis (P = 0.0340) and multivariate analysis (P = 0.0161). The present study identified hMLH1 methylation status as a predictor of the clinical response of malignant astrocytomas to chloroethylnitrosourea-based adjuvant therapy. The findings obtained suggest that determination of the methylation status of hMLH1 could provide a potential basis for designing rational chemotherapeutic strategies, as well as for predicting prognosis.

Cancer risks for MLH1 and MSH2 mutation carriers

OpenAIRE

Dowty, James G.; Win, Aung K.; Buchanan, Daniel D.; Lindor, Noralane M.; Macrae, Finlay A.; Clendenning, Mark; Antill, Yoland C.; Thibodeau, Stephen N.; Casey, Graham; Gallinger, Steve; Le Marchand, Loic; Newcomb, Polly A.; Haile, Robert W.; Young, Graeme P.; James, Paul A.

2013-01-01

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC) and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks to age 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, ...

Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan.

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Tentori, Lucio; Leonetti, Carlo; Muzi, Alessia; Dorio, Annalisa Susanna; Porru, Manuela; Dolci, Susanna; Campolo, Federica; Vernole, Patrizia; Lacal, Pedro Miguel; Praz, Françoise; Graziani, Grazia

2013-07-01

Poly(ADP-ribose) polymerase inhibitors (PARPi) are currently evaluated in clinical trials in combination with topoisomerase I (Top1) inhibitors against a variety of cancers, including colon carcinoma. Since the mismatch repair component MLH1 is defective in 10-15% of colorectal cancers we have investigated whether MLH1 affects response to the Top1 inhibitor irinotecan, alone or in combination with PARPi. To this end, the colon cancer cell lines HCT116, carrying MLH1 mutations on chromosome 3 and HCT116 in which the wild-type MLH1 gene was replaced via chromosomal transfer (HCT116+3) or by transfection of the corresponding MLH1 cDNA (HCT116 1-2) were used. HCT116 cells or HCT116+3 cells stably silenced for PARP-1 expression were also analysed. The results of in vitro and in vivo experiments indicated that MLH1, together with low levels of Top1, contributed to colon cancer resistance to irinotecan. In the MLH1-proficient cells SN-38, the active metabolite of irinotecan, induced lower levels of DNA damage than in MLH1-deficient cells, as shown by the weaker induction of γ-H2AX and p53 phosphorylation. The presence of MLH1 contributed to induce of prompt Chk1 phosphorylation, restoring G2/M cell cycle checkpoint and repair of DNA damage. On the contrary, in the absence of MLH1, HCT116 cells showed minor Chk1 phosphorylation and underwent apoptosis. Remarkably, inhibition of PARP function by PARPi or by PARP-1 gene silencing always increased the antitumor activity of irinotecan, even in the presence of low PARP-1 expression.

Utility of MLH1 methylation analysis in the clinical evaluation of Lynch Syndrome in women with endometrial cancer.

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Bruegl, Amanda S; Djordjevic, Bojana; Urbauer, Diana L; Westin, Shannon N; Soliman, Pamela T; Lu, Karen H; Luthra, Rajyalakshmi; Broaddus, Russell R

2014-01-01

Clinical screening criteria, such as young age of endometrial cancer diagnosis and family history of signature cancers, have traditionally been used to identify women with Lynch Syndrome, which is caused by mutation of a DNA mismatch repair gene. Immunohistochemistry and microsatellite instability analysis have evolved as important screening tools to evaluate endometrial cancer patients for Lynch Syndrome. A complicating factor is that 15-20% of sporadic endometrial cancers have immunohistochemical loss of the DNA mismatch repair protein MLH1 and high levels of microsatellite instability due to methylation of MLH1. The PCR-based MLH1 methylation assay potentially resolves this issue, yet many clinical laboratories do not perform this assay. The objective of this study was to determine if clinical and pathologic features help to distinguish sporadic endometrial carcinomas with MLH1 loss secondary to MLH1 methylation from Lynch Syndrome-associated endometrial carcinomas with MLH1 loss and absence of MLH1 methylation. Of 337 endometrial carcinomas examined, 54 had immunohistochemical loss of MLH1. 40/54 had MLH1 methylation and were designated as sporadic, while 14/54 lacked MLH1 methylation and were designated as Lynch Syndrome. Diabetes and deep myometrial invasion were associated with Lynch Syndrome; no other clinical or pathological variable distinguished the 2 groups. Combining Society of Gynecologic Oncology screening criteria with these 2 features accurately captured all Lynch Syndrome cases, but with low specificity. In summary, no single clinical/pathologic feature or screening criteria tool accurately identified all Lynch Syndrome-associated endometrial carcinomas, highlighting the importance of the MLH1 methylation assay in the clinical evaluation of these patients.

Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.

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Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke

2011-08-01

A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.

Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).

Science.gov (United States)

Newton, K; Jorgensen, N M; Wallace, A J; Buchanan, D D; Lalloo, F; McMahon, R F T; Hill, J; Evans, D G

2014-12-01

Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses.

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Haraldsdottir, Sigurdis; Hampel, Heather; Wu, Christina; Weng, Daniel Y; Shields, Peter G; Frankel, Wendy L; Pan, Xueliang; de la Chapelle, Albert; Goldberg, Richard M; Bekaii-Saab, Tanios

2016-09-01

Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups. Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included. MLH1-hm was established with BRAF mutational analysis or hypermethylation testing. Patients' charts were accessed for information on pathology, germ-line MMR mutation testing, and clinical course. A total of 143 patients had CRC associated with LS (37 patients, 26%) or MLH1-hm (106 patients, 74%). Patients with LS were younger, more often male, presented more often with stage III disease, and had more metachronous disease than patients with MLH1-hm tumors. There was no difference in cancer-specific survival (CSS) between the groups; overall survival was longer in patients with LS, but this difference was minimal after adjusting for age and stage at diagnosis. CSS did not differ in LS-associated CRC compared with MLH1-hm CRC, suggesting that they carry a similar prognosis.Genet Med 18 9, 863-868.

Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression.

Directory of Open Access Journals (Sweden)

Peng-Chieh Chen

2008-06-01

Full Text Available DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3(-/-;Apc(1638N and Mlh3(-/-;Pms2(-/-;Apc(1638N (MPA mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1(-/-;Apc(1638N mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression.

Regulation of MLH1 mRNA and protein expression by promoter methylation in primary colorectal cancer

DEFF Research Database (Denmark)

Jensen, Lars Henrik; Rasmussen, Anders Aamann; Byriel, Lene

2013-01-01

In colorectal cancer MLH1 deficiency causes microsatellite instability, which is relevant for the patient's prognosis and treatment, and its putative heredity. Dysfunction of MLH1 is caused by sporadic gene promoter hypermethylation or by hereditary mutations as seen in Lynch Syndrome. The aim...... of this study was to determine in detail how DNA methylation regulates MLH1 expression and impacts clinical management....

Evaluation of promoter methylation status of MLH1 gene in Iranian patients with colorectal tumors and adenoma polyps.

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Zarandi, Ashkan; Irani, Shiva; Savabkar, Sanaz; Chaleshi, Vahid; Ghavideldarestani, Maryam; Mirfakhraie, Reza; Khodadoostan, Mahsa; Nazemalhosseini-Mojarad, Ehsan; Asadzadeh Aghdaei, Hamid

2017-01-01

The aim of this study was to evaluate the methylation status of the promoter region of MLH1 gene in colorectal cancer (CRC) and its precursor lesions as well as elucidate its association with various clinicopathological characteristics among Iranian population. Epigenetic silencing of mismatch repair genes, such as MLH1 , by methylation of CpG islands of their promoter region has been proved to be an important mechanism in colorectal carcinogenesis. Fifty colorectal cancer and polyp tissue samples including 13 Primary colorectal tumor and 37 Adenoma polyp samples were enrolled in this study. Methylation-specific polymerase chain reaction (MSP) was performed to find the frequency of MLH1 Promoter Methylation. Promoter methylation of MLH1 gene was detected in 5 out of 13 tumor tissues and 4 out of 37 adenoma polyp. The frequency of MLH1 methylation in tumor samples was significantly higher compared to that in polyp tissues (P= 0.026). No significant association was observed between MLH1 promoter methylation and clinicopathological characteristics of the patients. The frequency of  MLH1  promoter methylation in CRC and colon polyp was 18%. Our findings indicated that methylation of MLH1 promoter region alone cannot be considered as a biomarker for early detection of CRC.

Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients.

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Petersen, Sanne M; Dandanell, Mette; Rasmussen, Lene J; Gerdes, Anne-Marie; Krogh, Lotte N; Bernstein, Inge; Okkels, Henrik; Wikman, Friedrik; Nielsen, Finn C; Hansen, Thomas V O

2013-10-03

Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomic rearrangements. However, a large number of mutations, including missense, silent, and intronic variants, are classified as variants of unknown clinical significance. Intronic MLH1, MSH2, or MSH6 variants were investigated using in silico prediction tools and mini-gene assay to asses the effect on splicing. We describe in silico and in vitro characterization of nine intronic MLH1, MSH2, or MSH6 mutations identified in Danish colorectal cancer patients, of which four mutations are novel. The analysis revealed aberrant splicing of five mutations (MLH1 c.588 + 5G > A, MLH1 c.677 + 3A > T, MLH1 c.1732-2A > T, MSH2 c.1276 + 1G > T, and MSH2 c.1662-2A > C), while four mutations had no effect on splicing compared to wild type (MLH1 c.117-34A > T, MLH1 c.1039-8 T > A, MSH2 c.2459-18delT, and MSH6 c.3439-16C > T). In conclusion, we classify five MLH1/MSH2 mutations as pathogenic, whereas four MLH1/MSH2/MSH6 mutations are classified as neutral. This study supports the notion that in silico prediction tools and mini-gene assays are important for the classification of intronic variants, and thereby crucial for the genetic counseling of patients and their family members.

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry

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Ward, Robyn L.; Dobbins, Timothy; Lindor, Noralane M.; Rapkins, Robert W.; Hitchins, Megan P.

2013-01-01

Purpose: Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome–associated cancers. This study investigated their frequency and inheritance. Methods: A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals. Results: Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays. Conclusion: Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor. PMID:22878509

Interdependence of DNA mismatch repair proteins MLH1 and MSH2 in apoptosis in human colorectal carcinoma cell lines.

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Hassen, Samar; Ali, Akhtar A; Kilaparty, Surya P; Al-Anbaky, Qudes A; Majeed, Waqar; Boman, Bruce M; Fields, Jeremy Z; Ali, Nawab

2016-01-01

The mammalian DNA mismatch repair (MMR) system consists of a number of proteins that play important roles in repair of base pair mismatch mutations and in maintenance of genomic integrity. A defect in this system can cause genetic instability, which can lead to carcinogenesis. For instance, a germline mutation in one of the mismatch repair proteins, especially MLH1 or MSH2, is responsible for hereditary non-polyposis colorectal cancer. These MMR proteins also play an important role in the induction of apoptosis. Accordingly, altered expression of or a defect in MLH1 or MSH2 may confer resistance to anti-cancer drugs used in chemotherapy. We hypothesized that the ability of these two MMR proteins to regulate apoptosis are interdependent. Moreover, a defect in either one may confer resistance to chemotherapy by an inability to trigger apoptosis. To this end, we studied three cell lines-SW480, LoVo, and HTC116. These cell lines were selected based on their differential expression of MLH1 and MSH2 proteins. SW480 expresses both MLH1 and MSH2; LoVo expresses only MLH1 but not MSH2; HCT116 expresses only MSH2 but not MLH1 protein. MTT assays, a measure of cytotoxicity, showed that there were different cytotoxic effects of an anti-cancer drug, etoposide, on these cell lines, effects that were correlated with the MMR status of the cells. Cells that are deficient in MLH1 protein (HCT116 cells) were resistant to the drug. Cells that express both MLH1 and MSH2 proteins (SW480 cells) showed caspase-3 cleavage, an indicator of apoptosis. Cells that lack MLH1 (HCT116 cells) did not show any caspase-3 cleavage. Expression of full-length MLH1 protein was decreased in MMR proficient (SW480) cells during apoptosis; it remained unchanged in cells that lack MSH2 (LoVo cells). The expression of MSH2 protein remained unchanged during apoptosis both in MMR proficient (SW480) and deficient (HCT116) cells. Studies on translocation of MLH1 protein from nucleus to cytosolic fraction, an

Tumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC)

Science.gov (United States)

Newton, K; Jorgensen, NM; Wallace, AJ; Buchanan, DD; Lalloo, F; McMahon, RFT; Hill, J; Evans, DG

2016-01-01

Background & Aims Lynch syndrome patients have DNA mismatch repair deficiency and up to 80% life-time risk of colorectal cancer. Screening of mutation carriers reduces colorectal cancer incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from Lynch Syndrome (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Methods Tumour DNA was extracted (FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Findings Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2–98.4%), specificity 87.7% (95% CI 77.9–94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7–76.5%), specificity 98.6% (95% CI 92.4–100.0%) for the identification of those with pathogenic MLH1 mutations. Conclusions Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours. PMID:25280751

MLH1 expression predicts the response to preoperative therapy and is associated with PD-L1 expression in esophageal cancer.

Science.gov (United States)

Momose, Kota; Yamasaki, Makoto; Tanaka, Koji; Miyazaki, Yasuhiro; Makino, Tomoki; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

2017-07-01

Programmed death-ligand 1 (PD-1/PD-L1) inhibition therapy demonstrates potential as a future treatment for esophageal cancer. Mismatch repair status and tumor PD-L1 expression are the candidate predictive biomarkers for response to this therapy. In colorectal cancer, mismatch repair-deficient tumors are associated with improved survival, although they are not sensitive to 5-fluorouracil-based chemotherapy. The purpose of the present study was to investigate the association between MutL homolog 1 (MLH1) expression and prognosis, response to therapy and PD-L1 expression in esophageal cancer. Immunohistochemistry was used to evaluate MLH1 and PD-L1 expression in 251 resected specimens. Of the specimens, 30.3% exhibited low MLH1 expression and 15.5% exhibited high PD-L1 expression. The 5-year overall survival rates for the high MLH1 expression group and the low MLH1 expression group were 51.3 and 55.6%, respectively (P=0.5260). The responder ratio was 45.7% in the high MLH1 expression group and 15.4% in the low MLH1 expression group (PMLH1 expression group (P=0.0064) and 25.0% in the low MLH1 expression group. MLH1 expression may be a predictive factor for the response to preoperative therapy in esophageal cancer, and esophageal cancer with low MLH1 expression may have a mechanism that assists in promoting tumor PD-L1 expression.

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

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Adar, Tomer; Rodgers, Linda H; Shannon, Kristen M; Yoshida, Makoto; Ma, Tianle; Mattia, Anthony; Lauwers, Gregory Y; Iafrate, Anthony J; Chung, Daniel C

2017-03-01

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, PMLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.

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Stark, Andreas M; Doukas, Alexander; Hugo, Heinz-Herrmann; Hedderich, Jürgen; Hattermann, Kirsten; Maximilian Mehdorn, H; Held-Feindt, Janka

2015-02-01

Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma. Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival. (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (PMLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation. Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation

DEFF Research Database (Denmark)

Therkildsen, Christina; Isinger-Ekstrand, Anna; Ladelund, Steen

2012-01-01

Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register...... to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks...... in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers....

MLH1 as a direct target of MiR-155 and a potential predictor of favorable prognosis in pancreatic cancer.

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Liu, Wen-Jing; Zhao, Yu-Pei; Zhang, Tai-Ping; Zhou, Li; Cui, Quan-Cai; Zhou, Wei-Xun; You, Lei; Chen, Ge; Shu, Hong

2013-08-01

The regulation of Mut L homologue 1 (MLH1) expression by microRNA (miR)-155 and its prognostic significance in pancreatic cancer (PC) remain to be elucidated. This study aimed to address the issues. MiR-155 mimics and inhibitor were transfected to PC cell lines, Panc-1 and Capan-1. Expression of MLH1 was subsequently evaluated. Then, luciferase activity was detected after miR-155 mimics and pRL-TK plasmids containing wild-type and mutant 3'UTRs of MLH1 mRNA were co-transfected. Finally, immunohistochemical staining for MLH1 was performed in PC samples. Transfection of miR-155 mimics and inhibitor led to reversely altered protein expressions of miR-155 and MLH1, whereas the corresponding mRNA expressions were similar. A significant decrease in luciferase activity in the cells transfected with the wild-type pRL-TK plasmid was shown in contrast to those transfected with the mutant one. In addition, MLH1 was less expressed in tumor than in para-tumor tissues of PC. Extensive MLH1 expression was significantly associated with favorable differentiation and less lymph node metastasis. MLH1 expression was found to be a prognosticator in univariate analysis, and being of marginally significant impact in multivariate test. MLH1 might serve as a direct target of miR-155 and a potential prognosis predictor in PC.

Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients.

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Fu, Tao; Liu, Yanliang; Li, Kai; Wan, Weiwei; Pappou, Emmanouil P; Iacobuzio-Donahue, Christine A; Kerner, Zachary; Baylin, Stephen B; Wolfgang, Christopher L; Ahuja, Nita

2016-12-27

We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

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Brammer, David W; Gillespie, Patrick J; Tian, Mei; Young, Daniel; Raveendran, Muthuswamy; Williams, Lawrence E; Gagea, Mihai; Benavides, Fernando J; Perez, Carlos J; Broaddus, Russell R; Bernacky, Bruce J; Barnhart, Kirstin F; Alauddin, Mian M; Bhutani, Manoop S; Gibbs, Richard A; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih; Rogers, Jeffrey; Abee, Christian R; Gelovani, Juri G

2018-03-13

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques ( Macaca mulatta ) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) and [ 18 F]fluoroacetate ([ 18 F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [ 18 F]fluorothymidine ([ 18 F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1 -rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans. Copyright © 2018 the Author(s). Published by PNAS.

Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

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Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

2015-03-01

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Association between promoter methylation of MLH1 and MSH2 and reactive oxygen species in oligozoospermic men-A pilot study.

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Gunes, S; Agarwal, A; Henkel, R; Mahmutoglu, A M; Sharma, R; Esteves, S C; Aljowair, A; Emirzeoglu, D; Alkhani, A; Pelegrini, L; Joumah, A; Sabanegh, E

2018-04-01

MLH1 and MSH2 are important genes for DNA mismatch repair and crossing over during meiosis and are implicated in male infertility. Therefore, the methylation patterns of the DNA mismatch repair genes MLH1 and MSH2 in oligozoospermic males were investigated. Ten oligozoospermic patients and 29 normozoospermic donors were analysed. Methylation profiles of the MLH1 and MSH2 promotors were analysed. In addition, sperm motility and seminal reactive oxygen species (ROS) were recorded. Receiver operating characteristic (ROC) analysis was conducted to determine the accuracy of the DNA methylation status of MLH1 and MSH2 to distinguish between oligozoospermic and normozoospermic men. In oligozoospermic men, MLH1 was significantly (p = .0013) more methylated compared to normozoospermic men. Additionally, there was a significant positive association (r = .384; p = .0159) between seminal ROS levels and MLH1 methylation. Contrary, no association between MSH2 methylation and oligozoospermia was found. ROC curve analysis for methylation status of MLH1 was significant (p = .0275) with an area under the curve of 61.1%, a sensitivity of 22.2% and a specificity of 100.0%. This pilot study indicates oligozoospermic patients have more methylation of MLH1 than normozoospermic patients. Whether hypermethylation of the MLH1 promoter plays a role in repairing relevant mismatches of sperm DNA strands in idiopathic oligozoospermia warrants further investigation. © 2017 Blackwell Verlag GmbH.

MLH1 Promoter Methylation and Prediction/Prognosis of Gastric Cancer: A Systematic Review and Meta and Bioinformatic Analysis.

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Shen, Shixuan; Chen, Xiaohui; Li, Hao; Sun, Liping; Yuan, Yuan

2018-01-01

Background: The promoter methylation of MLH1 gene and gastric cancer (GC)has been investigated previously. To get a more credible conclusion, we performed a systematic review and meta and bioinformatic analysis to clarify the role of MLH1 methylation in the prediction and prognosis of GC. Methods: Eligible studies were targeted after searching the PubMed, Web of Science, Embase, BIOSIS, CNKI and Wanfang Data to collect the information of MLH1 methylation and GC. The link strength between the two was estimated by odds ratio with its 95% confidence interval. The Newcastle-Ottawa scale was used for quantity assessment . Subgroup and sensitivity analysis were conducted to explore sources of heterogeneity. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were employed for bioinformatics analysis on the correlation between MLH1 methylation and GC risk, clinicopathological behavior as well as prognosis. Results: 2365 GC and 1563 controls were included in the meta-analysis. The pooled OR of MLH1 methylation in GC was 4.895 (95% CI: 3.149-7.611, PMLH1 methylation enhanced GC risk but might not related with GC clinicopathological features and prognosis. Conclusion: MLH1 methylation is an alive biomarker for the prediction of GC and it might not affect GC behavior. Further study could be conducted to verify the impact of MLH1 methylation on GC prognosis.

Nuclear import of human MLH1, PMS2, and MutLalpha: redundancy is the key.

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Leong, Vivian; Lorenowicz, Jessica; Kozij, Natalie; Guarné, Alba

2009-08-01

DNA mismatch repair maintains genomic stability by correcting errors that have escaped polymerase proofreading. Defects on mismatch repair genes lead to an increased mutation rate, microsatellite instability and predisposition to human non-polyposis colorectal cancer (HNPCC). Human MutLalpha is a heterodimer formed by the interaction of MLH1 and PMS2 that coordinates a series of key events in mismatch repair. It has been proposed that nuclear import of MutLalpha may be the first regulatory step on the activation of the mismatch repair pathway. Using confocal microscopy and mismatch repair deficient cells, we have identified the sequence determinants that drive nuclear import of human MLH1, PMS2, and MutLalpha. Transient transfection of the individual proteins reveals that MLH1 has a bipartite and PMS2 has a single monopartite nuclear localization signal. Although dimerization is not required for nuclear localization, the MutLalpha heterodimer is imported more efficiently than the MLH1 or PMS2 monomers. Interestingly, the bipartite localization signal of MLH1 can direct import of MutLalpha even when PMS2 encompasses a mutated localization signal. Hence we conclude that the presence of redundant nuclear localization signals guarantees nuclear transport of MutLalpha and, consequently, efficient mismatch repair.

Reduced MLH3 Expression in the Syndrome of Gan-Shen Yin Deficiency in Patients with Different Diseases.

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Du, Juan; Zhong, Maofeng; Liu, Dong; Liang, Shufang; Liu, Xiaolin; Cheng, Binbin; Zhang, Yani; Yin, Zifei; Wang, Yuan; Ling, Changquan

2017-01-01

Traditional Chinese medicine formulates treatment according to body constitution (BC) differentiation. Different constitutions have specific metabolic characteristics and different susceptibility to certain diseases. This study aimed to assess the characteristic genes of gan-shen Yin deficiency constitution in different diseases. Fifty primary liver cancer (PLC) patients, 94 hypertension (HBP) patients, and 100 diabetes mellitus (DM) patients were enrolled and classified into gan-shen Yin deficiency group and non-gan-shen Yin deficiency group according to the body constitution questionnaire to assess the clinical manifestation of patients. The mRNA expressions of 17 genes in PLC patients with gan-shen Yin deficiency were different from those without gan-shen Yin deficiency. However, considering all patients with PLC, HBP, and DM, only MLH3 was significantly lower in gan-shen Yin deficiency group than that in non-gen-shen Yin deficiency. By ROC analysis, the relationship between MLH3 and gan-shen Yin deficiency constitution was confirmed. Treatment of MLH3 (-/- and -/+) mice with Liuweidihuang wan, classical prescriptions for Yin deficiency, partly ameliorates the body constitution of Yin deficiency in MLH3 (-/+) mice, but not in MLH3 (-/-) mice. MLH3 might be one of material bases of gan-shen Yin deficiency constitution.

The mRNA level of MLH1 in peripheral blood is a biomarker for the diagnosis of hereditary nonpolyposis colorectal cancer.

Science.gov (United States)

Yu, Hong; Li, Hui; Cui, Yongan; Xiao, Wei; Dai, Guihong; Huang, Junxing; Wang, Chaofu

2016-01-01

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by functional defects in mismatch repair (MMR) genes, including mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2). This study aimed to assess whether the mRNA expression of MLH1 in peripheral blood could be used as a biomarkers for the diagnosis of HNPCC. The mRNA level of MLH1 was determined in 19 HNPCC families (46 members) using real-time quantitative polymerase chain reaction (qPCR). The mRNA levels of MLH1 in HNPCC were significantly lower than controls (P MLH1 for the diagnosis of HNPCC with the area under curve of 0.858. At an optimal cut-off value (0.511), the mRNA level of MLH1 had a sensitivity of 81.3% and a specificity of 86.7% for distinguishing HNPCC from controls. In conclusion, the mRNA expression of MLH1 in peripheral blood may serve as a biomarker for the diagnosis of HNPCC.

Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.

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Miralem Mrkonjic

Full Text Available We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734 and microsatellite unstable (MSI-H colorectal cancers (CRCs in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls and from Seattle (591 cases, 629 controls. Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter-methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value  = 0.72 vs. 2.3×10(-4 when the SNP was examined alone.The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both.

Cancer-Predicting Gene Expression Changes in Colonic Mucosa of Western Diet Fed Mlh1 +/- Mice

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Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi; Peltomäki, Päivi; Mutanen, Marja; Nyström, Minna

2013-01-01

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1 +/- mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1 +/+ littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1 +/- mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1 +/- and Mlh1 +/+ mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis. PMID:24204690

Cancer-predicting gene expression changes in colonic mucosa of Western diet fed Mlh1+/- mice.

Directory of Open Access Journals (Sweden)

Marjaana Pussila

Full Text Available Colorectal cancer (CRC is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age in the heterozygote Mlh1(+/- mice, an animal model for human Lynch syndrome (LS, and wild type Mlh1(+/+ littermates, fed by either Western-style (WD or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1(+/- mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1(+/- and Mlh1(+/+ mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis.

Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis

OpenAIRE

Avdievich, Elena; Reiss, Cora; Scherer, Stefan J.; Zhang, Yongwei; Maier, Sandra M.; Jin, Bo; Hou, Harry; Rosenwald, Andreas; Riedmiller, Hubertus; Kucherlapati, Raju; Cohen, Paula E.; Edelmann, Winfried; Kneitz, Burkhard

2008-01-01

Mutations in the human DNA mismatch repair (MMR) gene MLH1 are associated with hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) and a significant proportion of sporadic colorectal cancer. The inactivation of MLH1 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of DNA damaging agents. To study the effect of MLH1 missense mutations on cancer susceptibility, we generated a mouse line carrying the ...

Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: molecular and morphologic analysis of 6 cases.

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Pai, Rish K; Plesec, Thomas P; Abdul-Karim, Fadi W; Yang, Bin; Marquard, Jessica; Shadrach, Bonnie; Roma, Andres R

2015-07-01

Given that endometrial cancer (EC) is often the sentinel cancer for female Lynch syndrome patients, we have successfully implemented universal screening of ECs and have previously shown that this is the preferred method to identify these patients. However, during the course of universal screening of EC, we encountered 6 cases with an unusual pattern of mismatch-repair protein immunohistochemistry that has not been previously described in this setting. In these 6 cases, there was an abrupt loss of MLH1 and PMS2 expression in a portion of the tumor. In 3 cases, marked histologic differences were identified between the areas of the tumor with retained expression and areas with loss of expression. In 2 cases, the areas with loss of expression were of higher grade (1 demonstrated solid growth and the other demonstrated increased nuclear atypia with diffuse p53 expression). In 4 tumors, histologic features associated with microsatellite instability (MSI) were present, including increased intraepithelial lymphocytes. The areas with loss of and retained MLH1/PMS2 expression were separately microdissected and assessed for MSI and MLH1 promoter methylation. The areas with loss of MLH1 and PMS2 more commonly demonstrated MSI compared with the areas with intact expression (83% vs. 33%). MLH1 promoter methylation analysis demonstrated heterogenous hypermethylation, as all areas with loss of MLH1/PMS2 expression had more extensive methylation of MLH1 compared with those areas with retained expression. In summary, we describe the histologic and molecular features of 6 cases of EC with abrupt loss of MLH1 and PMS2 expression and demonstrate that heterogenous methylation of the MLH1 promoter results in this distinct and unusual pattern of immunohistochemical expression.

Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility.

Science.gov (United States)

Crépin, Michel; Dieu, Marie-Claire; Lejeune, Sophie; Escande, Fabienne; Boidin, Denis; Porchet, Nicole; Morin, Gilles; Manouvrier, Sylvie; Mathieu, Michèle; Buisine, Marie-Pierre

2012-01-01

Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling. © 2011 Wiley Periodicals, Inc.

Correlation of MLH1 and MGMT expression and promoter methylation with genomic instability in patients with thyroid carcinoma

International Nuclear Information System (INIS)

Santos, Juliana Carvalho; Bastos, André Uchimura; Cerutti, Janete Maria; Ribeiro, Marcelo Lima

2013-01-01

Gene silencing of the repair genes MLH1 and MGMT was shown to be a mechanism underlying the development of microsatellite instability (MSI), a phenotype frequently associated with various human malignancies. Recently, aberrant methylation of MLH1, MGMT and MSI were shown to be associated with mutations in genes such as BRAF, RAS and IDH1 in colon and brain tumours. Little is known about the methylation status of MLH1 and MGMT in thyroid tumours and its association with MSI and mutational status. In a series of 96 thyroid tumours whose mutational profiles of BRAF, IDH1 and NRAS mutations and RET/PTC were previously determined, we investigated MLH1 and MGMT expression and methylation status by qPCR and methylation-specific PCR after bisulphite treatment, respectively. MSI was determined by PCR using seven standard microsatellite markers. Samples with point mutations (BRAF, IDH1 and NRAS) show a decrease in MLH1 expression when compared to negative samples. Additionally, malignant lesions show a higher MSI pattern than benign lesions. The MSI phenotype was also associated with down-regulation of MLH1. The results of this study allow us to conclude that low expression of MLH1 is associated with BRAF V600E mutations, RET/PTC rearrangements and transitions (IDH1 and NRAS) in patients with thyroid carcinoma. In addition, a significant relationship between MSI status and histological subtypes was found

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

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Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M; Friedhoff, Peter; Plotz, Guido

2010-08-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome that predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased coexpression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations.

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.

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Castillejo, Adela; Hernández-Illán, Eva; Rodriguez-Soler, María; Pérez-Carbonell, Lucía; Egoavil, Cecilia; Barberá, Victor M; Castillejo, María-Isabel; Guarinos, Carla; Martínez-de-Dueñas, Eduardo; Juan, María-Jose; Sánchez-Heras, Ana-Beatriz; García-Casado, Zaida; Ruiz-Ponte, Clara; Brea-Fernández, Alejandro; Juárez, Miriam; Bujanda, Luis; Clofent, Juan; Llor, Xavier; Andreu, Montserrat; Castells, Antoni; Carracedo, Angel; Alenda, Cristina; Payá, Artemio; Jover, Rodrigo; Soto, José-Luis

2015-07-01

The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (pMLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Analysis of MLH3 C2531T Polymorphism in Infertile Men with Idiopathic Azoospermia or Severe Oligozoospermia

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MA Zaimy

2013-04-01

Full Text Available Introduction: Infertility is described as the inability to get pregnant after one year of unprotected intercourse. About half of infertility cases are because of male factors. Idiopathic azoospermia or severe oligozoospermia caused by genetic alterations is a significant part of male infertility. A key step of spermatogenesis is crossover events during meiotic reciprocal recombination. MLH3 protein has a crucial role in meiotic recombination and in spermatogenesis. We evaluated this function of MLH3 protein by examining the contribution of functional polymorphism in MLH3 (C2531T to the risk of male infertility. Methods: We studied this polymorphism in 110 infertile male with idiopathic azoospermia or severe oligozoospermia, and 110 fertile men with normozoospermia as a control group. MLH3 C2531T polymorphism was analyzed using the tetra-amplification refractory mutation system-PCR (4P-ARMS-PCR method. Results: Genotypes CC, CT and TT of the MLH3 gene presented frequencies of 13.6%,59.1% and 27.3%, respectively, in the men with idiopathic azoospermia or severe oligozoospermia and 37.3%,53.6% and 9.1% in the control group (p<0.001. Conclusion: The data suggest that the MLH3 C2531T polymorphism can be associated with risk of male infertility. The research data showed that presence of the polymorphic allele T leads to an increased risk of 2.35 times (OR =2.35, 95% CI =1.57-3.51; p<0.001 to develop infertility in relation to the normal control group. Therefore, the MLH3 gene polymorphism may be genetic determinant for defective spermatogenesis in the humans.

Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma.

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Shinsato, Yoshinari; Furukawa, Tatsuhiko; Yunoue, Shunji; Yonezawa, Hajime; Minami, Kentarou; Nishizawa, Yukihiko; Ikeda, Ryuji; Kawahara, Kohichi; Yamamoto, Masatatsu; Hirano, Hirofumi; Tokimura, Hiroshi; Arita, Kazunori

2013-12-01

Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours.

Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients.

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Kato, Aya; Sato, Naoki; Sugawara, Tae; Takahashi, Kazue; Kito, Masahiko; Makino, Kenichi; Sato, Toshiharu; Shimizu, Dai; Shirasawa, Hiromistu; Miura, Hiroshi; Sato, Wataru; Kumazawa, Yukiyo; Sato, Akira; Kumagai, Jin; Terada, Yukihiro

2016-06-01

Lynch syndrome (LS) is an autosomal-dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and is associated with increased risk for various cancers, particularly colorectal cancer and endometrial cancer (EC). Women with LS account for 2% to 6% of EC patients; it is clinically important to identify LS in such individuals for predicting and/or preventing additional LS-associated cancers. PMS2 germline mutation (PMS2-LS) is the rarest contribution to LS etiology among the 4 LS-associated MMR germline mutations, and its detection is complicated. Therefore, prudent screening for PMS2-LS is important as it leads to an efficient LS identification strategy. Immunohistochemistry is recommended as a screening method for LS in EC. Isolated loss of PMS2 (IL-PMS2) expression is caused not only by PMS2-LS but also by MLH1 germline mutation or MLH1 promoter hypermethylation (MLH-PHM). This study aimed to determine the association between MLH1-PHM and IL-PMS2 to avoid inappropriate genetic analysis. We performed MLH1 methylation analysis and MLH1/PMS2 germline mutation testing on the IL-PMS2 cases. By performing MMR-immunohistochemistry on 360 unselected ECs, we could select 8 (2.2%) cases as IL-PMS2. Heterogenous MLH1 staining and MLH1-PHM were detected in 4 of 8 (50%) IL-PMS2 tumors. Of the 5 IL-PMS2 patients who underwent genetic analysis, 1 had PMS2 germline mutation with normal MLH1 expression (without MLH1-PHM), and no MLH1 germline mutation was detected. We suggest that MLH1 promoter methylation analysis for IL-PMS2 EC should be performed to exclude sporadic cases before further PMS2 genetic testing.

Excess of extracolonic non-endometrial multiple primary cancers in MSH2 germline mutation carriers over MLH1.

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Lin-Hurtubise, Kevin M; Yheulon, Christopher G; Gagliano, Ronald A; Lynch, Henry T

2013-12-01

The lynch syndrome (LS) tumor spectrum involves colorectal cancer (CRC), endometrial cancer (EC), and less frequently various extracolonic non-endometrial cancers (non-EC). The organ-specific survival rates of these patients are well defined, however, the collective survival of all-cancers combined (CRC + EC + non-EC) are unclear. Fifty-two MSH2 patients and 68 MLH1 patients were followed for a median of 6.3 years after diagnosis of first cancer, regardless of type. The proportions of CRC only, EC, non-EC, and multiple primary cancers were compared between the two genotypes. Kaplan-Meier curves were developed for survival comparisons. MSH2 patients present less frequently with only CRC (37% MSH2, 62% MLH1, P = 0.0096), manifest more multiple primary cancers (38% MSH2, 18% MLH1, P = 0.013), develop more extracolonic cancers (62% MSH2, 38% MLH1, P = 0.003), non-EC only cancers (46% MSH2, 24% MLH1, P = 0.028) and carry a greater risk for urinary tract cancer (UTC) (13.4% MSH2, 1.5% MLH1, P = 0.024). There was no difference in 10-year survival between the two groups (P = 0.4). The additional propensity for UTC in MSH2 carriers argues in favor of UTC screening in MSH2 individuals. Other types of cancer screening should be tailored to the expression history of the specific LS mutation. © 2013 Wiley Periodicals, Inc.

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

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Roon, Eddy HJ van; Hes, Frederik J; Tops, Carli MJ; Wezel, Tom van; Boer, Judith M; Morreau, Hans; Puijenbroek, Marjo van; Middeldorp, Anneke; Eijk, Ronald van; Meijer, Emile J de; Erasmus, Dianhdra; Wouters, Kim AD; Engeland, Manon van; Oosting, Jan

2010-01-01

To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. We identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

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Hes Frederik J

2010-05-01

Full Text Available Abstract Background To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. Methods We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13. Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. Results We identified two cases (33 and 60 years with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044. CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Conclusion Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.

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Kim, Jung Ho; Bae, Jeong Mo; Cho, Nam-Yun; Kang, Gyeong Hoon

2016-03-22

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps.

BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations.

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Deihimi, Safoora; Lev, Avital; Slifker, Michael; Shagisultanova, Elena; Xu, Qifang; Jung, Kyungsuk; Vijayvergia, Namrata; Ross, Eric A; Xiu, Joanne; Swensen, Jeffrey; Gatalica, Zoran; Andrake, Mark; Dunbrack, Roland L; El-Deiry, Wafik S

2017-06-20

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

Repair genes expression profile of MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers.

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Alves, Mônica Ghislaine Oliveira; Carta, Celina Faig Lima; de Barros, Patrícia Pimentel; Issa, Jaqueline Scholz; Nunes, Fábio Daumas; Almeida, Janete Dias

2017-01-01

The aim of this study was to evaluate the effect of chronic smoking on the expression profile of the repair genes MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers and never smokers. The sample consisted of thirty exfoliative cytology smears per group obtained from Smokers and Never Smokers. Total RNA was extracted and expression of the MLH1, MSH2 and ATM genes were evaluated by quantitative real-time and immunocytochemistry. The gene and protein expression data were correlated to the clinical data. Gene expression was analyzed statistically using the Student t-test and Pearson's correlation coefficient, with pMLH1, MSH2 and ATM genes were downregulated in the smoking group compared to the control with significant values for MLH1 (p=0.006), MSH2 (p=0.0001) and ATM (p=0.0001). Immunocytochemical staining for anti-MLH1, anti-MSH2 and anti-ATM was negative in Never Smokers; in Smokers it was rarely positive. No significant correlation was observed among the expression of MLH1, MSH2, ATM and age, number of cigarettes consumed per day, time of smoking during life, smoking history or levels of CO in expired air. The expression of genes and proteins related to DNA repair mechanism MLH1, MSH2 and ATM in the normal oral mucosa of chronic smokers was reduced. Copyright © 2016 Elsevier Ltd. All rights reserved.

DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway.

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de Barros, Andrea C; Takeda, Agnes A S; Dreyer, Thiago R; Velazquez-Campoy, Adrian; Kobe, Boštjan; Fontes, Marcos R M

2018-03-01

MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLα comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLα is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-α bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-α as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLα heterodimer is discussed. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Artefactual punctate MLH1 staining can lead to erroneous reporting of isolated PMS2 loss.

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Niu, Bonnie T; Hammond, Rory F L; Leen, Sarah L S; Faruqi, Asma Z; Trevisan, Giorgia; Gilks, C Blake; Singh, Naveena

2018-05-31

Germline mutations in the PMS2 gene are an uncommon cause of Lynch Syndrome (LS), present in PMS2 immunohistochemical expression, with retained MLH1 expression, triggers referral to genetics services due to the significant risk of LS 3 . As detection of PMS2 germline mutations is problematic 4 , this may result in patients being labeled as "Lynch-like", with implications for future surveillance 5 . A recent study suggested that some cases of isolated PMS2 loss result from MLH1 promoter methylation and are sporadic rather than likely LS 6 ; they therefore recommended MLH1 promoter methylation testing in all cases of isolated PMS2 loss 6 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A modifier of Huntington's disease onset at the MLH1 locus.

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Lee, Jong-Min; Chao, Michael J; Harold, Denise; Abu Elneel, Kawther; Gillis, Tammy; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F

2017-10-01

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Impact of MLH1 expression on tumor evolution after curative surgical tumor resection in a murine orthotopic xenograft model for human MSI colon cancer.

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Meunier, Katy; Ferron, Marianne; Calmel, Claire; Fléjou, Jean-François; Pocard, Marc; Praz, Françoise

2017-09-01

Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumor evolution after curative surgical resection using a xenograft tumor model. Transplantable tumors established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumors were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumor evolution in mice who underwent curative surgical resection and in mice whose tumor was left in situ. Our data indicate that the behavior of MLH1-deficient CRC is not only governed by mutations arising in genes harboring microsatellite repeated sequences but also from their defect in MLH1 as such. © 2017 Wiley Periodicals, Inc.

Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

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Andersen, Sofie Dabros; Liberti, Sascha Emilie; Lützen, Anne

2012-01-01

Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch Syndrome (LS), also known as Hereditary Nonpolyposis Colorectal Cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise...... localization and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer...

Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells

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Jia, Pingping; Chastain, Megan; Zou, Ying; Her, Chengtao

2017-01-01

Abstract Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI. Moreover, TSI requires telomerase activity but is independent of the functional status of p53 and Rb. Lastly, we show that TSI is associated with chromosome instabilities including chromosome loss, micronuclei formation and chromosome breakage that are further elevated by replication stress. Our studies uncover a novel link between MLH1, telomerase, telomere and genome stability. PMID:28180301

Epitope-positive truncating MLH1 mutation and loss of PMS2: implications for IHC-directed genetic testing for Lynch syndrome.

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Zighelboim, Israel; Powell, Matthew A; Babb, Sheri A; Whelan, Alison J; Schmidt, Amy P; Clendenning, Mark; Senter, Leigha; Thibodeau, Stephen N; de la Chapelle, Albert; Goodfellow, Paul J

2009-01-01

We assessed mismatch repair by immunohistochemistry (IHC) and microsatellite instability (MSI) analysis in an early onset endometrial cancer and a sister's colon cancer. We demonstrated high-level MSI and normal expression for MLH1, MSH2 and MSH6. PMS2 failed to stain in both tumors, strongly implicating a PMS2 defect. This family did not meet clinical criteria for Lynch syndrome. However, early onset endometrial cancers in the proband and her sister, a metachronous colorectal cancer in the sister as well as MSI in endometrial and colonic tumors suggested a heritable mismatch repair defect. PCR-based direct exonic sequencing and multiplex ligation-dependent probe amplification (MLPA) were undertaken to search for PMS2 mutations in the germline DNA from the proband and her sister. No mutation was identified in the PMS2 gene. However, PMS2 exons 3, 4, 13, 14, 15 were not evaluated by MLPA and as such, rearrangements involving those exons cannot be excluded. Clinical testing for MLH1 and MSH2 mutation revealed a germline deletion of MLH1 exons 14 and 15. This MLH1 germline deletion leads to an immunodetectable stable C-terminal truncated MLH1 protein which based on the IHC staining must abrogate PMS2 stabilization. To the best of our knowledge, loss of PMS2 in MLH1 truncating mutation carriers that express MLH1 in their tumors has not been previously reported. This family points to a potential limitation of IHC-directed gene testing for suspected Lynch syndrome and the need to consider comprehensive MLH1 testing for individuals whose tumors lack PMS2 but for whom PMS2 mutations are not identified.

Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein

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Dominguez-Valentin, Mev; Drost, Mark; Therkildsen, Christina

2014-01-01

>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers....

Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review.

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Metcalf, Alexander M; Spurdle, Amanda B

2014-03-01

Colorectal cancer (CRC) that displays high microsatellite instability (MSI-H) can be caused by either germline mutations in mismatch repair (MMR) genes, or non-inherited transcriptional silencing of the MLH1 promoter. A correlation between MLH1 promoter methylation, specifically the 'C' region, and BRAF V600E status has been reported in CRC studies. Germline MMR mutations also greatly increase risk of endometrial cancer (EC), but no systematic review has been undertaken to determine if these tumour markers may be useful predictors of MMR mutation status in EC patients. Endometrial cancer cohorts meeting review inclusion criteria encompassed 2675 tumours from 20 studies for BRAF V600E, and 447 tumours from 11 studies for MLH1 methylation testing. BRAF V600E mutations were reported in 4/2675 (0.1%) endometrial tumours of unknown MMR mutation status, and there were 7/823 (0.9%) total sequence variants in exon 11 and 27/1012 (2.7%) in exon 15. Promoter MLH1 methylation was not observed in tumours from 32 MLH1 mutation carriers, or for 13 MSH2 or MSH6 mutation carriers. MMR mutation-negative individuals with tumour MLH1 and PMS2 IHC loss displayed MLH1 methylation in 48/51 (94%) of tumours. We have also detailed specific examples that show the importance of MLH1 promoter region, assay design, and quantification of methylation. This review shows that BRAF mutations occurs so infrequently in endometrial tumours they can be discounted as a useful marker for predicting MMR-negative mutation status, and further studies of endometrial cohorts with known MMR mutation status are necessary to quantify the utility of tumour MLH1 promoter methylation as a marker of negative germline MMR mutation status in EC patients.

Single nucleotide polymorphisms of DNA mismatch repair genes MSH2 and MLH1 confer susceptibility to esophageal cancer.

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Sun, Ming-Zhong; Ju, Hui-Xiang; Zhou, Zhong-Wei; Jin, Hao; Zhu, Rong

2014-01-01

Defects in DNA mismatch repair genes like MSH2 and MLH1 confer increased risk of cancers. Here, single nucleotide polymorphisms (SNPs) in MSH2 and MLH1 were investigated for their potential contribution to the risk of esophageal cancer. This study recruited 614 participants from Affiliated Yancheng Hospital, School of Medicine, Southeast University, of which 289 were patients with esophageal cancer, and the remainder was healthy individuals who served as a control group. Two SNPs, MSH2 c.2063T>G and MLH1 IVS14-19A>G, were genotyped using PCR-RFLP. Statistical analysis was performed using chi-square test and logistic regression analysis. Carriers of the MSH2 c.2063G allele were at significantly higher risk for esophageal cancer compared to individuals with the TT genotype [OR = 3.36, 95% confidence interval (CI): 1.18-11.03]. The MLH1 IVS14-19A>G allele also conferred significantly increased (1.70-fold) for esophageal cancer compared to the AA genotype (OR = 1.70, 95% CI: 1.13-5.06). Further, the variant alleles interacted such that individuals with the susceptible genotypes at both MSH2 and MLH1 had a significantly exacerbated risk for esophageal cancer (OR = 12.38, 95% CI: 3.09-63.11). In brief, SNPs in the DNA mismatch repair genes MSH2 and MLH1 increase the risk of esophageal cancer. Molecular investigations are needed to uncover the mechanism behind their interaction effect.

Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma

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Sondes Karray-Chouayekh

2009-01-01

Full Text Available Aberrant hypermethylation of gene promoter regions is one of the mechanisms for inactivation of tumour suppressor genes in many human cancers including breast carcinoma. In the current study, we aimed to assess by MSP, the methylation pattern of two cancer-related genes involved in DNA repair: hMLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli and BRCA1 (breast cancer 1, early onset in 78 primary breast cancers from Tunisian patients. The methylation frequencies were 24.36% for hMLH1 and 46% for BRCA1. BRCA1 methylation correlated with age at diagnosis (P=.015 and 5-years disease free survival (P=.016 while hMLH1 methylation was more frequent in larger tumors (P=.002 and in presence of distant metastasis (P=.004. Furthermore, methylation of hMLH1 significantly correlated with high level of P53 expression (P=.006 and with overall survival (P=.015 suggesting that silencing of hMLH1 through aberrant promoter methylation could be used as a poor prognosis indicator in breast cancer.

Modulation of transcription factor binding and epigenetic regulation of the MLH1 CpG island and shore by polymorphism rs1800734 in colorectal cancer.

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Savio, Andrea J; Bapat, Bharati

2017-06-03

The MLH1 promoter polymorphism rs1800734 is associated with MLH1 CpG island hypermethylation and expression loss in colorectal cancer (CRC). Conversely, variant rs1800734 is associated with MLH1 shore, but not island, hypomethylation in peripheral blood mononuclear cell DNA. To explore these distinct patterns, MLH1 CpG island and shore methylation was assessed in CRC cell lines stratified by rs1800734 genotype. Cell lines containing the variant A allele demonstrated MLH1 shore hypomethylation compared to wild type (GG). There was significant enrichment of transcription factor AP4 at the MLH1 promoter in GG and GA cell lines, but not the AA cell line, by chromatin immunoprecipitation studies. Preferential binding to the G allele was confirmed by sequencing in the GA cell line. The enhancer-associated histone modification H3K4me1 was enriched at the MLH1 shore; however, H3K27ac was not, indicating the shore is an inactive enhancer. These results demonstrate the role of variant rs1800734 in altering transcription factor binding as well as epigenetics at regions beyond the MLH1 CpG island in which it is located.

Completion of meiosis in male zebrafish (Danio rerio) despite lack of DNA mismatch repair gene mlh1

NARCIS (Netherlands)

Leal, M.C.; Feitsma, H.; Cuppen, E.; França, L.R.; Schulz, R.W.

2008-01-01

Mlh1 is a member of DNA mismatch repair (MMR) machinery and is also essential for the stabilization of crossovers during the first meiotic division. Recently, we have shown that zebrafish mlh1 mutant males are completely infertile because of a block in metaphase I, whereas females are fertile

Completion of meiosis in male zebrafish (Danio rerio) despite lack of DNA mismatch repair gene mlh1.

NARCIS (Netherlands)

Leal, M.C.; Feitsma, H.; Cuppen, E.; Franca, L.R.; Schulz, R.W.

2008-01-01

Mlh1 is a member of DNA mismatch repair (MMR) machinery and is also essential for the stabilization of crossovers during the first meiotic division. Recently, we have shown that zebrafish mlh1 mutant males are completely infertile because of a block in metaphase I, whereas females are fertile but

MLH1-Silenced and Non-Silenced Subgroups of Hypermutated Colorectal Carcinomas Have Distinct Mutational Landscapes

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Donehower, Lawrence A.; Creighton, Chad J.; Schultz, Nikolaus; Shinbrot, Eve; Chang, Kyle; Gunaratne, Preethi H.; Muzny, Donna; Sander, Chris; Hamilton, Stanley R.; Gibbs, Richard A.; Wheeler, David

2014-01-01

Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analyzed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRC (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of hypermutated CRC exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRC lacked MLH1 silencing, contained tumors with the highest mutation rates (“ultramutated” CRC), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRC. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRC with MLH1 silencing had greatly reduced levels of WNT signaling and increased BRAF signaling relative non-hypermutated CRC. Our findings suggest that hypermutated CRC include one subgroup with fundamentally different pathways to malignancy than the majority of CRC. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions. PMID:22899370

Perceptions of Public Relations Education.

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Stacks, Don W.; Botan, Carl; Turk, Judy VanSlyke

1999-01-01

Surveys 258 public-relations educators and practitioners, finding they agree that public-relations education is on track; that systematic assessment is an important feature of public-relations education; and that they agreed on how public-relations education should be structured, and demonstrated a high degree of similarity in their preferences…

Immunohistochemical and DNA sequencing analysis on human mismatch repair gene MLH1 in cervical squamous cell carcinoma with LOH of this gene

NARCIS (Netherlands)

Hu, X.; Guo, Z.; Pang, T.; Li, Q.; Afink, G.; Pontén, J.

2000-01-01

BACKGROUND: The human MLH1 gene (hMLH1) is one of the DNA mismatch repair genes. Defects in these genes are believed to be the underlying cause of microsatellite instability (MSI). MSI has been demonstrated in many human cancers such as colon cancer and some female-specific tumors. The hMLH1 gene

Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

DEFF Research Database (Denmark)

Christensen, Lise Lotte; Kariola, Reetta; Korhonen, Mari K

2009-01-01

Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some...... of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity...

I219V polymorphism in hMLH1 gene in patients affected with ulcerative colitis.

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Vietri, Maria Teresa; Riegler, Gabriele; De Paola, Marialaura; Simeone, Serena; Boggia, Maria; Improta, Alessia; Parisi, Mariarita; Molinari, Anna Maria; Cioffi, Michele

2009-04-01

hMLH1 gene, lying on chromosome 3p21-23, is a key factor of the mismatch repair (MMR) complex, which amends DNA replication errors. MMR alterations are involved in the development of both hereditary and sporadic forms of colorectal carcinoma related to ulcerative colitis (UC). I219V Polymorphism is located on exon 8 of hMLH1 and provides an aminoacidic substitution of isoleucine to valine, on the protein codon 219. This may affect the speed and fidelity of protein synthesis because of a tRNA paucity or changes in the mRNA secondary structure. Most of the hereditary nonpolyposis colon cancer-associated missense mutations of hMLH1 cause structural changes of the amino- or carboxy-terminal regions, involving the domains that interact with ATP and hPMS2. In this study, we analyzed the hMLH1 I219V polymorphism frequency in colectomized patients with UC. Venous blood from 100 ulcerative patients and 97 apparently healthy subjects has been collected. Out of 100 patients affected with UC, 75 noncolectomized showed an alternating course of disease, while 25 did not respond to the common drugs, and underwent colectomy. Genotyping was performed by polymerase chain reaction and following enzymatic digestion by BccI. No significant differences were found between patients with UC and controls both for genotype and allele frequencies. However, our data show a significant association when colectomized and noncolectomized patients are compared. The frequencies of G homozygosity were 28% in colectomized and 10.7% in noncolectomized patients (p < 0.05, chi(2) = 4.4, Odds ratio = 3.3). The allele frequencies of allele A were 52% in colectomized and 68% in noncolectomized patients; while those of allele G were 48% and 32%, respectively. I219V polymorphism in hMLH1 could influence the clinical course of the disease and lead to resistance to therapy.

A Mononucleotide Markers Panel to Identify hMLH1/hMSH2 Germline Mutations

Directory of Open Access Journals (Sweden)

M. Pedroni

2007-01-01

Full Text Available Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI. MSI is present in 85–90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the “Bethesda panel”. Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites.

GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1.

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Inaguma, Shingo; Riku, Miho; Hashimoto, Mitsuyoshi; Murakami, Hideki; Saga, Shinsuke; Ikeda, Hiroshi; Kasai, Kenji

2013-12-15

The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. ©2013 AACR.

The mutational profile and infiltration pattern of murine MLH1-/- tumors: concurrences, disparities and cell line establishment for functional analysis.

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Maletzki, Claudia; Beyrich, Franziska; Hühns, Maja; Klar, Ernst; Linnebacher, Michael

2016-08-16

Mice lines homozygous negative for one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, PMS2, MSH6) were generated as models for MMR deficient (MMR-D) diseases. Clinically, hereditary forms of MMR-D include Lynch syndrome (characterized by a germline MMR gene defect) and constitutional MMR-D, the biallelic form. MMR-D knockout mice may be representative for both diseases. Here, we aimed at characterizing the MLH1-/- model focusing on tumor-immune microenvironment and identification of coding microsatellite mutations in lymphomas and gastrointestinal tumors (GIT).All tumors showed microsatellite instability (MSI) in non-coding mononucleotide markers. Mutational profiling of 26 coding loci in MSI+ GIT and lymphomas revealed instability in half of the microsatellites, two of them (Rfc3 and Rasal2) shared between both entities. MLH1-/- tumors of both entities displayed a similar phenotype (high CD71, FasL, PD-L1 and CTLA-4 expression). Additional immunofluorescence verified the tumors' natural immunosuppressive character (marked CD11b/CD200R infiltration). Vice versa, CD3+ T cells as well as immune checkpoints molecules were detectable, indicative for an active immune microenvironment. For functional analysis, a permanent cell line from an MLH1-/- GIT was established. The newly developed MLH1-/- A7450 cells exhibit stable in vitro growth, strong invasive potential and heterogeneous drug response. Moreover, four additional MSI target genes (Nktr1, C8a, Taf1b, and Lig4) not recognized in the primary were identified in this cell line.Summing up, molecular and immunological mechanisms of MLH1-/- driven carcinogenesis correlate well with clinical features of MMR-D. MLH1-/- knockout mice combine characteristics of Lynch syndrome and constitutional MMR-D, making them suitable models for preclinical research aiming at MMR-D related diseases.

Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors.

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Pineda, M; González-Acosta, M; Thompson, B A; Sánchez, R; Gómez, C; Martínez-López, J; Perea, J; Caldés, T; Rodríguez, Y; Landolfi, S; Balmaña, J; Lázaro, C; Robles, L; Capellá, G; Rueda, D

2015-06-01

Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Gift of Education: Public Education and Venture Philanthropy. Education, Politics and Public Life

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Saltman, Kenneth J.

2010-01-01

This is a cutting edge book that not only maps and criticizes venture philanthropy, but also offers a new and different way of conceptualizing public education in response to the neoliberal climate affecting all aspects of public education. This book contains the following chapters: (1) The Trojan School: How Venture Philanthropy is Corporatizing…

Mlh1 is required for female fertility in Drosophila melanogaster: An outcome of effects on meiotic crossing over, ovarian follicles and egg activation.

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Vimal, Divya; Kumar, Saurabh; Pandey, Ashutosh; Sharma, Divya; Saini, Sanjay; Gupta, Snigdha; Ravi Ram, Kristipati; Chowdhuri, Debapratim Kar

2018-03-01

Mismatch repair (MMR) system, a conserved DNA repair pathway, plays crucial role in DNA recombination and is involved in gametogenesis. The impact of alterations in MMR family of proteins (bacterial MutS and MutL homologues) on mammalian fertility is well documented. However, an insight to the role of MMR in reproduction of non-mammalian organisms is limited. Hence, in the present study, we analysed the impact of mlh1 (a MutL homologue) on meiotic crossing over/recombination and fertility in a genetically tractable model, Drosophila melanogaster. Using mlh1 e00130 hypomorphic allele, we report female specific adverse reproductive outcome for reduced mlh1 in Drosophila: mlh1 e00130 homozygous females had severely reduced fertility while males were fertile. Further, mlh1 e00130 females contained small ovaries with large number of early stages as well as significantly reduced mature oocytes, and laid fewer eggs, indicating discrepancies in egg production and ovulation. These observations contrast the sex independent and/or male specific sterility and normal follicular development as well as ovulation reported so far for MMR family proteins in mammals. However, analogous to the role(s) of mlh1 in meiotic crossing over and DNA repair processes underlying mammalian fertility, ovarian follicles from mlh1 e00130 females contained significantly increased DNA double strand breaks (DSBs) and reduced synaptonemal complex foci. In addition, large proportion of fertilized eggs display discrepancies in egg activation and fail to proceed beyond stage 5 of embryogenesis. Hence, reduction of the Mlh1 protein level leads to defective oocytes that fail to complete embryogenesis after fertilization thereby reducing female fertility. Copyright © 2017 Elsevier GmbH. All rights reserved.

Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation.

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von Salomé, Jenny; Liu, Tao; Keihäs, Markku; Morak, Moni; Holinski-Feder, Elke; Berry, Ian R; Moilanen, Jukka S; Baert-Desurmont, Stéphanie; Lindblom, Annika; Lagerstedt-Robinson, Kristina

2017-12-29

Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.

Clinical and prognosis value of the CIMP status combined with MLH1 or p16 INK4a methylation in colorectal cancer.

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Saadallah-Kallel, Amana; Abdelmaksoud-Dammak, Rania; Triki, Mouna; Charfi, Slim; Khabir, Abdelmajid; Sallemi-Boudawara, Tahia; Mokdad-Gargouri, Raja

2017-08-01

Aberrant DNA methylation of CpG islands occurred frequently in CRC and associated with transcriptional silencing of key genes. In this study, the CIMP combined with MLH1 or p16 INK4a methylation status was determined in CRC patients and correlated with clinicopathological parameters and overall survival. Our data showed that CIMP+ CRCs were identified in 32.9% of cases and that CACNAG1 is the most frequently methylated promoter. When we combined the CIMP with the MLH1 or the p16 INK4a methylation status, we found that CIMP-/MLH1-U (37.8%) and CIMP-/p16 INK4a -U (35.4%) tumors were the most frequent among the four subtypes. Statistical analysis showed that tumor location, lymphovascular invasion, TNM stage, and MSI differed among the group of patients. Kaplan-Meier analyses revealed differences in overall survival according to the CIMP combined with MLH1 or p16 INK4a methylation status. In a multivariate analysis, CIMP/MLH1 and CIMP/p16 INK4a methylation statuses were predictive of prognosis, and the OS was longer for patients with tumors CIMP-/MLH1-M, as well as CIMP-/p16 INK4a -M. Furthermore, DNMT1 is significantly overexpressed in tumors than in normal tissues as well as in CIMP+ than CIMP- tumors. Our results suggest that tumor classification based on the CIMP status combined with MLH1 or p16 INK4a methylation is useful to predict prognosis in CRC patients.

The silent mutation MLH1 c.543C>T resulting in aberrant splicing can cause Lynch syndrome: a case report.

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Yamaguchi, Tatsuro; Wakatsuki, Tomokazu; Kikuchi, Mari; Horiguchi, Shin-Ichiro; Akagi, Kiwamu

2017-06-01

The proband was a 67-year-old man with transverse and sigmoid colon cancer. Microsatellite instability analysis revealed a high frequency of microsatellite instability, and immunohistochemical staining showed the absence of both MLH1 and PMS2 proteins in the sigmoid colon cancer tissue specimens from the patient. DNA sequencing revealed a nucleotide substitution c.543C>T in MLH1, but this variant did not substitute an amino acid. The MLH1 c.543C>T variant was located 3 bases upstream from the end of exon 6 and created a new splice donor site 4 bases upstream from the end of exon 6. Consequently, the last 4 bases of exon 6 were deleted and frameshift occurred. Thus, the MLH1 c.543C>T silent mutation is considered 'pathogenic'. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols : A Prospective Lynch Syndrome Database report

NARCIS (Netherlands)

Seppala, Toni; Pylvanainen, Kirsi; Evans, Dafydd Gareth; Jarvinen, Heikki; Renkonen-Sinisalo, Laura; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind; Rodland, Einar Andreas; Tharmaratnam, Kukatharmini; Cappel, Wouter H. de Vos tot Nederveen; Hill, James; Wijnen, Juul; Jenkins, Mark; Genuardi, Maurizio; Green, Kate; Lalloo, Fiona; Sunde, Lone; Mints, Miriam; Bertario, Lucio; Pineda, Marta; Navarro, Matilde; Morak, Monika; Frayling, Ian M.; Plazzer, John-Paul; Sampson, Julian R.; Capella, Gabriel; Moslein, Gabriela; Mecklin, Jukka-Pekka; Moller, Pal

2017-01-01

BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenicMLH1variants(path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation

Epigenetic silencing of the DNA mismatch repair gene, MLH1, induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1

Science.gov (United States)

Lu, Yuhong; Wajapeyee, Narendra; Turker, Mitchell S.; Glazer, Peter M.

2014-01-01

SUMMARY Silencing of the MLH1 gene is frequently seen in sporadic cancers. We report that hypoxia causes decreased H3K4 methylation at the MLH1 promoter via the H3K4 demethylases, LSD1 and PLU-1, and promotes long-term silencing of the promoter in a pathway that requires LSD1. Knockdown of LSD1 or its co-repressor, CoREST, also prevents the re-silencing (and cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC). The results demonstrate that hypoxia is a critical driving force for silencing of MLH1 through chromatin modification and indicate that the LSD1/CoREST complex is essential for MLH1 silencing. PMID:25043185

Correlation of MLH1 and MGMT methylation levels between peripheral blood leukocytes and colorectal tissue DNA samples in colorectal cancer patients.

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Li, Xia; Wang, Yibaina; Zhang, Zuoming; Yao, Xiaoping; Ge, Jie; Zhao, Yashuang

2013-11-01

CpG island methylation in the promoter regions of the DNA mismatch repair gene mutator L homologue 1 ( MLH1 ) and DNA repair gene O 6 -methylguanine-DNA methyltransferase ( MGMT ) genes has been shown to occur in the leukocytes of peripheral blood and colorectal tissue. However, it is unclear whether the methylation levels in the blood leukocytes and colorectal tissue are correlated. The present study analyzed and compared the levels of MGMT and MLH1 gene methylation in the leukocytes of peripheral blood and colorectal tissues obtained from patients with colorectal cancer (CRC). The methylation levels of MGMT and MLH1 were examined using methylation-sensitive high-resolution melting (MS-HRM) analysis. A total of 44 patients with CRC were selected based on the MLH1 and MGMT gene methylation levels in the leukocytes of the peripheral blood. Corresponding colorectal tumor and normal tissues were obtained from each patient and the DNA methylation levels were determined. The correlation coefficients were evaluated using Spearman's rank test. Agreement was determined by generalized κ-statistics. Spearman's rank correlation coefficients (r) for the methylation levels of the MGMT and MLH1 genes in the leukocytes of the peripheral blood and normal colorectal tissue were 0.475 and 0.362, respectively (P=0.001 and 0.016, respectively). The agreement of the MGMT and MLH1 gene methylation levels in the leukocytes of the peripheral blood and normal colorectal tissue were graded as fair and poor (κ=0.299 and 0.126, respectively). The methylation levels of MGMT and MLH1 were moderately and weakly correlated between the patient-matched leukocytes and the normal colorectal tissue, respectively. Blood-derived DNA methylation measurements may not always represent the levels of normal colorectal tissue methylation.

Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

Science.gov (United States)

Pussila, Marjaana; Törönen, Petri; Einarsdottir, Elisabet; Katayama, Shintaro; Krjutškov, Kaarel; Holm, Liisa; Kere, Juha; Peltomäki, Päivi; Mäkinen, Markus J; Linden, Jere; Nyström, Minna

2018-01-01

Abstract Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/−) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC. PMID:29701748

Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer.

Science.gov (United States)

Montazer Haghighi, Mahdi; Radpour, Ramin; Aghajani, Katayoun; Zali, Narges; Molaei, Mahsa; Zali, Mohammad Reza

2009-08-01

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found. The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing. We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient. In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.

Radiation risk and public education

International Nuclear Information System (INIS)

Faden, R.R.

1983-01-01

Two issues which deal with the public's perception of radiation hazards are discussed. The goal of public education about radiation, and the relative role of scientific and moral beliefs in public education are examined

Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing.

Science.gov (United States)

Kenyon, Jonathan; Nickel-Meester, Gabrielle; Qing, Yulan; Santos-Guasch, Gabriela; Drake, Ellen; PingfuFu; Sun, Shuying; Bai, Xiaodong; Wald, David; Arts, Eric; Gerson, Stanton L

Normal human hematopoietic stem and progenitor cells (HPC) lose expression of MLH1 , an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the MLH1 promoter is a contributing factor to acquired loss of MLH1 expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the MLH1 transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1 . We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of MLH1 expression and increased MLH1 promoter methylation in CFC derived from CD34 + selected hematopoietic stem and progenitor cells.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

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Medeiros, Fabiola; Lindor, Noralane M.; Couch, Fergus J.; Highsmith, W. Edward

2013-01-01

Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes. PMID:22426235

Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression.

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Dudley, Beth; Brand, Randall E; Thull, Darcy; Bahary, Nathan; Nikiforova, Marina N; Pai, Reetesh K

2015-08-01

Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression

Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort.

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Rosty, Christophe; Clendenning, Mark; Walsh, Michael D; Eriksen, Stine V; Southey, Melissa C; Winship, Ingrid M; Macrae, Finlay A; Boussioutas, Alex; Poplawski, Nicola K; Parry, Susan; Arnold, Julie; Young, Joanne P; Casey, Graham; Haile, Robert W; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A; Potter, John D; DeRycke, Melissa; Lindor, Noralane M; Thibodeau, Stephen N; Baron, John A; Win, Aung Ko; Hopper, John L; Jenkins, Mark A; Buchanan, Daniel D

2016-02-19

Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

CpG Island Methylator Phenotype Positive Tumors in the Absence of MLH1 Methylation Constitute a Distinct Subset of Duodenal Adenocarcinomas and Are Associated with Poor Prognosis

Science.gov (United States)

Fu, Tao; Pappou, Emmanouil P.; Guzzetta, Angela A.; Jeschke, Jana; Kwak, Ruby; Dave, Pujan; Hooker, Craig M.; Morgan, Richard; Baylin, Stephen B.; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Ahuja, Nita

2012-01-01

Purpose Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Experimental Design Demographics, tumor characteristics and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation and CpG island methylator phenotype (CIMP) status was performed. A Cox proportional hazard model was built to predict survival. Results CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas, and was associated with MSI (P = 0.011) and MLH1 methylation (P CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed tumors classified by CIMP, CIMP/MLH1 methylation status or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), while CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value regarding both OS (P CIMP+/MLH1-U tumors had the worst OS and TTR. Conclusions Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI or CIMP development. PMID:22825585

Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: An immunohistochemical study

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Giaginis, Constantinos; Michailidi, Christina; Stolakis, Vasileios; Alexandrou, Paraskevi; Tsourouflis, Gerasimos; Klijanienko, Jerzy; Delladetsima, Ioanna; Theocharis, Stamatios

2011-01-01

Summary Background DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, and minimizes cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations in the expression levels of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins MSH2, MLH1 and MGMT in benign and malignant thyroid lesions. Material/Methods MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues from 90 patients with benign and malignant lesions. Results The expression levels of MLH1 was significantly upregulated in cases with malignant compared to those with benign thyroid lesions (p=0.038). The expression levels of MGMT was significantly downregulated in malignant compared to benign thyroid lesions (p=0.001). Similar associations for both MLH1 and MGMT between cases with papillary carcinoma and hyperplastic nodules were also noted (p=0.014 and p=0.026, respectively). In the subgroup of malignant thyroid lesions, MSH2 downregulation was significantly associated with larger tumor size (p=0.031), while MLH1 upregulation was significantly associated with the presence of lymphatic and vascular invasion (p=0.006 and p=0.002, respectively). Conclusions Alterations in the mismatch repair proteins MSH2 and MLH1 and the direct repair protein MGMT may result from tumor development and/or progression. Further studies are recommended to draw definite conclusions on the clinical significance of DNA repair proteins in thyroid neoplasia. PMID:21358597

DIFFERENT SIDES OF THE SAME COIN: MIXED VIEWS OF PUBLIC RELATIONS EDUCATORS AND PRACTITIONER ABOUT PUBLIC RELATIONS EDUCATION

OpenAIRE

BİR, Çisil Sohodol

2010-01-01

Public relations education is a topic of seemingly perpetual importance and interest for practitioners and educators alike In recent years, numerous researches have surveyed both practitioners and educators to identify appropriate ways to strengthen public relations education to prepare students for practitioner’s role. According to these research results public relations educators and practitioners disagree about the priorities they assign to qualities and goals of public relations education...

A novel deletion in the splice donor site of MLH1 exon 6 in a Japanese colon cancer patient with Lynch syndrome.

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Yamaguchi, Junya; Sato, Yuri; Kita, Mizuho; Nomura, Sachio; Yamamoto, Noriko; Kato, Yo; Ishikawa, Yuichi; Arai, Masami

2015-10-01

Lynch syndrome is an autosomal dominantly inherited disease that is characterized by a predisposition to cancers, mainly colorectal cancer. Germline mutations of DNA mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2 have been described in patients with Lynch syndrome. Here, we report deletion of 2 bp in the splice donor site of the MLH1 exon 6 (c.545+4_545+5delCA) in a 48-year-old Japanese woman with Lynch syndrome. RT-PCR direct sequencing analysis revealed that this mutation led to an increase in the level of an MLH1 transcript in which exon 6 was skipped, and may cause a frameshift (p.E153FfsX8). Therefore, this mutation appears to be pathogenic and is responsible for Lynch syndrome. Additionally, analysis of the patient's tumor cells indicated microsatellite instability high phenotype and loss of the MLH1 and PMS2 proteins. To our knowledge, this is a germline splice site mutation of MLH1 that has not been reported previously. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.

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Smith, Catherine E; Mendillo, Marc L; Bowen, Nikki; Hombauer, Hans; Campbell, Christopher S; Desai, Arshad; Putnam, Christopher D; Kolodner, Richard D

2013-10-01

Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.

Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.

Directory of Open Access Journals (Sweden)

Catherine E Smith

2013-10-01

Full Text Available Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.

Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium

International Nuclear Information System (INIS)

Sun Hong; Zhou Xue; Chen Haobin; Li Qin; Costa, Max

2009-01-01

Hexavalent chromium [Cr(VI)] is a mutagen and carcinogen, and occupational exposure can lead to lung cancers and other adverse health effects. Genetic changes resulting from DNA damage have been proposed as an important mechanism that mediates chromate's carcinogenicity. Here we show that chromate exposure of human lung A549 cells increased global levels of di- and tri-methylated histone H3 lysine 9 (H3K9) and lysine 4 (H3K4) but decreased the levels of tri-methylated histone H3 lysine 27 (H3K27) and di-methylated histone H3 arginine 2 (H3R2). Most interestingly, H3K9 dimethylation was enriched in the human MLH1 gene promoter following chromate exposure and this was correlated with decreased MLH1 mRNA expression. Chromate exposure increased the protein as well as mRNA levels of G9a a histone methyltransferase that specifically methylates H3K9. This Cr(VI)-induced increase in G9a may account for the global elevation of H3K9 dimethylation. Furthermore, supplementation with ascorbate, the primary reductant of Cr(VI) and also an essential cofactor for the histone demethylase activity, partially reversed the H3K9 dimethylation induced by chromate. Thus our studies suggest that Cr(VI) may target histone methyltransferases and demethylases, which in turn affect both global and gene promoter specific histone methylation, leading to the silencing of specific tumor suppressor genes such as MLH1.

Education and Asset Composition.

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Bradley, Michael G.; Graham, John W.

1988-01-01

Investigates the relationship between educational attainment and married couples' efficiency at managing their assets. Using 1976 data, this study of over 750 Illinois couples disclosed little empirical evidence that education imparts efficiency to the realm of personal finance. Includes 6 tables, 5 notes, and 17 references. (MLH)

Identification and verification of a pathogenic MLH1 mutation c.1145dupA in a Lynch syndrome family

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Huang Feifei

2017-06-01

Full Text Available Lynch syndrome (LS, an autosomal-dominant disorder with an increased risk of predominantly colorectal and endometrial cancers, is caused by germ-line mutations in mismatch repair genes. The identification of germ-line mutations that predispose to cancer is important to further our understanding of tumorigenesis, guide patient management and inform the best practice for healthcare. A 45-year-old woman with atypical endometrial hyperplasia who suffered colon cancer at the age of 30 years underwent hysterectomy and genetic counseling. Pedigree analysis revealed her family fulfilling the Amsterdam I criteria. Next-generation sequencing was offered to the patient. A mutation in the MLH1 gene, c.1145dupA, was identified and verified by Sanger sequencing. In addition, her nine family members were tested for the mutation. Two were affected (colon cancer at the age of 43 years and 45 years and one healthy relative carried the same mutation in the MLH1 gene. The mutation resulted in a frame-shift (p.Met383Aspfs*12 located in exon12, as well as a polypeptide truncation of 393 amino acids by the formation of a premature stop codon. An immunohistochemistry analysis of endometrial hyperplasia tissues revealed defects in MLH1 and PMS2 protein expression in the patient. Based on the 2015 American College of Medical Genetics and Genomics (ACMG guideline, we report this MLH1 c.1145dupA variation to be a pathogenic mutation that contributes to a strongly increased cancer risk in this LS family. Proper screening suggestions were offered to the three affected patients and the healthy carrier. To the best of our knowledge, this germ-line mutation of MLH1 was previously submitted to the Leiden Open Variation Database (LOVD database, but no comprehensive evidence or supporting observations were reported previously in the literature. The present report found a single nucleotide insertion in exon12 of the MLH1 gene, which can be considered causative of Lynch phenotype

Public Energy Education: Issues for Discussion. Draft.

Science.gov (United States)

Public Energy Education Task Force.

This paper was intended to stimulate discussion of energy education issues at a conference on energy issues. The discussion ranges through numerous topics at issue in energy education including public energy awareness, definition of public education, the distinction between public education and public relations, and the presentation of a model…

Public education - Whose responsibility?

International Nuclear Information System (INIS)

Elliott, Alva E.

1977-01-01

One of the major problems of the nuclear industry is the lack of public education as to the true facts of nuclear energy. This paper describes some of the misconceptions the general public have concerning reactors, and what program the University of Missouri-Rolla Reactor Facility is following to educate the more than three thousand visitors that tour the facility each year. (author)

Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management

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Ramsoekh Dewkoemar

2009-12-01

Full Text Available Abstract Background Lynch syndrome (LS is associated with a high risk for colorectal cancer (CRC and extracolonic malignancies, such as endometrial carcinoma (EC. The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers. Methods The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis. Results MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61% compared to MLH1 (25% and MSH2 (49%. Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2. Conclusions Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704.

Science.gov (United States)

Lawrence, Yaacov R; Moughan, Jennifer; Magliocco, Anthony M; Klimowicz, Alexander C; Regine, William F; Mowat, Rex B; DiPetrillo, Thomas A; Small, William; Simko, Jeffry P; Golan, Talia; Winter, Kathryn A; Guha, Chandan; Crane, Christopher H; Dicker, Adam P

2018-02-01

The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment. Cancer 2018;124:491-8. © 2017 American Cancer Society. © 2017 American Cancer Society.

Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome

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Jose Miguel Moreno-Ortiz

2016-01-01

Full Text Available Background. Lynch Syndrome (LS is characterized by germline mutations in the DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC, and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del and c.1852_1853delinsGC (p.K618A in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population.

Science.gov (United States)

Zhu, Xiaonian; Liu, Wei; Qiu, Xiaoqiang; Wang, Zhigang; Tan, Chao; Bei, Chunhua; Qin, Linyuan; Ren, Yuan; Tan, Shengkui

2017-10-03

Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 ( MLH1 ) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

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Zavodna, Katarina; Krivulcik, Tomas; Bujalkova, Maria Gerykova [Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia); Slamka, Tomas; Martinicky, David; Ilencikova, Denisa [National Cancer Institute, Department of Oncologic Genetics, Klenova 1, 833 01 Bratislava (Slovakia); Bartosova, Zdena [Laboratory of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia)

2009-11-20

Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

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Ilencikova Denisa

2009-11-01

Full Text Available Abstract Background Depending on the population studied, large genomic rearrangements (LGRs of the mismatch repair (MMR genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC. It has been reported that loss of heterozygosity (LOH at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. Methods The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. Results We found six rearrangements in the MSH2 gene (five deletions and dup5-6, and one aberration in the MLH1 gene (del5-6. The MSH2 deletions were of three types (del1, del1-3, del1-7. We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. Conclusion LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

International Nuclear Information System (INIS)

Zavodna, Katarina; Krivulcik, Tomas; Bujalkova, Maria Gerykova; Slamka, Tomas; Martinicky, David; Ilencikova, Denisa; Bartosova, Zdena

2009-01-01

Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (MMR) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from MLH1/MSH2 deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts. The main MMR genes responsible for HNPCC, MLH1, MSH2, MSH6, and PMS2, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose MLH1/MSH2 genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the MLH1 and MSH2 genes. We found six rearrangements in the MSH2 gene (five deletions and dup5-6), and one aberration in the MLH1 gene (del5-6). The MSH2 deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single MLH1 case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region. LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or

In Search of...Brain-Based Education.

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Bruer, John T.

1999-01-01

Debunks two ideas appearing in brain-based education articles: the educational significance of brain laterality (right brain versus left brain) and claims for a sensitive period of brain development in young children. Brain-based education literature provides a popular but misleading mix of fact, misinterpretation, and fantasy. (47 references (MLH)

MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

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Chiu, Chao-Hua; Ho, Hsiang-Ling; Doong, Howard; Yeh, Yi-Chen; Chen, Mei-Yu; Chou, Teh-Ying; Tsai, Chun-Ming

2015-04-10

A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short ( 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

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Kwok, C.T.; Vogelaar, I.P.; Zelst-Stams, W.A.G. van; Mensenkamp, A.R.; Ligtenberg, M.J.L.; Rapkins, R.W.; Ward, R.L.; Chun, N.; Ford, J.M.; Ladabaum, U.; McKinnon, W.C.; Greenblatt, M.S.; Hitchins, M.P.

2014-01-01

Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma.

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Pećina-Šlaus, Nives; Kafka, Anja; Bukovac, Anja; Vladušić, Tomislav; Tomas, Davor; Hrašćan, Reno

2017-07-01

Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ 2  = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

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Weijenberg, Matty P; Lüchtenborg, Margreet; de Goeij, Anton F P M; Brink, Mirian; van Muijen, Goos N P; de Bruïne, Adriaan P; Goldbohm, R Alexandra; van den Brandt, Piet A

2007-10-01

To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18-1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.

The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1-93G>A polymorphism in normal tissues and colorectal cancer.

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Savio, Andrea J; Mrkonjic, Miralem; Lemire, Mathieu; Gallinger, Steven; Knight, Julia A; Bapat, Bharat

2017-01-01

Colorectal cancers (CRCs) undergo distinct genetic and epigenetic alterations. Expression of mutL homolog 1 ( MLH1 ), a mismatch repair gene that corrects DNA replication errors, is lost in up to 15% of sporadic tumours due to mutation or, more commonly, due to DNA methylation of its promoter CpG island. A single nucleotide polymorphism (SNP) in the CpG island of MLH1 ( MLH1 -93G>A or rs1800734) is associated with CpG island hypermethylation and decreased MLH1 expression in CRC tumours. Further, in peripheral blood mononuclear cell (PBMC) DNA of both CRC cases and non-cancer controls, the variant allele of rs1800734 is associated with hypomethylation at the MLH1 shore, a region upstream of its CpG island that is less dense in CpG sites . To determine whether this genotype-epigenotype association is present in other tissue types, including colorectal tumours, we assessed DNA methylation in matched normal colorectal tissue, tumour, and PBMC DNA from 349 population-based CRC cases recruited from the Ontario Familial Colorectal Cancer Registry. Using the semi-quantitative real-time PCR-based MethyLight assay, MLH1 shore methylation was significantly higher in tumour tissue than normal colon or PBMCs ( P  MLH1 was not associated with MSI status or promoter CpG island hypermethylation, regardless of genotype. To confirm these results, bisulfite sequencing was performed in matched tumour and normal colorectal specimens from six CRC cases, including two cases per genotype (wildtype, heterozygous, and homozygous variant). Bisulfite sequencing results corroborated the methylation patterns found by MethyLight, with significant hypomethylation in normal colorectal tissue of variant SNP allele carriers. These results indicate that the normal tissue types tested (colorectum and PBMC) experience dynamic genotype-associated epigenetic alterations at the MLH1 shore, whereas tumour DNA incurs aberrant hypermethylation compared to normal DNA.

Performance of Lynch syndrome predictive models in quantifying the likelihood of germline mutations in patients with abnormal MLH1 immunoexpression.

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Cabreira, Verónica; Pinto, Carla; Pinheiro, Manuela; Lopes, Paula; Peixoto, Ana; Santos, Catarina; Veiga, Isabel; Rocha, Patrícia; Pinto, Pedro; Henrique, Rui; Teixeira, Manuel R

2017-01-01

Lynch syndrome (LS) accounts for up to 4 % of all colorectal cancers (CRC). Detection of a pathogenic germline mutation in one of the mismatch repair genes is the definitive criterion for LS diagnosis, but it is time-consuming and expensive. Immunohistochemistry is the most sensitive prescreening test and its predictive value is very high for loss of expression of MSH2, MSH6, and (isolated) PMS2, but not for MLH1. We evaluated if LS predictive models have a role to improve the molecular testing algorithm in this specific setting by studying 38 individuals referred for molecular testing and who were subsequently shown to have loss of MLH1 immunoexpression in their tumors. For each proband we calculated a risk score, which represents the probability that the patient with CRC carries a pathogenic MLH1 germline mutation, using the PREMM 1,2,6 and MMRpro predictive models. Of the 38 individuals, 18.4 % had a pathogenic MLH1 germline mutation. MMRpro performed better for the purpose of this study, presenting a AUC of 0.83 (95 % CI 0.67-0.9; P < 0.001) compared with a AUC of 0.68 (95 % CI 0.51-0.82, P = 0.09) for PREMM 1,2,6 . Considering a threshold of 5 %, MMRpro would eliminate unnecessary germline mutation analysis in a significant proportion of cases while keeping very high sensitivity. We conclude that MMRpro is useful to correctly predict who should be screened for a germline MLH1 gene mutation and propose an algorithm to improve the cost-effectiveness of LS diagnosis.

First report of a de novo germline mutation in the MLH1 gene

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Stulp, Rein P; Vos, Yvonne J; Mol, Bart; Karrenbeld, Arend; de Raad, Monique; van der Mijle, Huub J C; Sijmons, Rolf H

2006-01-01

Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast

Continuing-education needs of the currently employed public health education workforce.

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Allegrante, J P; Moon, R W; Auld, M E; Gebbie, K M

2001-08-01

This study examined the continuing-education needs of the currently employed public health education workforce. A national consensus panel of leading health educators from public health agencies, academic institutions, and professional organizations was convened to examine the forces creating the context for the work of public health educators and the competencies they need to practice effectively. Advocacy; business management and finance; communication; community health planning and development, coalition building, and leadership; computing and technology; cultural competency; evaluation; and strategic planning were identified as areas of critical competence. Continuing education must strengthen a broad range of critical competencies and skills if we are to ensure the further development and effectiveness of the public health education workforce.

45 CFR 84.33 - Free appropriate public education.

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2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Free appropriate public education. 84.33 Section..., Elementary, and Secondary Education § 84.33 Free appropriate public education. (a) General. A recipient that operates a public elementary or secondary education program or activity shall provide a free appropriate...

45 CFR 605.33 - Free appropriate public education.

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2010-10-01

... 45 Public Welfare 3 2010-10-01 2010-10-01 false Free appropriate public education. 605.33 Section... Preschool, Elementary, and Secondary Education § 605.33 Free appropriate public education. (a) General. A recipient that operates a public elementary or secondary education program shall provide a free appropriate...

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis.

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Hu, Guimei; Qin, Lijun; Zhang, Xinjun; Ye, Guoliang; Huang, Tao

2018-01-01

Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI. © 2018 The Author(s). Published by S. Karger AG, Basel.

Otolaryngology Education: Recent Trends in Publication.

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Cass, Nathan D; Okland, Tyler S; Rodriguez, Kenny; Mann, Scott E

2017-06-01

Objectives (1) Evaluate peer-reviewed publications regarding education in otolaryngology since 2000. (2) Analyze publication trends as compared with overall otolaryngology publications. Study Design Bibliometric analysis. Setting Academic medical center. Subjects and Methods A search for articles regarding education in otolaryngology from 2000 to 2015 was performed with MEDLINE and EMBASE databases, yielding 1220 articles; 362 relevant publications were categorized by topic, subspecialty, subject, article type, and funding source. Impact factors for each journal by year were obtained, and trends of each category over time were analyzed. These were then compared with publication numbers and impact factors for all otolaryngology journals. Results From 2000 to 2015, publications in otolaryngology education increased more rapidly than the field of otolaryngology overall. The most published topics included operative skills training, surgical simulation, and professionalism/career development. Recently there has been a decline in publications related to residency administration and duty hours relative to other topics. Only 12.2% of publications reported a funding source, and only 12.2% of studies were controlled. Conclusion Recent trends in otolaryngology literature reflect an increasing focus on education; however, this work is underfunded and often lacks high-quality evidence.

Age-Dependent Cancer Risk Is not Different in between MSH2 and MLH1 Mutation Carriers

International Nuclear Information System (INIS)

Olschwang, S.; Olschwang, S.; Yu, K.

2009-01-01

Lynch syndrome is mostly characterized by early-onset colorectal and endometrial adenocarcinomas. Over 90% of the causal mutations occur in two mismatch repair genes, MSH2 and MLH1. The aim of this study was to evaluate the age-dependent cancer risk in MSH2 or MLH1 mutation carriers from data of DNA diagnostic laboratories. To avoid overestimation, evaluation was based on the age-dependent proportion of mutation carriers in asymptomatic first-degree relatives of identified mutation carriers. Data from 859 such eligible relatives were collected from 8 centers; 387 were found to have inherited the mutation from their relatives. Age-dependent risks were calculated either using a nonparametric approach for four discrete age groups or assuming a modified Weibull distribution for the dependence of risk on age. Cancer risk was estimated starting at 28 (25-32 0.68 confidence interval) and to reach near 0.70 at 70 years. The risks were very similar for MSH2 and MLH1 mutation carriers. Although not statistically significant, the risk in males appeared to precede that for females by ten years. This difference needs to be investigated on a larger dataset. If confirmed, this would indicate that the onset of the colonoscopic surveillance may be different in male and female mutation carriers.

Future Directions in Public Relations Education.

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Kalupa, Frank B.; Allen, T. Harrell

1982-01-01

Survey of public relations practitioners and educators shows strong agreement for (1) changes and improvements in public relations education; (2) more business courses and greater emphasis on social science research; and (3) separate degree programs, not public relations majors within a journalism degree. For journal availability, see CS 705 902.…

Transforming Public Education: Cases in Education Entrepreneurship

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Childress, Stacey M., Ed.

2010-01-01

For nearly two decades, education entrepreneurs have been working to transform the K-12 public education system in the United States. "Social entrepreneurship" has become part of the language of a new generation of idealists, many of whom are focused on education. The nineteen cases in this book profile entrepreneurs who are pursuing…

Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.

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Buchanan, Daniel D; Tan, Yen Y; Walsh, Michael D; Clendenning, Mark; Metcalf, Alexander M; Ferguson, Kaltin; Arnold, Sven T; Thompson, Bryony A; Lose, Felicity A; Parsons, Michael T; Walters, Rhiannon J; Pearson, Sally-Ann; Cummings, Margaret; Oehler, Martin K; Blomfield, Penelope B; Quinn, Michael A; Kirk, Judy A; Stewart, Colin J; Obermair, Andreas; Young, Joanne P; Webb, Penelope M; Spurdle, Amanda B

2014-01-10

Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations. Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS). Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered. Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one.

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Goel, Ajay; Nguyen, Thuy-Phuong; Leung, Hon-Chiu E; Nagasaka, Takeshi; Rhees, Jennifer; Hotchkiss, Erin; Arnold, Mildred; Banerji, Pia; Koi, Minoru; Kwok, Chau-To; Packham, Deborah; Lipton, Lara; Boland, C Richard; Ward, Robyn L; Hitchins, Megan P

2011-02-15

Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma-wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation-associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair-deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1. Copyright © 2010 UICC.

Higher Education Research in Asia: A Publication and Co-Publication Analysis

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Jung, Jisun; Horta, Hugo

2013-01-01

This study explores higher education research in Asia. Drawing on scientometrics, the mapping of science and social network analysis, this paper examines the publications of 38 specialised journals on higher education over the past three decades. The findings indicate a growing number of higher education research publications but the proportion of…

Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1.

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Treas, Justin; Tyagi, Tulika; Singh, Kamaleshwar P

2013-11-01

Chronic exposure to arsenic and estrogen is associated with risk of prostate cancer, but their mechanism is not fully understood. Additionally, the carcinogenic effects of their co-exposure are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic, estrogen, and their combination, on cell growth and transformation, and identify the mechanism behind these effects. RWPE-1 human prostate epithelial cells were chronically exposed to arsenic and estrogen alone and in combination. Cell growth was measured by cell count and cell cycle, whereas cell transformation was evaluated by colony formation assay. Gene expression was measured by quantitative real-time PCR and confirmed at protein level by Western blot analysis. MLH1 promoter methylation was determined by pyrosequencing method. Exposure to arsenic, estrogen, and their combinations increases cell growth and transformation in RWPE-1 cells. Increased expression of Cyclin D1 and Bcl2, whereas decreased expression of mismatch repair genes MSH4, MSH6, and MLH1 was also observed. Hypermethylation of MLH1 promoter further suggested the epigenetic inactivation of MLH1 expression in arsenic and estrogen treated cells. Arsenic and estrogen combination caused greater changes than their individual treatments. Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1-mediated apoptotic response, and consequently increased cellular transformation. © 2013 Wiley Periodicals, Inc.

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

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Shigeyasu, Kunitoshi; Nagasaka, Takeshi; Mori, Yoshiko; Yokomichi, Naosuke; Kawai, Takashi; Fuji, Tomokazu; Kimura, Keisuke; Umeda, Yuzo; Kagawa, Shunsuke; Goel, Ajay; Fujiwara, Toshiyoshi

2015-01-01

Background To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. Methods This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox’s proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). Results By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. Conclusions CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer. PMID:26121593

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer.

Directory of Open Access Journals (Sweden)

Kunitoshi Shigeyasu

Full Text Available To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP and microsatellite instability (MSI have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown.This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS.By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088, better tumor differentiation (P = 0.0267 and CIMP-high and MLH1 3' methylated status (P = 0.0312. Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

Promoter hypermethylation of CDKN2A, MGMT, MLH1, and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients.

Science.gov (United States)

Pierini, Stefano; Jordanov, Stanislav H; Mitkova, Atanaska V; Chalakov, Ivan J; Melnicharov, Mincho B; Kunev, Kuncho V; Mitev, Vanio I; Kaneva, Radka P; Goranova, Teodora E

2014-08-01

Laryngeal squamous cell carcinoma (laryngeal SCC) is a frequently occurring cancer of the head and neck area. Epigenetic changes of tumor-related genes contribute to its genesis and progression. We assessed promoter methylation status of the selected genes (CDKN2A, MGMT, MLH1, and DAPK) using methylation-sensitive high resolution melting (MS-HRM) in 100 patients with laryngeal SCC and studied the correlations with clinical characteristics. The prevalence of promoter methylation in MGMT, CDKN2A, MLH1, and DAPK was 59 of 97 (60.8%), 46 of 97 (47.4%), 45 of 97 (46.4%), and 41 of 97 patients (42.3%), respectively. Significantly increased methylation of CDKN2A was observed in heavy smokers. Epigenetic inactivation of CDKN2A and MLH1 were found to be associated with lymph node involvement. An inverse correlation was present between MLH1 methylation and alcohol consumption. Our results strongly suggest that deregulation of p16-associated, and MLH1-associated pathways, because of promoter hypermethylation, is associated with increased cancer cell migration, tumor invasiveness, and, thus, aggressive phenotype. Copyright © 2013 Wiley Periodicals, Inc.

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

Science.gov (United States)

Schneider, Nayê Balzan; Pastor, Tatiane; Paula, André Escremim de; Achatz, Maria Isabel; Santos, Ândrea Ribeiro Dos; Vianna, Fernanda Sales Luiz; Rosset, Clévia; Pinheiro, Manuela; Ashton-Prolla, Patricia; Moreira, Miguel Ângelo Martins; Palmero, Edenir Inêz

2018-05-01

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice-site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one-third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

38 CFR 18.433 - Free appropriate public education.

Science.gov (United States)

2010-07-01

... education. 18.433 Section 18.433 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS..., Secondary, and Adult Education § 18.433 Free appropriate public education. (a) General. A recipient that operates a public elementary or secondary education program shall provide a free appropriate public...

Gender issues in medical and public health education.

Science.gov (United States)

Wong, Y L

2000-01-01

There is no doubt that gender bias has been inherent in medical and public health education, research, and clinical practice. This paper discusses the central question for medical and public health educators viz. whether women's health concerns and needs could be best addressed by the conventional biomedical approach to medical and public health education, research, and practice. Gender inequalities in health and gender bias in medical and public health education are revealed. It is found that in most public health and prevention issues related to women's health, the core issue is male-female power relations, and not merely the lack of public health services, medical technology, or information. There is, thus, an urgent need to gender-sensitize public health and medical education. The paper proposes a gender analysis of health to distinguish between biological causes and social explanations for the health differentials between men and women. It also assessed some of the gender approaches to public health and medical education currently adopted in the Asia-Pacific region. It poses the pressing question of how medical and public health educators integrate the gender perspective into medical and public health education. The paper exhorts all medical and public health practitioners to explore new directions and identify innovative strategies to formulate a gender-sensitive curriculum towards the best practices in medicine and public health that will meet the health needs of women and men in the 21st century.

ARES Education and Public Outreach

Science.gov (United States)

Allen, Jaclyn; Galindo, Charles; Graff, Paige; Willis, Kim

2014-01-01

The ARES Directorate education team is charged with translating the work of ARES scientists into content that can be used in formal and informal K-12 education settings and assisting with public outreach. This is accomplished through local efforts and national partnerships. Local efforts include partnerships with universities, school districts, museums, and the Lunar and Planetary Institute (LPI) to share the content and excitement of space science research. Sharing astromaterials and exploration science with the public is an essential part of the Directorate's work. As a small enclave of physical scientists at a NASA Center that otherwise emphasizes human space operations and engineering, the ARES staff is frequently called upon by the JSC Public Affairs and Education offices to provide presentations and interviews. Scientists and staff actively volunteer with the JSC Speaker's Bureau, Digital Learning Network, and National Engineers Week programs as well as at Space Center Houston activities and events. The education team also participates in many JSC educator and student workshops, including the Pre-Service Teacher Institute and the Texas Aerospace Scholars program, with workshop presentations, speakers, and printed materials.

Public higher education in the Philippines

Science.gov (United States)

Cardozier, V. R.

1984-06-01

Clearly, the national government of the Philippines has decided to increase the number and comprehensiveness of its public colleges and universities. While private colleges and universities are likely to dominate higher education in the Philippines for the remainer of this century, it appears that public, tax-supported higher education will become increasingly available there. The Philippines is not a wealthy country but it is devoting a substantial portion of its national resources to public higher education. In 1983, higher education received 2.85 percent of the national budget, a figure that has been rising for years. Compared with some highly developed countries, this is not a large percentage, but for a country that has traditionally relied on private higher education, it is a major and growing investment in the public sector. While many of the better universities in the Philippines are private, many other private educational institutions are small and struggling. As their financial resources become more limited, and as less expensive, tax-supported higher education becomes increasingly available, a lot of the struggling private colleges will probably close. This process is also being hastened by actions of the government to upgrade quality, for example in the case of the many private colleges that developed after World War II. In an attempt to improve the academic quality of these marginal institutions, the Ministry of Education, Culture and Sports has been given extensive authority, and while its intrusion into private institutions has been modest by some measures, its requirements are affecting them all and will speed the demise of some. This is bound to lead to a stronger role for public higher education in the Philippines, a country that is striving diligently to improve the education and hence the quality of life of its people.

Common mutations identified in the MLH1 gene in familial Lynch syndrome

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Jisha Elias

2017-12-01

In this study we identified three families with Lynch syndrome from a rural cancer center in western India (KCHRC, Goraj, Gujarat, where 70-75 CRC patients are seen annually. DNA isolated from the blood of consented family members of all three families (8-10 members/family was subjected to NGS sequencing methods on an Illumina HiSeq 4000 platform. We identified unique mutations in the MLH1 gene in all three HNPCC family members. Two of the three unrelated families shared a common mutation (154delA and 156delA. Total 8 members of a family were identified as carriers for 156delA mutation of which 5 members were unaffected while 3 were affected (age of onset: 1 member <30yrs & 2 were>40yr. The family with 154delA mutation showed 2 affected members (>40yr carrying the mutations.LYS618DEL mutation found in 8 members of the third family showed that both affected and unaffected carried the mutation. Thus the common mutations identified in the MLH1 gene in two unrelated families had a high risk for lynch syndrome especially above the age of 40.

Synthesis of Research on Compensatory and Remedial Education.

Science.gov (United States)

Anderson, Lorin W.; Pellicer, Leonard O.

1990-01-01

Current Chapter 1 remedial and compensatory education programs may not be worth the substantial funds being poured into them. To address shortcomings, such programs should be upgraded, reconceptualized as educational (not funding) programs, and fully integrated into the total school program. Includes 14 references. (MLH)

Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis

DEFF Research Database (Denmark)

Hinrichsen, Inga; Brieger, Angela; Trojan, Jörg

2013-01-01

Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results...

Educating the Public Health Workforce: A Scoping Review

Directory of Open Access Journals (Sweden)

Donghua Tao

2018-02-01

Full Text Available The aim of this scoping review was to identify and characterize the recent literature pertaining to the education of the public health workforce worldwide. The importance of preparing a public health workforce with sufficient capacity and appropriate capabilities has been recognized by major organizations around the world (1. Champions for public health note that a suitably educated workforce is essential to the delivery of public health services, including emergency response to biological, manmade, and natural disasters, within countries and across the globe. No single repository offers a comprehensive compilation of who is teaching public health, to whom, and for what end. Moreover, no international consensus prevails on what higher education should entail or what pedagogy is optimal for providing the necessary education. Although health agencies, public or private, might project workforce needs, the higher level of education remains the sole responsibility of higher education institutions. The long-term goal of this study is to describe approaches to the education of the public health workforce around the world by identifying the peer-reviewed literature, published primarily by academicians involved in educating those who will perform public health functions. This paper reports on the first phase of the study: identifying and categorizing papers published in peer-reviewed literature between 2000 and 2015.

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

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Guimei Hu

2018-01-01

Full Text Available Background/Aims: Human mutL homolog 1 (MLH1 promoter methylation was reported in gastric cancer (GC. This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. Methods: The combined odds ratio (OR or hazard ratio (HR and their corresponding 95% confidence intervals (95% CI were calculated. The pooled sensitivity, specificity, and area under the curve (AUC were analyzed. Results: A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI, but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (< 0.5 in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS samples were 0.64, 0.96, and 0.90, respectively. Conclusions: Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI.

First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome.

Science.gov (United States)

Ziada-Bouchaar, H; Sifi, K; Filali, T; Hammada, T; Satta, D; Abadi, N

2017-01-01

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.

7 CFR 15b.22 - Free appropriate public education.

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Free appropriate public education. 15b.22 Section 15b... Extension Education § 15b.22 Free appropriate public education. (a) General. A recipient that operates a public elementary or secondary education program or activity shall provide a free appropriate public...

Integrated Public Education, Fertility and Human Capital

Science.gov (United States)

Azarnert, Leonid V.

2014-01-01

This paper analyzes the consequences of integration in public education. I show that the flight from the integrated multicultural public schools to private education increases private educational expenditures and, as a result, decreases fertility among more affluent parents whose children flee. In contrast, among less prosperous parents…

Small suitability of the DLEC1, MLH1 and TUSC4 mRNA expression analysis as potential prognostic or differentiating markers for NSCLC patients in the Polish population.

Science.gov (United States)

Kordiak, Jacek; Czarnecka, Karolina H; Pastuszak-Lewandoska, Dorota; Antczak, Adam; Migdalska-Sęk, Monika; Nawrot, Ewa; Domańska-Senderowska, Daria; Kiszałkiewicz, Justyna; Brzeziańska-Lasota, Ewa

2017-06-01

According to the latest data, lung cancer is one of the most common cancer worldwide, men contributing nearly 21.2% and women 8.6% of all diagnosed cancers. Late detection of tumour drastically reduces the chance for a cure. Thus, it is important to search for candidate biomarkers for screening of early stage nonsmall cell lung carcinoma (NSCLC). Tumour suppressor genes, DLEC1, TUSC4 and MLH1, localized on 3p21 are recognized to play a role in NSCLC carcinogenesis. The aim of this study was to assess the relationship between the DLEC1, TUSC4 and MLH1 mRNA expression, and clinical features of NSCLC patients, tobacco addiction, and tumour histopathological characteristics. The DLEC1, TUSC4 and MLH1 expression was analysed in lung tumour tissue samples obtained from 69 patients diagnosed with NSCLC: squamous cell carcinoma (n = 34), adenocarcinoma (n = 24), large cell carcinoma (n = 5), carcinoma adenosquamosum (n = 5). A decreased gene expression (RQ MLH1 in 50.7% and for TUSC4 in 26% of NSCLC samples. DLEC1 was decreased in more aggressive subtypes: large cell carcinoma and adenocarcinoma-squamous cell carcinoma. The simultaneous downregulation of two of the studied genes, DLEC1 andMLH1,was observed in 30.4% of NSCLCsamples, highlighting the importance of these two genes in lung carcinogenesis. We found no correlation between the DLEC1, TUSC4 and MLH1 gene expression and NSCLC patient characteristics (gender, age and smoking) or cancer histopathology. No significant differences in the gene expression among NSCLC subtypes indicate the weakness of DLEC1, TUSC4 and MLH1 expression analysis as potential differentiating markers of NSCLC subtypes in the Polish population.

Efficient molecular screening of Lynch syndrome by specific 3' promoter methylation of the MLH1 or BRAF mutation in colorectal cancer with high-frequency microsatellite instability.

Science.gov (United States)

Nakagawa, Hitoshi; Nagasaka, Takeshi; Cullings, Harry M; Notohara, Kenji; Hoshijima, Naoko; Young, Joanne; Lynch, Henry T; Tanaka, Noriaki; Matsubara, Nagahide

2009-06-01

It is sometimes difficult to diagnose Lynch syndrome by the simple but strict clinical criteria, or even by the definitive genetic testing for causative germline mutation of mismatch repair genes. Thus, some practical and efficient screening strategy to select highly possible Lynch syndrome patients is exceedingly desirable. We performed a comprehensive study to evaluate the methylation status of whole MLH1 promoter region by direct bisulfite sequencing of the entire MLH1 promoter regions on Lynch and non-Lynch colorectal cancers (CRCs). Then, we established a convenient assay to detect methylation in key CpG islands responsible for the silencing of MLH1 expression. We studied the methylation status of MLH1 as well as the CpG island methylator phenotype (CIMP) and immunohistochemical analysis of mismatch repair proteins on 16 cases of Lynch CRC and 19 cases of sporadic CRCs with high-frequency microsatellite instability (MSI-H). Sensitivity to detect Lynch syndrome by MLH1 (CCAAT) methylation was 88% and the specificity was 84%. Positive likelihood ratio (PLR) was 5.5 and negative likelihood ratio (NLR) was 0.15. Sensitivity by mutational analysis of BRAF was 100%, specificity was 84%, PLR was 6.3 and NLR was zero. By CIMP analysis; sensitivity was 88%, specificity was 79%, PLR was 4.2, and NLR was 0.16. BRAF mutation or MLH1 methylation analysis combined with MSI testing could be a good alternative to screen Lynch syndrome patients in a cost effective manner. Although the assay for CIMP status also showed acceptable sensitivity and specificity, it may not be practical because of its rather complicated assay.

Education for Corporate Public Relations.

Science.gov (United States)

Baxter, Bill L.

1985-01-01

Surveyed members of the Public Relations Society of America who reported that (1) students planning public relations careers in corporations should take courses in this order of priority: journalism, public relations, internships, speech communication, marketing, etc., and (2) an MBA degree was the best advanced education degree. (PD)

Adult Education in Museums and Public Libraries.

Science.gov (United States)

Miller, Harry G.

Both museums and public libraries are available sources of education for adults. Besides their traditional functions of collecting and preserving items from human artistic or scientific history, museums have taken on a more active role in educating the public, particularly adults. Some educational services provided by museums are dioramas, period…

Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells

Science.gov (United States)

Yoneshima, Yasuto; Abolhassani, Nona; Iyama, Teruaki; Sakumi, Kunihiko; Shiomi, Naoko; Mori, Masahiko; Shiomi, Tadahiro; Noda, Tetsuo; Tsuchimoto, Daisuke; Nakabeppu, Yusaku

2016-01-01

Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity. PMID:27618981

In-house training, formal education and public outreach

International Nuclear Information System (INIS)

Willis, Y.A.

1992-01-01

This paper assumes that a stronger national commitment to public education on nuclear energy and, most particularly radioactive waste management, it needed to overcome public resistance to nuclear projects. Effective public education must become the superordinate goal uniting industry, government, professional societies, national laboratories and the educational community. Since instruction is labor intensive, we must search for more cost effective ways of achieving results. Therefore, this paper proposes: Collaborative training and educational strategies involving as many of the stakeholders as possible; and Innovative tools to improve the credibility, quality and cost effectiveness of education. This win-win approach can reduce the collective expenditures through cost-sharing, as well as the sharing of resources and products. It can close gaps in both in-house training and formal education. Finally, in public outreach, the joint approach addresses the politics of sponsorship by providing checks and balances, and thus improving credibility and public acceptance

Education of healthcare professionals and the public.

Science.gov (United States)

McNulty, Cliodna A M; Cookson, Barry D; Lewis, Michael A O

2012-07-01

In the winter of 2007-08 a new public-facing antimicrobial campaign was agreed by the Advisory Committee on Antimicrobial Resistance and Healthcare-Associated Infection (ARHAI) Education sub-Group (later divided into subgroups for professional and public education): it comprised posters with a positive message on how the public could help themselves when they had a cold. However, the poster campaign, used in isolation in England, did not improve antibiotic use; therefore, the Public Education sub-Group took forward educational approaches to change the behaviour of the public and health professionals. Professionals have been encouraged to give patients clear information about the likely duration of symptoms, self-care, and benefits and harms of antibiotics, reinforcing the public poster campaigns in surgeries, hospitals and pharmacies. Since 2008, campaigns have been launched in England to coincide with European Antibiotic Awareness Day (EAAD) on 18 November, using Department of Health and EAAD materials. Professional education has been facilitated by the 2008 National Institute for Health and Clinical Excellence respiratory tract infection delayed prescribing guidance for general practitioners. A toolkit of materials for medicines management teams, to facilitate good antimicrobial stewardship in primary care (ASPIC), is being taken forward by the Public Education sub-Group and professional societies. After advice from ARHAI, in 2009 the General Medical Council requested that all postgraduate deans and Royal Colleges ensure infection prevention and control and antimicrobial prescribing become standard practice implemented in all clinical settings, and that they are emphasized strongly in undergraduate and postgraduate medical training. ARHAI has also taken a keen interest in reviewing, advising and leading on a number of European Union initiatives dealing with professional education.

Online Education in Public Affairs

Science.gov (United States)

Ginn, Martha H.; Hammond, Augustine

2012-01-01

This exploratory study provides an overview of the current landscape of online education in the fields of Master of Public Administration and Master of Public Policy (MPA/MPP) utilizing a dataset compiled from content analysis of MPA/MPP programs' websites and survey of 96 National Association of Schools of Public Affairs and Administration…

Small suitability of the DLEC1, MLH1 and TUSC4 mRNA expression ...

Indian Academy of Sciences (India)

JACEK KORDIAK

2017-06-18

Jun 18, 2017 ... The DLEC1, TUSC4 and MLH1 expression was analysed in lung tumour tissue samples obtained from ... among men, however, the incidence is also rising in women ... rate of lung cancer patients is still poor, mainly because .... Up to 30 PYs. 18 ..... study performed by our group, high percentage (78%).

Fruits, vegetables and hMLH1 protein-deficient and-proficient colon cancer: the Netherlands Cohort Study

NARCIS (Netherlands)

Wark, P.A.; Weijenberg, M.P.; Veer, van 't P.; Wijhe, van G.; Luchtenborg, M.; Muijen, van G.N.P.; Goeij, de A.F.P.M.; Goldbohm, R.A.; Brandt, van den P.A.

2005-01-01

Clinical and pathologic differences exist between colon carcinomas deficient and proficient in the mismatch repair protein hMLH1. Animal and in vitro studies suggest that fruits, vegetables, folate, and antioxidants are associated with colonic expression of mismatch repair genes.METHODS:

Educational Needs of Public Library Users

Directory of Open Access Journals (Sweden)

Simona Šinko

2014-09-01

Full Text Available AbstractPurpose: The article explains the role of user education in public libraries based on the assessment of users’ educational needs in a selected public library. We present a part of the results of the needs assessment study conducted on users of the Ljubljana City Library (LCL. In this presentation, we focus on the thematic areas of users’ interest, the most appropriate time of day and the most appropriate period of the year for participating in education. The aim of presenting this information is to support the development of an appropriate adult education provision and an effective use of human, financial and material resources in public libraries.Methodology/approach: The basic research method used was descriptive and causal non- experimental. The study involved 943 adults LCL users who have filled in an online or a printed form of the questionnaire.Results: Results of data analysis showed that users express a greater degree of interest in the following course topics: travel, foreign languages, literature, public speaking and health. They express the lowest degree of interest in the topics: policy, motoring and mathematics. Afternoons and evenings suit them best, whereas the autumn and winter season are in their view the best time of the year for participating in education. The analysis also showed some statistically significant differences in relation to sex, age, status and educational level of the users.Research limitation: By the practical application of results the characteristics of the sample of users and the environment from which they come, as well as the shortcomings of the questionnaire as an instrument for data collection, have to be considered.Originality/practical implications: The data obtained are useful in preparing the basis of educational activities in LCL, as well as for the design of educational programs in other comparable public libraries and other providers of adult education. The survey results can also

Education and Social Change: Perspectives from the Developing and Developed World.

Science.gov (United States)

Wright, David H. M.

1986-01-01

Discusses education's purpose as bringing about change and the attraction of using education to effect social change in countries like Australia and newly independent Zimbabwe. Examines both the efficacy and the legitimacy of education's role and contribution to social change as related to particular political positions and thinking styles. (MLH)

Germline Hypermethylation of MLH1 and EPCAM Deletions Are a Frequent Cause of Lynch Syndrome

NARCIS (Netherlands)

Niessen, Renee C.; Hofstra, Robert M. W.; Westers, Helga; Ligtenberg, Marjolijn J. L.; Kooi, Krista; Jager, Paul O. J.; de Groote, Marloes L.; Dijkhuizen, Trijnie; Olderode-Berends, Maran J. W.; Hollema, Harry; Kleibeuker, Jan H.; Sijmons, Rolf H.

It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation.

Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome.

NARCIS (Netherlands)

Niessen, R.C.; Hofstra, R.M.; Westers, H.; Ligtenberg, M.J.L.; Kooi, K.; Jager, P.O.; Groote, M.L. de; Dijkhuizen, T.; Olderode-Berends, M.J.; Hollema, H.; Kleibeuker, J.H.; Sijmons, R.H.

2009-01-01

It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation.

Radiation protection, public policies and education

International Nuclear Information System (INIS)

Alves, Simone F.; Jacomino, Vanusa M.F.; Barreto, Alberto A.

2011-01-01

The objective of this paper is to inform about the aspects of radiation protection public policies concerning the public spheres and the ordinary population. It is known that information has been considered a very important good in several knowledge areas. However, the efficiency of their transmission mechanisms should be periodically evaluated, checking existing critical and stagnation points. Nuclear area can be mentioned as a historically typical case, where the public policies assume relevant importance as tool for promotion, control and education of the population in general. Considering the polemic nature of such subject, it is clear that there is a need for conducting the construction of educational contents taking in account the educator training necessities. The addressing of radiation protection aspects applied to nuclear techniques conducts, for example, to the awareness on the benefits of radiation and its industrial and medical applications, which are established considering the worldwide adopted basic principles of radiation protection. Such questions, concerned with (or related to) public policies, establish a link between radiation protection and education, themes explored in this article to provide a better view of the current Brazilian scenario. (author)

OPTIMIZATION OF FINANCING PUBLIC HIGHER EDUCATION INSTITUTIONS IN UKRAINE

Directory of Open Access Journals (Sweden)

Z. Varnaliy

2017-09-01

Full Text Available The paper considers the ways to optimize financing public higher education institutions of Ukraine. Public higher education institutions acutely feel the lack of financial resources. The study describes that it is necessary to reform the models, methods and forms of financing higher education institutions. The paper explains the impact of autonomy of higher education institutions on their development. The autonomy level of university determines the possibilities for diversification from additional sources. The results found that more autonomy of higher education institutions will allow them effectively generate and use financial resources. The review outlines the diversification of financial resources public universities. One of the key factors of the university success is to implement the diversification strategy into the overall academic strategy and mission of the higher education institution. The analysis recommends the performance-based funding system and public higher education institutions achieve certain performance indicators. The performance-based funding system will promote higher competitiveness of education institutions and improve the quality of higher education in general. The conclusions suggest the development trends of financing public higher education institutions of Ukraine.

Effect of nuclear education on public attitude

International Nuclear Information System (INIS)

Ohnishi, Teruaki

1995-01-01

A method is proposed to assess the effect of nuclear education. In this method, the nuclear education is treated as a part of the activities for public acceptance (PA), and a unit PA activity is assumed to give the same effect on the public, in essence, as a unit of nuclear information given by the newsmedia. Moreover, the change of attitude to nuclear energy is assumed to originate from enhanced understanding which, in turn, is brought by the stimulus given by the nuclear education. With the values of constants determined by using the data in Japan, example calculations were made for the educational time b 0 and the infiltration rate of education into minors B as parameters. It became clear from this calculation that the attitude to nuclear energy formed in the age of school children plays an essential role in shaping future public opinion since it is held in individuals without any notable modification for a long time after its formation, and that the effect of nuclear education to minors emerges depending on the variables b 0 and B in a highly non-linear manner. It was also found that there exists an optimum condition for nuclear education to attain the maximum amelioration of public opinion under a given condition of man-power for educational workers. (author)

Current Crises in Public Education.

Science.gov (United States)

Hawkins, Robert B., Jr.

1983-01-01

Argues that the organizational crisis and the crisis in legitimacy that face public education stem from a fundamental violation of the moral precepts that underlie our experiment in self-government. Citizens and parents have become limited partners in educational decision making. (JOW)

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

Science.gov (United States)

Seppälä, Toni; Pylvänäinen, Kirsi; Evans, Dafydd Gareth; Järvinen, Heikki; Renkonen-Sinisalo, Laura; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind; Rødland, Einar Andreas; Tharmaratnam, Kukatharmini; de Vos Tot Nederveen Cappel, Wouter H; Hill, James; Wijnen, Juul; Jenkins, Mark; Genuardi, Maurizio; Green, Kate; Lalloo, Fiona; Sunde, Lone; Mints, Miriam; Bertario, Lucio; Pineda, Marta; Navarro, Matilde; Morak, Monika; Frayling, Ian M; Plazzer, John-Paul; Sampson, Julian R; Capella, Gabriel; Möslein, Gabriela; Mecklin, Jukka-Pekka; Møller, Pål

2017-01-01

We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1 ) despite follow-up with colonoscopy including polypectomy. The cohort included Finnish carriers enrolled in 3-yearly colonoscopy ( n  = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently ( n  = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively ( p  > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending

Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases.

Science.gov (United States)

Springuel, Lorraine; Losdyck, Elisabeth; Saussoy, Pascale; Turcq, Béatrice; Mahon, François-Xavier; Knoops, Laurent; Renauld, Jean-Christophe

2016-12-01

Genomic instability drives cancer progression by promoting genetic abnormalities that allow for the multi-step clonal selection of cells with growth advantages. We previously reported that the IL-9-dependent TS1 cell line sequentially acquired activating substitutions in JAK1 and JAK3 upon successive selections for growth factor independent and JAK inhibitor-resistant cells, suggestive of a defect in mutation avoidance mechanisms. In the first part of this paper, we discovered that the gene encoding mutL homolog-1 (MLH1), a key component of the DNA mismatch repair system, is silenced by promoter methylation in TS1 cells. By means of stable ectopic expression and RNA interference methods, we showed that the high frequencies of growth factor-independent and inhibitor-resistant cells with activating JAK mutations can be attributed to the absence of MLH1 expression. In the second part of this paper, we confirm the clinical relevance of our findings by showing that chronic myeloid leukemia relapses upon ABL-targeted therapy correlated with a lower expression of MLH1 messenger RNA. Interestingly, the mutational profile observed in our TS1 model, characterized by a strong predominance of T:A>C:G transitions, was identical to the one described in the literature for primitive cells derived from chronic myeloid leukemia patients. Taken together, our observations demonstrate for the first time a causal relationship between MLH1-deficiency and incidence of oncogenic point mutations in tyrosine kinases driving cell transformation and acquired resistance to kinase-targeted cancer therapies.

The new frontier of public health education.

Science.gov (United States)

Birnbaum, David; Gretsinger, Kathryn; Ellis, Ursula

2017-02-06

Purpose The aim of this paper is to describe the experience and educational benefits of a course that has several unique educational design features. Design/methodology/approach This includes narrative description of faculty and student experience from participants in a flipped-instructional-design inter-professional education course. Findings "Improving Public Health - An Interprofessional Approach to Designing and Implementing Effective Interventions" is an undergraduate public health course open to students regardless of background. Its student activities mirror the real-life tasks and challenges of working in a public health agency, including team-building and leadership; problem and project definition and prioritization; evidence-finding and critical appraisal; written and oral presentation; and press interviews. Students successfully developed project proposals to address real problems in a wide range of communities and settings and refined those proposals through interaction with professionals from population and public health, journalism and library sciences. Practical implications Undergraduate public health education is a relatively new endeavor, and experience with this new approach may be of value to other educators. Originality/value Students in this course, journalism graduate students who conducted mock interviews with them and instructors who oversaw the course all describe unique aspects and related personal benefit from this novel approach.

Contemporary Education for Public Administration

Directory of Open Access Journals (Sweden)

Ivan Koprić

2007-01-01

Full Text Available The paper examines the development of contemporary administrative education, as a crucial criterion without which it is not possible to achieve professionalism in public administration. While the term professionalism has a variety of meanings, today it is largely deemed that specific educational preparation is a foundation without which other elements of professionalism in public administration cannot be achieved. The level of professionalism, competence, education and knowledge thus become critical variables of administration reforms in transitional countries. Afterwards, the author examines the trends in the development of contemporary administrative education, pointing particularly to the importance of establishing a coherent, vertically passable system, i.e. a system which encompasses all levels of education – from secondary school education to doctoral studies. In this matter, one of the most important features in the development of administrative studies is their diversification, with simultaneous strengthening of the general administrative profile. Thus, the general administrative profile becomes modified, updated and extended by new teaching disciplines. In the final section of the paper, the author addresses the performance of administrative education in Croatia, pointing to its underdevelopment. Indeed, the author suggests that there are no sustainable results of reforms without the training of staff for administration.

LSST: Education and Public Outreach

Science.gov (United States)

Bauer, Amanda; Herrold, Ardis; LSST Education and Public Outreach Team

2018-01-01

The Large Synoptic Survey Telescope (LSST) will conduct a 10-year wide, fast, and deep survey of the night sky starting in 2022. LSST Education and Public Outreach (EPO) will enable public access to a subset of LSST data so anyone can explore the universe and be part of the discovery process. LSST EPO aims to facilitate a pathway from entry-level exploration of astronomical imagery to more sophisticated interaction with LSST data using tools similar to what professional astronomers use. To deliver data to the public, LSST EPO is creating an online Portal to serve as the main hub to EPO activities. The Portal will host an interactive Skyviewer, access to LSST data for educators and the public through online Jupyter notebooks, original multimedia for informal science centers and planetariums, and feature citizen science projects that use LSST data. LSST EPO will engage with the Chilean community through Spanish-language components of the Portal and will partner with organizations serving underrepresented groups in STEM.

Selling School: The Marketing of Public Education

Science.gov (United States)

DiMartino, Catherine; Jessen, Sarah Butler

2018-01-01

This timely book outlines the growth and development of marketing and branding practices in public education. The authors highlight why these practices have become important across key fields within public education, including leadership and governance, budgeting and finance, strategic initiatives, use of new technology, the role of teachers in…

Doubts about Religious Education in Public Schooling

Science.gov (United States)

Moulin, Daniel

2015-01-01

This article considers potential problems concerning Religious Education in public (state-funded) secondary schools in England in order to inform ongoing debates about religion in public education in the United States and elsewhere. Findings of empirical studies conducted in England are discussed in relation to arguments that critique Religious…

Public Education and Growth in Developing Countries

DEFF Research Database (Denmark)

Schuppert, Christiane; Wirz, Nadja

Human capital plays a key role in fostering technology adoption, the major source of economic growth in developing countries. Consequently, enhancing the level of human capital should be a matter of public concern. The present paper studies public education incentives in an environment in which...... governments can invest in human capital to facilitate the adoption of new technologies invented abroad or, instead, focus on consumptive public spending. Although human capital is pivotal for growth, the model reveals that incentives to invest in public education vanish if a country is poorly endowed...

Future directions for Public Health Education reforms in India

Directory of Open Access Journals (Sweden)

Sanjay P Zodpey

2014-09-01

Full Text Available Health systems globally are experiencing a shortage of competent public health professionals. Public health education across developing countries is stretched by capacity generation and maintaining an adequate ‘standard’ and ‘quality’ of their graduate product. We analyzed the Indian public health education scenario using the institutional and instructional reforms framework advanced by the Lancet Commission report on Education of Health Professionals. The emergence of a new century necessitates a re-visit on the institutional and instructional challenges surrounding public health education. Currently, there is neither an accreditation council nor a formal structure or system of collaboration between academic stakeholders. Health systems have little say in health professional training with limited dialogue between health systems and public health education institutions. Despite a recognized shortfall of public health professionals, there are limited job opportunities for public health graduates within the health system and absence of a structured career pathway for them. Public health institutions need to evolve strategies to prevent faculty attrition. A structured development program in teaching-learning methods and pedagogy is the need of the hour.

Reframing the Public in Public Education: The Landless Workers Movement (MST) and Adult Education in Brazil

Science.gov (United States)

Thapliyal, Nisha

2013-01-01

Education for rural Brazilians has historically been dominated by two imperatives: human capital and political patronage. For the last four decades, the Landless Workers Movement (MST) have maintained a struggle to democratise public education and democracy itself. In this article, I make a situated analysis of the educational politics of the MST…

Education Improves Public Health and Promotes Health Equity.

Science.gov (United States)

Hahn, Robert A; Truman, Benedict I

2015-01-01

This article describes a framework and empirical evidence to support the argument that educational programs and policies are crucial public health interventions. Concepts of education and health are developed and linked, and we review a wide range of empirical studies to clarify pathways of linkage and explore implications. Basic educational expertise and skills, including fundamental knowledge, reasoning ability, emotional self-regulation, and interactional abilities, are critical components of health. Moreover, education is a fundamental social determinant of health - an upstream cause of health. Programs that close gaps in educational outcomes between low-income or racial and ethnic minority populations and higher-income or majority populations are needed to promote health equity. Public health policy makers, health practitioners and educators, and departments of health and education can collaborate to implement educational programs and policies for which systematic evidence indicates clear public health benefits. © The Author(s) 2015.

Innovation in NASA's Astrophysics Education and Public Outreach

Science.gov (United States)

Hasan, H.; Smith, D.

2014-07-01

New technology and media are being rapidly incorporated in NASA's Astrophysics Education and Public Outreach (EPO) portfolio. In addition to web pages that provide basic information on missions and links to educational sites, missions have developed Facebook and Twitter followers. Recent highlights are presented about the innovative techniques used in presenting NASA science to the public, educators and students, together with representative examples. The immense treasure trove of electronic NASA EPO material is available to the public.

On the Eroding Foundations of Teacher Education.

Science.gov (United States)

Sirotnik, Kenneth A.

1990-01-01

When 128 students were queried regarding the values, beliefs, or moral imperatives underlying their teacher education program, most were speechless at first. Students either indicated their unawareness of any underlying philosophy or responded in generalities akin to moral relativism. Includes 19 references. (MLH)

Thesis by Publication in Education: An Autoethnographic Perspective for Educational Researchers

Science.gov (United States)

Merga, Margaret K.

2015-01-01

Despite its growing popularity, the thesis by publication is a less conventional format for doctoral dissertations in the field of education. The author successfully undertook a thesis by publication in education from 2012, to submission in 2014. This paper draws on both the literature in the field and the experiences of the author through an…

2015 Fact Book: Arkansas Public Higher Education

Science.gov (United States)

Arkansas Department of Higher Education, 2015

2015-01-01

This publication provides governmental and higher education decision-makers a statewide perspective of Arkansas public higher education finance for the 2015-17 biennium, as well as trends for the past several years. It also contains a detailed financial profile of each institution and presents a basis for comparative assessments of revenue sources…

Promoter hypermethylation of DNA repair genes MLH1 and MSH2 in adenocarcinomas and squamous cell carcinomas of the lung

Directory of Open Access Journals (Sweden)

A. Gomes

2014-01-01

Full Text Available Five years survival of lung cancer is 16%, significantly lower than in prostate (99.9%, breast (88.5% and colon (64.1% carcinomas. When diagnosed in the surgical stage it increases to 50% but this group only comprises 14–16% of the cases. DNA methylation has emerged as a potential cancer-specific biomarker. Hypermethylation of CpG islands located in the promoter regions of tumour suppressor genes is now firmly established as an important mechanism for gene inactivation.This retrospective study included 40 squamous cell carcinomas and 40 adenocarcinomas in various surgical TNM stages to define methylation profile and possible silencing of DNA repair genes – MLH1 and MSH2 – using Methylation-Specific PCR and protein expression by immunohistochemistry in tumoural tissue, preneoplastic lesions and respiratory epithelium with normal histological features.The protein expression of MLH1 and MSH2 genes, in the available preneoplastic lesions and in normal cylindrical respiratory epithelium appeared reduced. The frequency of promoter hypermethylation found on these DNA repair genes was elevated, with a higher prevalence of methylation of MLH1 gene in 72% of squamous cell carcinoma. The differences are not so obvious for MSH2 promoter hypermethylation. No correlation was found among the status of methylation, the protein expression and the clinicopathological characteristics.With a larger study, a better characterization of the hypermethylation status of neoplastic and preneoplastic lesions in small biopsies would be achieved, inherent to tumour histology, heterogeneity and preservation, and finally differences in the study population to elucidate other possible mechanisms of altered expression of the hMLH1 and hMSH. Resumo: A sobrevivência aos cinco anos no cancro do pulmão é de 16%, significativamente inferior que nos carcinomas na próstata (99,9%, mama (88,5% e cólon (64,1%. Quando diagnosticado na fase cir

Meeting the needs of tomorrow's public service: Guidelines for professional education in public administration

Science.gov (United States)

Chapman, R. L.; Cleaveland, F. N.

1973-01-01

The educational programs for public administration were studied to develop guidelines for meeting the requirements of public service in the 1980's. The current state of education for public service is discussed along with a prospective view of the service over the next decade. Criteria for evaluating graduate programs are presented.

Public Telecommunications Policies and Education's Options.

Science.gov (United States)

Norwood, Frank W.

The use of satellite telecommunications for educational and other public service purposes has been restricted by educators' lack of awareness of the potential that exists. While industry actively promotes its own interests, educators rarely even realize that international policies being made today will affect critically the options available for…

Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome

Czech Academy of Sciences Publication Activity Database

Švec, Jiří; Schwarzová, L.; Janošíková, B.; Štekrová, J.; Mandys, V.; Kment, M.; Vodička, Pavel

2014-01-01

Roč. 7, č. 8 (2014), s. 5196-5202 ISSN 1936-2625 Grant - others:GA MŠk(CZ) Prvouk-P27/LF1/1; Univerzita Karlova(CZ) CZ.2.16/3.1.00/24024 Institutional support: RVO:68378041 Keywords : germline mutation * gastric cancer * MLH1 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.891, year: 2014

Public education and risk management

OpenAIRE

Tabachnick, J.; McCartan, K. F.

2017-01-01

This chapter will highlight research and practice internationally on ways to educate the public regarding sex abuse and how successful they have been. The chapter will cover issues including the relationship between experts and the public, public criminology, media narratives as well as engagement and political positions, and debates, on this topic. The chapter will highlight ways in which society has tried to engage on the topic of sexual harm (including, bystander intervention, government p...

Public and Private Schooling in France: An Investigation into Family Choice.

Science.gov (United States)

Langouet, Gabriel; Leger, Alain

2000-01-01

During the 1980s, 35 percent of French pupils attended private schools at some point. The private sector (largely state-supported Catholic schools) offered a second chance that was not seized equally. Research shows public-sector recruitment was more democratic; private schools equalized results more successfully. (Contains 12 references.) (MLH)

Public education and participation

International Nuclear Information System (INIS)

Kelly, J.E.

1982-01-01

As prescribed in Step 1 of the Public Education and Participation Process (attachment 1), industry, public interest groups, and decision-makers were briefed about the Subseabed Disposal Program. In regard to public interest groups, Drs. Hollister and Kelly were invited to present the technical and policy aspects of the Subseabed Program at a public forum in Hawaii sponsored by the Hawaii League of Women Voters, the Health Physics Society, and the East-West Center. The sponsors videotaped the forum for a film, entitled Slowly Dying Embers: Radioactive Waste and the Pacific, which will be shown on television in Hawaii. In response to requests for information about the Subseabed Program, Congressional Staff, Representatives, and Senators (attachment 2) were briefed about the Subseabed Program as legislation related to the Program moved through Congress (attachment 3). Science oriented publications also were contacted about the Program

Training Informal Educators Provides Leverage for Space Science Education and Public Outreach

Science.gov (United States)

Allen, J. S.; Tobola, K. W.; Betrue, R.

2004-01-01

How do we reach the public with the exciting story of Solar System Exploration? How do we encourage girls to think about careers in science, math, engineering and technology? Why should NASA scientists make an effort to reach the public and informal education settings to tell the Solar System Exploration story? These are questions that the Solar System Exploration Forum, a part of the NASA Office of Space Science Education (SSE) and Public Outreach network, has tackled over the past few years. The SSE Forum is a group of education teams and scientists who work to share the excitement of solar system exploration with colleagues, formal educators, and informal educators like museums and youth groups. One major area of the SSE Forum outreach supports the training of Girl Scouts of the USA (GS) leaders and trainers in a suite of activities that reflect NASA missions and science research. Youth groups like Girl Scouts structure their activities as informal education.

Educational Democracy in Graduate Education: Public Policies and Affirmative Action

Science.gov (United States)

Vasconcelos Medeiros, Hugo Augusto; Mello Neto, Ruy de Deus e; Mendes Catani, Afrânio

2017-01-01

This paper is a discussion on the possibilities of educational democracy in Brazilian Graduate Education, with a focus on the current Graduate Education Field regulations and the recent affirmative actions and public policies of access. We analyzed laws, decrees, government plans and selections edicts, through categories derived from historical…

Educating the public: Where do we begin?

International Nuclear Information System (INIS)

Sevel, F.

1997-01-01

Despite the extensive regulatory concurrence regarding the need to educate the public in changing utility markets, the task of doing so remains one of the most salient and challenging tasks facing regulators. As they transition from an environment earmarked by ratebase rate-of-return regulation to the new more-competitive environment, regulators ponder the degree to which the public understands the new competitive environment, the impacts of this environment on their utility service and fees, and the roles, responsibilities, and the mission of the public utilities commission in context of the new regulatory environment. In an effort to mitigate potential fears, confusions, and withdrawal of public support, public utility commissions have begun the monumental task of educating the public and, in the process, repositioning the public utility commission in the eyes of the myriad of consumer, media, governmental, industry, and special interest groups often referred to as the public

The Impact of Consumer Credentialism on Employee and Entrepreneur Returns to Higher Education.

Science.gov (United States)

Tucker, Irvin B., III

1987-01-01

Examines the relative importance of education credentials in consumer perceptions of self-employed business people. Using 1980 national cross-sectional data on goods- and service-producing occupations, the regression analysis shows that highly educated entrepreneurs are not influenced by consumer credentialism. Includes 17 references. (MLH)

Educational power of public libraries

Directory of Open Access Journals (Sweden)

Silva Novljan

2004-01-01

Full Text Available Education services also define the activities of Slovene public libraries. In planning targeted services they are often faced with development lagging. The accelerated progress in this field also reminds them of their lagging and points to a very uneven development and quality level of library activities in the various environments they are centered in. Perhaps due to such conditions public libraries do not excell in developing activities to satisfy education needs of their users. Even so, some successful cases point to the fact that libraries know how to act and could be successful under suitable conditions. The article presents an overview on how the law-defined needs for liferlong education (learning, education of users and information literacy, are meet through aquisition policies and through the realisation of different events taking into account the various levels of literacy of the participating population. The analysis of available reports and data point to the fact that libraries could be more successful if supported by increased expert help backed by financial aid.

The Student Equity Effects of the Public School Finance System in Louisiana.

Science.gov (United States)

Geske, Terry G.; LaCost, Barbara Y.

1990-01-01

Investigates the student equity effects of Louisiana's public school finance program in terms of fiscal neutrality and revenue inequality over a nine-year period, using regression techniques. Overall, Louisiana's system became less equal over the time period examined, while revenue distribution became more equal. Includes 35 references. (MLH)

Public opinion, information and education

International Nuclear Information System (INIS)

De La Poza Galiano, A.

1994-01-01

The molding of public opinion by media, concerning nuclear energy, is analyzed, and the assumptions such as: nuclear plants equal atomic bombs or 'nuclear plants, no thanks', are emphasized. A response to this media hammering in Spain has been developed through teachers' education seminars organized by the Spanish Atomic forum and the Book on Energy, edited by specialized educators

Evaluating Public Higher Education in Mexico

Science.gov (United States)

Varela-Petito, Gonzalo

2011-01-01

In an effort to ensure accountability, and in order to prepare students for a globalised world, the higher education sector in Mexico is seeking to implement an evaluation of public higher education. Higher education institutions (HEIs) need to balance this goal against the need to protect their autonomy. This would be preserved if each…

A Disciplinary Perspective: The Internationalization of Australian Public Relations Education

Science.gov (United States)

Fitch, Kate

2013-01-01

This article investigates the internationalization of public relations education, by examining public relations education in Australia, its relation with the public relations industry, and its growth in response to international student- and market-led demand. The discussion highlights the tensions within what is essentially an education project…

Properties of publications on anatomy in medical education literature.

Science.gov (United States)

Vorstenbosch, Marc; Bolhuis, Sanneke; van Kuppeveld, Sascha; Kooloos, Jan; Laan, Roland

2011-01-01

Publications on anatomy in medical education appear to be largely anecdotal. To explore this, we investigated the literature on anatomy in medical education, aiming first to evaluate the contribution of the literature on anatomy in medical education to "best evidence medical education" (BEME) and second to evaluate the development of this literature toward more "best evidence" between 1985 and 2009. Four databases were searched for publications on anatomy in medical education published between 1985 and 2009, resulting in 525 references. Hundred publications were characterized by five variables (journal category, paper subject, paper category, author perspective, and paper perspective). Statements from these publications were characterized by two variables (category and foundation). The publications contained 797 statements that involved the words "anatomy," "anatomical," or "anatomist." Forty-five percent of the publications contained no explicit research question. Forty percent of the statements made were about "teaching methods" and 17% about "teaching content," 8% referred to "practical value," and 10% to "side effects" of anatomy education. Ten percent of the statements were "positional," five percent "traditional," four percent "self-evident," and two percent referred to "quality of care." Fifty-six percent of the statements had no foundation, 17% were founded on empirical data, and 27% by references. These results substantiated the critical comments about the anecdotal nature of the literature. However, it is encouraging to see that between 1985 and 2009 the number of publications is rising that these publications increasingly focus on teaching methods and that an academic writing style is developing. This suggests a growing body of empirical literature about anatomy education. Copyright © 2011 American Association of Anatomists.

Teaching with Social Media: Disrupting Present Day Public Education

Science.gov (United States)

Meabon Bartow, Susan

2014-01-01

Because social technologies present illuminating educational, ethical, economic, and structural challenges to existing constructions of public education, they catalyze a fundamental examination of what public education should look like and be like in a democracy. Given their performances in other arenas, mobile and electronic technologies have the…

PUBLIC AND PRIVATE HIGHER EDUCATION INSTITUTIONS IN MALAYSIA: COMPETING, COMPLEMENTARY OR CROSSBREEDS AS EDUCATION PROVIDERS

OpenAIRE

Wan Chang Da

2007-01-01

Delivery of higher education used to be exclusive to the public sector in Malaysia. However, legislative changes made in 1996 led to the coexistence of public and private higher education institutions. In 2007, there were 20 public universities compared to more than 500 private institutions, of which 30 are currently categorised as universities or university colleges. Looking at their respective roles as higher education providers, public and private institutions display characteristics of be...

Computer-Based Simulation Games in Public Administration Education

OpenAIRE

Kutergina Evgeniia

2017-01-01

Computer simulation, an active learning technique, is now one of the advanced pedagogical technologies. Th e use of simulation games in the educational process allows students to gain a firsthand understanding of the processes of real life. Public- administration, public-policy and political-science courses increasingly adopt simulation games in universities worldwide. Besides person-to-person simulation games, there are computer-based simulations in public-administration education. Currently...

34 CFR 300.17 - Free appropriate public education.

Science.gov (United States)

2010-07-01

... 34 Education 2 2010-07-01 2010-07-01 false Free appropriate public education. 300.17 Section 300.17 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION OF...

Applying Constructivism to Improve Public Relations for Education

Science.gov (United States)

Marek, Michael

2005-01-01

Educators are often hesitant to use techniques of public relations and marketing communication to attempt to alter undesirable understandings of the rationale and processes of education held by external constituencies. This paper shows that contemporary practice in public relations and marketing communication can be conceptualized as an…

Public health leadership education in North America

OpenAIRE

Uno, Hideo; Zakariasen,Kenneth

2010-01-01

Hideo Uno, Kenneth ZakariasenDepartment of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, AB, CanadaAbstract: Public health leadership is one of the priority disciplines public health professionals need to learn well if they are to deal with demanding public health issues effectively and efficiently. This article looks at the trends in public health leadership education by reviewing the literature and using the Internet to explore the public health leadershi...

Transforming Public Education: Cases in Education Entrepreneurship. Instructor's Guide

Science.gov (United States)

Childress, Stacey M., Ed.

2010-01-01

This instructor's guide is intended for use with "Transforming Public Education: Cases in Education Entrepreneurship." This volume includes a teaching note for each case in the student edition; the note provides basic guidance in how to initaite and organize the flow of the case discussion as well as how the case links to others before…

Situating Preparedness Education within Public Pedagogy

Science.gov (United States)

Kitagawa, Kaori

2017-01-01

Both "disaster preparedness" and "public pedagogy" have been broadly defined and diversely utilised. Preparedness has been dealt with in disciplines such as civil engineering, the sociology of disasters, public health and psychology, rather than education. Recently, inquiries into the learning and teaching of preparedness have…

Improving Publication: Advice for Busy Higher Education Academics

Science.gov (United States)

Gibbs, Anita

2016-01-01

A major challenge for higher education academics is to research and publish when faced with substantial teaching responsibilities, higher student numbers, and higher output expectations. The focus of this piece is to encourage publication more generally by educators, and to build publication capacity, which academic developers can facilitate. The…

Comparing Administrative Satisfaction in Public and Private Higher Education.

Science.gov (United States)

Volkwein, James Fredericks; Parmley, Kelli

This study examined job satisfaction among administrators in public and private higher education. Data on nearly 1,200 administrators, ranging from directors to presidents, was obtained through surveys of 120 public and private universities. It was found that both public and private higher education administrators were most satisfied with the…

Public education for energy policy decisions

International Nuclear Information System (INIS)

Frigren, S.

1977-01-01

A brief review is given of the changes that took place in 1972-1973 in public opinion and political views in Sweden, leading to new attitudes and increasing interest in matters of energy policy. Although nuclear power was from the beginning the main issue, it became more and more widely recognized that a number of complex and technically difficult problems were involved. In late 1973, the Government decided to prepare a comprehensive energy policy programmme for the period 1975-1985 and to put this programme before Parliament in the spring of 1975. In order to involve the public in the decision-making process, a public education programme was introduced in January 1974. The essentials of this programme are described. The main effort was provided by the adult education associations, which were given financial incentives to start energy study circles and prepared their own study material. Journalist seminars were also arranged. The paper outlines the links between the educational efforts, the discussions in the study circles, and the standpoints ultimately taken by the different political parties on the energy issues. (author)

SAYNPS Participation in Nuclear Public Education in South Africa

Energy Technology Data Exchange (ETDEWEB)

Thugwane, S.J. [South African Young Nuclear Professionals Society, P.O. Box 582 Pretoria 0001 (South Africa); Khathi, N.F.; Rasweswe, M.A. [South African Young Nuclear Professionals Society, P.O. Box 582 Pretoria 0001 (South Africa); South African Nuclear Energy Corporation, P.O. Box 582 Pretoria 0001 (South Africa)

2008-07-01

The South African Young Nuclear Professionals Society (SAYNPS) has an objective to help inform and educate the public about the importance and benefits of nuclear science and technology. In South Africa, the government hosts annual national science campaigns to promote science and technology. These include the National Science Week, Science Olympiads and Energy week. SAYNPS encourages its members to participate in these campaigns through exhibitions and schools outreach programmes. Through these campaigns, schoolteachers and learners are educated about the benefits of safe usage of nuclear technology and about different careers in the nuclear industry. Through participation in the different campaigns it was acknowledged that participation of young professionals in public education will help preserve nuclear knowledge in the country. It was concluded that public education is still a task that needs to be intensified in order for the public to know the benefits of safe usage of nuclear technology. Scope: This paper presents the role that SAYNPS has played in nuclear public education in South Africa in 2006 and 2007. (authors)

SAYNPS Participation in Nuclear Public Education in South Africa

International Nuclear Information System (INIS)

Thugwane, S.J.; Khathi, N.F.; Rasweswe, M.A.

2008-01-01

The South African Young Nuclear Professionals Society (SAYNPS) has an objective to help inform and educate the public about the importance and benefits of nuclear science and technology. In South Africa, the government hosts annual national science campaigns to promote science and technology. These include the National Science Week, Science Olympiads and Energy week. SAYNPS encourages its members to participate in these campaigns through exhibitions and schools outreach programmes. Through these campaigns, schoolteachers and learners are educated about the benefits of safe usage of nuclear technology and about different careers in the nuclear industry. Through participation in the different campaigns it was acknowledged that participation of young professionals in public education will help preserve nuclear knowledge in the country. It was concluded that public education is still a task that needs to be intensified in order for the public to know the benefits of safe usage of nuclear technology. Scope: This paper presents the role that SAYNPS has played in nuclear public education in South Africa in 2006 and 2007. (authors)

The Promise of Mobile Technology for Public Religious Education

Science.gov (United States)

Daily, Eileen M.

2013-01-01

This article reviews the history of public religious education in the United States with an eye to its learning outcomes, contexts, and approaches. That history suggests that public religious education is still needed today but that informal learning contexts may be more appropriate than public schools. Recent trends in learning habits are then…

Public education through safety culture demonstration

International Nuclear Information System (INIS)

Wanitsuksombut, Warapon

2005-01-01

The activities relating to nuclear energy have been world widely opposed against, because there have existed scars in the past; atomic bombs and a few accidents in nuclear facilities. It cannot be denied that the most effective education of public is through Medias such as news or documentary on newspaper and television. Once such cases appeared to public, it is difficult to erase the bad pictures from their memory. Since education for public is mainly depending on media, it is recommended putting harder effort on dissemination of information on regulation and regulatory function to public. The regulatory function of each country is the key of safe utilization of nuclear energy. Since prime responsibility of maintenance and operation are rested on the operators. To achieve the goal of safety, regulatory authority's task now is emphasized on encouraging operators of nuclear facilities to implement their safety culture. This will reduce the probability of unwanted events and therefore raising credit of nuclear energy. (author)

Education for public health in Europe and its global outreach

Science.gov (United States)

Bjegovic-Mikanovic, Vesna; Jovic-Vranes, Aleksandra; Czabanowska, Katarzyna; Otok, Robert

2014-01-01

Introduction At the present time, higher education institutions dealing with education for public health in Europe and beyond are faced with a complex and comprehensive task of responding to global health challenges. Review Literature reviews in public health and global health and exploration of internet presentations of regional and global organisations dealing with education for public health were the main methods employed in the work presented in this paper. Higher academic institutions are searching for appropriate strategies in competences-based education, which will increase the global attractiveness of their academic programmes and courses for continuous professional development. Academic professionals are taking advantage of blended learning and new web technologies. In Europe and beyond they are opening up debates about the scope of public health and global health. Nevertheless, global health is bringing revitalisation of public health education, which is recognised as one of the core components by many other academic institutions involved in global health work. More than ever, higher academic institutions for public health are recognising the importance of institutional partnerships with various organisations and efficient modes of cooperation in regional and global networks. Networking in a global setting is bringing new opportunities, but also opening debates about global harmonisation of competence-based education to achieve functional knowledge, increase mobility of public health professionals, better employability and affordable performance. Conclusions As public health opportunities and threats are increasingly global, higher education institutions in Europe and in other regions have to look beyond national boundaries and participate in networks for education, research and practice. PMID:24560263

Public education for energy policy decisions

International Nuclear Information System (INIS)

Frigren, S.

1977-01-01

A brief review is given of the changes that took place in 1972-73 in public opinion and political views in Sweden, leading to new attitudes and increasing interest in matters is of energy policy. Although nuclear power was from the beginning the main issue, it became more and more widely recognized that a number of complex and technically difficult problems were involved. In late 1973 the Government decided to prepare a comprehensive energy policy programme for the period 1975-85 and to put this programme before Parliament in the spring of 1975. In order to involve the public in the decision making process, a public education programme was introduced in January 1974. The essentials of this programme are described. The main effort was provided by the adult education associations. These were given financial incentives to start energy study circles and prepared their own study material. Journalist seminars were also arranged. The paper then describes how the public, by its activities in the energy study circles, was given a possibility to influence the formulation of the new Swedish energy policy. It outlines the links between the educational efforts, the discussions in the study circles, and the standpoints ultimately taken by the different political parties on the key energy issues, especially as regards the future role of nuclear power. Finally, it also tries to evaluate to what extent this effort in education and involvement can be expected to react on the implementation of the energy policy programme and on future energy policy decisions

A Study of Public Radio Stations' Educational Services, 1978-79.

Science.gov (United States)

Corporation for Public Broadcasting, Washington, DC.

This second national survey of public radio stations' involvement in educational services to schools, colleges, and universities was conducted by the Corporation for Public Broadcasting (CPB) for use by individual public radio stations, educational agencies, and other organizations interested and involved in planning public radio's services to…

Users education in the virtual public library. Resources and procedures in the Spanish public libraries

Directory of Open Access Journals (Sweden)

Francisco Javier García Gómez

2004-01-01

Full Text Available Some Spanish public libraries have sites Web in a new digital work environment. These libraries are already delivered some services in their virtual branches. We are interesting to analyze user education in their sites Web. We are reviewed and tested some digital resources and services for user education in public libraries at World Wide Web. Level developing obtained in this library work is shown in conclusions. Likewise, we contributed some references about public library web sites design focused in user education and library instruction

Private vs. Public Higher Education Budgeting

Science.gov (United States)

Beamer, Sarah A.

2011-01-01

Private higher education institutions are those entities owned and operated by the private sector, while public institutions are those established, supported, and controlled by a governmental agency, most often a state. Key differences exist between private and public institutions that affect budgeting in critical ways. Such differences include…

Moche CAPE Formula: Cost Analysis of Public Education.

Science.gov (United States)

Moche, Joanne Spiers

The Moche Cost Analysis of Public Education (CAPE) formula was developed to identify total and per pupil costs of regular elementary education, regular secondary education, elementary special education, and secondary special education. Costs are analyzed across five components: (1) comprehensive costs (including transportation and supplemental…

7 CFR 295.3 - Informational and educational publications.

Science.gov (United States)

2010-01-01

... PUBLIC § 295.3 Informational and educational publications. FNS publishes a wide variety of informational... how to obtain them, write the Director, Public Information Staff, Food and Nutrition Service, USDA...

Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients

DEFF Research Database (Denmark)

Petersen, Sanne M; Dandanell, Mette; Rasmussen, Lene J

2013-01-01

Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomi...

PUBLIC AND PRIVATE HIGHER EDUCATION INSTITUTIONS IN MALAYSIA: COMPETING, COMPLEMENTARY OR CROSSBREEDS AS EDUCATION PROVIDERS

Directory of Open Access Journals (Sweden)

Wan Chang Da

2007-01-01

Full Text Available Delivery of higher education used to be exclusive to the public sector in Malaysia. However, legislative changes made in 1996 led to the coexistence of public and private higher education institutions. In 2007, there were 20 public universities compared to more than 500 private institutions, of which 30 are currently categorised as universities or university colleges. Looking at their respective roles as higher education providers, public and private institutions display characteristics of being substitutes while at the same time serving complementary roles to one another. This dichotomy between public and private higher education institutions can, in fact, be seen as inclining towards a hybrid model that allows both to operate within a single system of higher education provision in the country. Such a hybrid model is evident in how the clientele is being divided between public and private higher institutions. It is also evident in the different roles played by the respective faculty members as well as in the programmes being made available in either type of institutions.

Importance of Public Communication Campaigns and Art Activities in Social Education

OpenAIRE

Bilgehan Gültekin; Tuba Gültekin

2012-01-01

Universities have an important role in social education in many aspects. In terms of creating awareness and convincing public about social issues, universities take a leading position for public. The best way to provide public support for social education is to develop public communication campaigns. The aim of this study is to present a public communication model which will be guided in social education practices. The study titled “Importance of public communication campaigns and art activit...

34 CFR 104.33 - Free appropriate public education.

Science.gov (United States)

2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Free appropriate public education. 104.33 Section 104.33 Education Regulations of the Offices of the Department of Education OFFICE FOR CIVIL RIGHTS, DEPARTMENT OF EDUCATION NONDISCRIMINATION ON THE BASIS OF HANDICAP IN PROGRAMS OR ACTIVITIES RECEIVING...

Who will keep the public healthy?: educating public health professionals for the 21st century

National Research Council Canada - National Science Library

Gebbie, Kristine M; Rosenstock, Linda; Hernandez, Lyla M

2003-01-01

...? Who Will Keep the Public Healthy? provides an overview of the past, present, and future of public health education, assessing its readiness to provide the training and education needed to prepare men and women to face 21st century challenges...

Public information and education in England

Energy Technology Data Exchange (ETDEWEB)

Ginniff, M E

1994-09-01

The paper discusses the importance of public information and education in the field of energy and particularly in the field of nuclear power development. The attempt is maid to explain some issues connected with the nuclear fuel cycle. Appendix contains comments on the United Kingdom educational materials in this area.

Public information and education in England

International Nuclear Information System (INIS)

Ginniff, M.E.

1993-01-01

The paper discusses the importance of public information and education in the field of energy and particularly in the field of nuclear power development. The attempt is made to explain some issues connected with the nuclear fuel cycle. Appendix contains comments on the United Kingdom educational materials in this area

Public information and education in England

International Nuclear Information System (INIS)

Ginniff, M.E.

1994-01-01

The paper discusses the importance of public information and education in the field of energy and particularly in the field of nuclear power development. The attempt is maid to explain some issues connected with the nuclear fuel cycle. Appendix contains comments on the United Kingdom educational materials in this area

Avaliação da expressão tecidual do gene de reparo MLH1 e dos níveis de dano oxidativo ao DNA em doentes com câncer colorretal Evaluation of expression of mismatch repair gene MLH1 and levels of oxidative DNA damage in normal and neoplastic tissues of patients with colorectal cancer

Directory of Open Access Journals (Sweden)

Carlos Augusto Real Martinez

2009-09-01

Full Text Available O dano oxidativo ao DNA provocado por radicais livres de oxigênio representa um dos principais mecanismos responsáveis pelas etapas iniciais da carcinogênese colorretal. O estresse oxidativo ocasiona erros de pareamento de bases possibilitando o aparecimento de mutações em genes controladores do ciclo celular. As células possuem um sistema de defesa representado pelos genes de reparo do DNA que corrigindo os erros de pareamento impedem o desenvolvimento de mutações. Poucos estudos avaliaram a relação entre dano oxidativo ao DNA e a expressão tecidual do gene de reparo MLH1. OBJETIVO: O objetivo do presente estudo foi avaliar os níveis de estresse oxidativo ao DNA e a expressão tecidual do gene de reparo MLH1 nas células da mucosa cólica normal e neoplásica de doentes com câncer colorretal. MATERIAL E MÉTODO: Foram estudados 44 doentes com diagnóstico de adenocarcinoma colorretal. Foram excluídos os doentes com câncer colorretal hereditário, portadores de câncer relacionado às doenças inflamatórias intestinais e os submetidos à radioquimioterapia neoadjuvante. Para a avaliação dos níveis de dano oxidativo ao DNA utilizou-se a técnica da eletroforese alcalina em gel de célula isolada (ensaio do cometa avaliando 100 células obtidas dos tecidos normal e neoplásico. Para a avaliação da expressão do gene MLH1 utilizou-se a técnica de reação de polimerase em cadeia em tempo real (RT-PCR com primer especificamente desenhados para amplificação do gene. A comparação dos resultados encontrados para os níveis de estresse oxidativo ao DNA, e expressão do gene MLH1 nos tecidos normais e neoplásicos foi feito pelo teste t de Student, adotando-se nível de significância de 5% (pThe oxidative DNA damage caused by oxygen free radicals is one of the most important mechanisms responsible for the initial steps of colorectal carcinogenesis. The oxidative stress can cause errors in the pairing of nitrogenous bases that

PUBLIC POLICIES OF RIGHT TO EDUCATION FOR ELDERLY PATIENTS

Directory of Open Access Journals (Sweden)

Hamilton de Oliveira Telles Júnior

2017-08-01

Full Text Available The people are living more. The population is going by great transformations, so much social as technological, that point to the need of specific education processes for senior people. The seniors tend to be separated socially, with damages for his/her health and, consequently, his/her life quality. This study, of qualitative approach, has as objective to describe the public politics for the senior's education interned in hospitals or institutions and to analyze the applicable Public Politics to the education based an express analysis model by Di Giovanni, where there are the actors of this public policy and its related interests. How possible middle for attainment of a program driven to the seniors' education is evidenced in the inclusion possibility in the hospital class and the possibility of the use of education programs for youths and adults, with the initiative of third sector, that in the extent of the education no formal he/she brings great transformations for society and education for the senior.

Mechanisms in the privatization process of public education

Directory of Open Access Journals (Sweden)

Cristina Díez Pampliega

2010-08-01

Full Text Available The situation in the district of Puente de Vallecas (Madrid, Spani can be taken as an example of the progressive development of private schools held by public funds at the expense of the public schools network. This situation is the result of different mechanisms: first, the lost perception of education as a common good; second, the neglect of the right to free compulsory education in all schools supported by public funds; and third, the unfair distribution of students from economic and cultural disadvantaged backgrounds.

Public education and enforcement research study (PEERS).

Science.gov (United States)

2013-08-01

In 2001, the Federal Railroad Administration (FRA) and the Illinois Commerce Commission (ICC) established the Public Education and Enforcement Research Study (PEERS) to test the effectiveness of various education and enforcement (E&E) techniques to i...

Cost Efficiency in Public Higher Education.

Science.gov (United States)

Robst, John

This study used the frontier cost function framework to examine cost efficiency in public higher education. The frontier cost function estimates the minimum predicted cost for producing a given amount of output. Data from the annual Almanac issues of the "Chronicle of Higher Education" were used to calculate state level enrollments at two-year and…

Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer

NARCIS (Netherlands)

Vogel, S. de; Bongaerts, B.W.C.; Wouters, K.A.D.; Kester, A.D.M.; Schouten, L.J.; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Engeland, M. van; Weijenberg, M.P.

2008-01-01

Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related

Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

NARCIS (Netherlands)

Weijenberg, M.P.; Luchtenborg, M.; Goeij, A.F. de; Brink, M.; Muijen, G.N.P. van; Bruine, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

2007-01-01

OBJECTIVE: To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat

Promoting a Positive Image: Public Relations Strategies for Special Educators.

Science.gov (United States)

Brennan, Kathleen B.; Miller, April D.; Brennan, J. Patrick, II

2000-01-01

A positive public relations campaign specific to special education can stimulate teacher cooperation and principal support, improve community perceptions of special education students, and increase hiring of special education students by local businesses. A monthly calendar of suggested activities and guidelines for starting a public relations…

Marketing strategies in higher education with specific reference to public and private educational institutions within Gauteng, South Africa

OpenAIRE

2012-01-01

M.B.A. The researcher proposes that there are similarities as well as differences between the private and public institutions. Is it true that the results regarding achievements and quality are better with private education institutions than with public institutions, with much more difficulties facing private education than public education? What are the fundamental differences and similarities between the private and public Higher Educational institutions that lead to their marketing stra...

The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance.

Science.gov (United States)

Varga, Elizabeth; Chao, Elizabeth C; Yeager, Nicholas D

2015-09-01

Next-generation sequencing (NGS) technology is increasingly utilized to identify therapeutic targets for patients with malignancy. This technology also has the capability to reveal the presence of constitutional genetic alterations, which may have significant implications for patients and their family members. Here we present the case of a 23 year old Caucasian patient with recurrent undifferentiated sarcoma who had NGS-based tumor analysis using an assay which simultaneously analyzed the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes often rearranged or altered in cancer. Pathogenic alterations were reported in tumor as the predicted protein alterations, BRCA2 "R645fs*15″ and MLH1 "E694*". Because constitutional BRCA2 and MLH1 gene mutations are associated with Hereditary Breast Ovarian Cancer Syndrome (HBOCS) and Lynch syndrome respectively, sequence analysis of DNA isolated from peripheral blood was performed. The presence of the alterations, BRCA2 c.1929delG and MLH1 c.2080G>T, corresponding to the previously reported predicted protein alterations, were confirmed by Sanger sequencing in the constitutional DNA. An additional DNA finding was reported in this analysis, MLH1 c.2081A>C at the neighboring nucleotide. Further evaluation of the family revealed that all alterations were paternally inherited and the two MLH1 substitutions were in cis, more appropriately referred to as MLH1 c.2080_2081delGAinsTC, which is classified as a variant of uncertain significance. This case illustrates important considerations related to appropriate interpretation of NGS tumor results and follow-up of patients with potentially deleterious constitutional alterations.

Innovating undergraduate pathology education through public engagement.

Science.gov (United States)

Mukundu Nagesh, Navin; Chiva Giurca, Bogdan; Lishman, Suzy

2018-05-01

The trends in modern undergraduate medical education focus on a patient-centred approach through problem-based learning over the traditional modular curriculum. Integrating pathology into this style of learning has resulted in the dilution of core scientific principles which may have contributed to reduced understanding and interest in the subject. We aim to innovate pathology education by utilising National Pathology Week which is organised by the Royal College of Pathologists to develop the public engagement model which empowers students to learn pathology by teaching the public. Through this model, we hope to generate a greater interest in pathology at both undergraduate and postgraduate stages of education. We obtained funding from the Royal College of Pathologists to organise National Pathology Week at Exeter Medical School and the Royal Devon & Exeter Hospital. We involved 125 undergraduate student volunteers from health-related courses. We designed a curriculum aiming to educate both students and public on current topics such as cancer screening programmes, antibiotic resistance, diagnosis of inflammatory bowel disease and the role of pathologists. We hosted 15 pathologists, biomedical scientists and microbiologists to engage with students, share experiences and offer an insight into their careers. Through this project, we interacted with over 500 members of the public and 150 school students. The medical student volunteers developed a range of skills including competent use of microscopes to visualise pathology slides, effective communication with lay audiences to teach pathology and understanding of the clinical application of pathology. We believe the public engagement model of teaching undergraduate students has the potential to develop a greater interest in pathology whilst benefitting the wider community.

The cost-effectiveness of public postsecondary education subsidies.

Science.gov (United States)

Muennig, P; Fahs, M

2001-02-01

Although educational attainment is a well-recognized covariate of health status, it is rarely thought of as a tool to be used to improve health. Since fewer than 40% of U.S. citizens have a college degree, it may be possible for the government to improve the health status of the population by assuming a larger burden of the cost of postsecondary education. This paper examines the costs and health effects of a government subsidy for public postsecondary education institutions. All high school graduates in 1997 were included in a decision analysis model as a hypothetical cohort. Data from the U.S. Department of Education, the World Health Organization, and the National Center for Health Statistics were used as model inputs. Results. Relative to the present educational system, a federal subsidy for public and private colleges equal to the amount now paid by students for tuition and living expenses would save $6,176 and avert 0.0018 of a disability-adjusted life-year (DALY) per person annually if enrollment increased 5%. The overall savings among 1997 high school graduates would be $17.1 billion and 4,992 DALYs would be averted per year relative to the present educational system. If enrollment increased by just 3%, $3,743 would be saved and 0.0011 DALYs would be averted per person. An enrollment increase of 7% would lead to savings of $8,610 and 0.0025 DALYs would be averted per person relative to the present educational system. If the government were to offer a full subsidy for college tuition at public universities, both lives and money would be saved, so long as enrollment levels increased. Providing a free postsecondary education for students attending public schools may be more cost-effective than most health investments. Copyright 2001 American Health Foundation and Academic Press.

Leadership Academies: Elixir for Common School Ills.

Science.gov (United States)

School Administrator, 1989

1989-01-01

Describes a model leadership academy program at Topeka (Kansas) Public Schools in cooperation with Kansas State University. Created in 1987, the academy was designed to serve the school system's unique needs while fostering innovative educational experiences for administrator preparation. Includes four references. (MLH)

Higher education status in public value orientation

Directory of Open Access Journals (Sweden)

Olehnovica E.

2012-10-01

Full Text Available In the article the interrelationships between the types of dominating values in the society and corresponding consequences for higher education aims and objectives. In the context of the mentioned interrelationships, there are given the examples of studies offered by the USA and Daugavpils University, as well as the access to value structuring and typology found in scientific literature. The surveyed study results render the public evaluation on the instrumental and terminal values of the higher education. Authors pay a special attention to systemic view or four quadrant matrix use in the analysis of value formation process. Semantic analysis of the concept “knowledge” and hermeneutic interpretation depict the direct connection of the education with individual and collective values. By determining the values dominating in the public, one can predict its expectations in the field of education and adapt it to the necessary changes.

Blurring the Boundaries of Public and Private Education in Brazil

Science.gov (United States)

Akkari, Abdeljalil

2013-01-01

A typical analysis of the privatization of education in Latin America focuses on private sector development at the expense of public education. In this paper, I propose a different view that will highlight the blurring of boundaries between public and private education in Brazil. This confusion perpetuates the historical duality of the education…

Growth or Stagnation? The Role of Public Education

OpenAIRE

Kenneth Beauchemin

1999-01-01

This paper presents a political-economic theory of growth and human capital accumulation. Age heterogeneity is put forth as the primary source of disagreement between individuals over various levels public education expenditures. An overlapping generations model with with two-period lived agents is constructed to capture the heterogeneity. With a growing population, the equilibrium quantity of public education reflects the preferences of youth and is therefore foward looking. As such, policy ...

Florida's Opinion on K-12 Public Education Spending

Science.gov (United States)

Forster, Greg

2006-01-01

This scientifically representative poll of 1,200 Floridians finds that public opinion about K-12 public education spending is seriously misinformed. Floridians think public schools need more money, but the main reason is that they are badly mistaken about how much money the public schools actually get. Key findings of the study include: (1) Half…

Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent MLH1 hypermethylation and MSH2 somatic mutations.

Science.gov (United States)

Wang, Tao; Stadler, Zsofia K; Zhang, Liying; Weiser, Martin R; Basturk, Olca; Hechtman, Jaclyn F; Vakiani, Efsevia; Saltz, Lenard B; Klimstra, David S; Shia, Jinru

2018-04-01

Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient's age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.

Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival.

Science.gov (United States)

Cosgrove, Casey M; Cohn, David E; Hampel, Heather; Frankel, Wendy L; Jones, Dan; McElroy, Joseph P; Suarez, Adrian A; Zhao, Weiqiang; Chen, Wei; Salani, Ritu; Copeland, Larry J; O'Malley, David M; Fowler, Jeffrey M; Yilmaz, Ahmet; Chassen, Alexis S; Pearlman, Rachel; Goodfellow, Paul J; Backes, Floor J

2017-09-01

To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort. Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed. 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm 3 compared to 3321mm 3 and 2,846mm 3 , for MMR proficient and probable MMR mutations respectively (PMLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS. Copyright © 2017 Elsevier Inc. All rights reserved.

Public and Constitutional Support for Character Education.

Science.gov (United States)

Vessels, Gordon G.; Boyd, Stephen M.

1996-01-01

Character education thrives on an informed understanding of constitutional principles and an inclusive commitment-building process. U.S. Supreme Court opinions that clarify public school students' free speech rights have established values education as a constitutionally acceptable practice. Challenges might lie in possible violations of the First…

Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer

International Nuclear Information System (INIS)

Vodusek, Ana Lina; Novakovic, Srdjan; Stegel, Vida; Jereb, Berta

2011-01-01

Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. Our patient developed secondary breast cancer after the treatment for Hodgkin’s disease in childhood. DNA was isolated from the patients’ blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer

The WTO and the Millennium Round: What Is at Stake for Public Education? Common Concerns for Workers in Education and the Public Sector.

Science.gov (United States)

Education International, Brussels (Belgium).

On the eve of the year 2000, global public spending on education tops one trillion dollars. Against the backdrop of globalization, public education is currently being subjected to attacks by proponents of privatization and deregulation. The process is already underway, as is apparent from an important agreement reached by the World Trade…

An Exploratory Look at Graduate Public Relations Education.

Science.gov (United States)

Aldoory, Linda; Toth, Elizabeth L.

2000-01-01

Conducts a content analysis of web pages to examine 26 United States Masters degree programs in public relations for their degree requirements, core courses, public relations courses, and optional courses. Finds a lack of adherence to the recommendations of the Foundation for Public Relations Research and Education. (NH)

Intercultural Interpretations: Making Public Relations Education Culturally Relevant

Science.gov (United States)

Chia, Joy

2009-01-01

Public relations educators delivering courses to international students find that each cohort of students interprets and understands public relations theory and its application to practice according to their respective cultures. The premise of this paper is to reflect on some of the interpretations and expectations of public relations students…

Enhancing the Impact of NASA Astrophysics Education and Public Outreach: Sharing Best Practices

Science.gov (United States)

Bartolone, Lindsay; Smith, D. A.; Astrophysics Science Education, NASA; Public Outreach Forum Team

2013-01-01

The NASA Science Education and Public Outreach Forums support the NASA Science Mission Directorate (SMD) and its education and public outreach community in enhancing the coherence, efficiency, and effectiveness of SMD-funded education and public outreach programs. As part of this effort, the four Forums (Astrophysics, Earth Science, Heliophysics, and Planetary Science) work together to coordinate resources and opportunities that enable sharing of best practices relevant to SMD-funded education and public outreach. Efforts include collaborating with SMD-funded education and public outreach programs to identify community needs for professional development; raising awareness of the existing body of best practices and educational research; and, organizing distance learning and face-to-face professional development opportunities. Topics include best practices in navigating NASA SMD education and public outreach program requirements, social media, engaging girls in science, and student misconceptions / reasoning difficulties. Opportunities to share best practices and learn from experts are extended to the broader astronomy and astrophysics community through the annual Astronomical Society of the Pacific education and public outreach conference. Evaluation of community professional development resources and opportunities is in progress.

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.

Science.gov (United States)

Berginc, Gasper; Bracko, Matej; Ravnik-Glavac, Metka; Glavac, Damjan

2009-01-01

Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.

Modernising Education: New Public Management Reform in the Norwegian Education System

Science.gov (United States)

Møller, Jorunn; Skedsmo, Guri

2013-01-01

Since the end of the 1980s, the Norwegian education system has gone through major reform, influenced largely by new managerialist ideas. Strategies to renew the public sector were promoted as the new public management (NPM). This paper investigates the way ideas connected to NPM reforms have been introduced and interpreted in the Norwegian…

Nuclear education in public health and nursing

International Nuclear Information System (INIS)

Winder, A.E.; Stanitis, M.A.

1988-01-01

Twenty-three public health schools and 492 university schools of nursing were surveyed to gather specific information on educational programs related to nuclear war. Twenty public health schools and 240 nursing schools responded. Nuclear war-related content was most likely to appear in disaster nursing and in environmental health courses. Three schools of public health report that they currently offer elective courses on nuclear war. Innovative curricula included political action projects for nuclear war prevention

From School Choice to Student Voice.

Science.gov (United States)

Heckman, Paul E.; Montera, Viki L.

2001-01-01

Educational mass marketing approaches are like fast-food franchises; they offer homogeneous, standardized products that cannot satisfy every consumer's needs. A niche market looks inside the masses to address more individual, specialized choices missing from the menu. Variability, not uniformity, should guide development of public schooling. (MLH)

IMMUNOHISTOCHEMICAL STUDY OF MSH2, MSH6, PMS2, MLH1 IN EVALUATION OF DIFFERENTIATION GRADE OF COLON ADENOCARCINOMA

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G. A. Raskin

2015-01-01

Full Text Available Microsatellite instability is associated with dysfunction of the MSH2, MLH1, PMS2 and MSH6 genes, which participate in the repair of unpaired nucleotides of DNA. It is known that microsatellite instability is an independent prognostic factor in determining the differentiation grade of colon cancer. The use of immunohistochemistry to study the repair system of unpaired nucleotides has its own characteristics and limitations. Materials and methods. The study included 39 patients with colon adenocarcinoma. Moderately-differentiated colon adenocarcinoma was the most common histological type (72 %. There were 8 % of well-differentiated and 12 % poorly-differentiated carcinomas. Immunohistochemical analysis of SH2, MSH6, PMS2 and MLH1 proteins was done according to the standard protocol. Results. Out of 39 cases, 6 (15 % had loss of expression of at least one of the studied proteins. Out of these 6 cases with indirect signs of MSI-H, 3 were poorlydifferentiated, 1 was mucinous and 2 were moderately differentiated adenocarcinomas. Conclusion. Thus, immunohistochemical analysis of DNA repair genes can be used to determine the histological differentiation of colon adenocarcinoma.

Public Radio Stations' Educational Services, 1982-83.

Science.gov (United States)

Katz, Joan H.; Wood, Denise E.

Highlights are presented from a third survey of educational services provided by public radio stations to elementary, secondary, and postsecondary educational institutions throughout the United States for the 2-year period from September 1, 1981 to August 30, 1983. Findings presented are based on the responses of 49 stations out of the 132…

Engineering Accountability for Results into Public Education.

Science.gov (United States)

Lessinger, Leon

"Accountability" is a classical term in management theory, but new in education. It is the product of the process of performance contracting, in which a public authority grants money to a local educational agency to contract with private enterprise to achieve specific goals within a specific period for specific costs. This process can be…

34 CFR 300.101 - Free appropriate public education (FAPE).

Science.gov (United States)

2010-07-01

... EDUCATION OF CHILDREN WITH DISABILITIES State Eligibility Fape Requirements § 300.101 Free appropriate... ensure that FAPE is available to any individual child with a disability who needs special education and... 34 Education 2 2010-07-01 2010-07-01 false Free appropriate public education (FAPE). 300.101...

Digital publics and participatory education

Directory of Open Access Journals (Sweden)

Brian J. McNely

2010-10-01

Full Text Available This article—a collaborative exploration between instructors, students, and members of the broader, digital classroom community—explores how the strategic incorporation of sociotechnical networks and digital technologies facilitates literate practices that extend the classroom in productive ways. The article builds toward coauthors’ reflective practices (Schön, 1983, or “participatory perspectives”, had during an undergraduate English Studies course at a mid-sized, public, American university. Specifically, participants argue that these literate practices afforded not just information sharing, but the opening up of a traditional classroom to include broader digital publics and collaborative knowledge work (Spinuzzi, 2006. Toward this end, we ground literate practice in scholarship that attends to public writing in online spaces, and theoretically frame our argument using Jenkins et al.’s (2006 principles of participatory education. We then detail the specific curricular approach deliberately designed to create digitally connected publics and end with generalizable significance of coauthors’ participatory perspectives.

Educating the Public about Deep-Earth Science

Science.gov (United States)

Cronin, V. S.

2010-12-01

The nature of Earth’s interior is an active frontier of scientific research. Much of our current understanding of sub-crustal Earth is based on knowledge acquired in the last 2-3 decades, made possible by public funding and by dense seismic arrays, satellite remote sensing, increases in computer power that enable use of enhanced numerical techniques, improved theoretical and experimental knowledge of high PT mineral physics and chemistry, and a vigorous scientific community that has been trained to take advantage of these opportunities. An essential component of science is effective communication; therefore, providing for public education about science is a responsibility of the research community. Current public understanding of Earth’s interior is meager at best. In pre-college texts and in non-technical mass media, Earth's interior is typically visualized as an onion or baseball of concentric different-colored shells along whose upper surface "crustal" plates move like packages on conveyor belts of convecting mantle. Or the crust is thought to float on a molten mantle, as in the 19th century ideas of William Lowthian Green. Misconceptions about Earth that are brought to the undergraduate classroom must be confronted frankly and replaced by current understanding based on good science. Persistent ignorance has consequences. What do we want the public to know? First, the public should understand that knowledge of Earth's interior is important, not irrelevant. The public should know that deep-Earth processes result in Earth's dynamic magnetic field. Deep-Earth processes affect how radiation from the Sun reaches Earth, consequently affecting the atmosphere, the oceans, and the viability of life on Earth. The composition and differentiated structure of Earth's interior is a result of the early accretionary history of Earth and the Earth-Moon system. The public should also know that lithospheric tectonics, with all of its consequences (dynamic topography, volcanoes

Civic Education at Public Islamic Higher Education (PTKIN and Pesantren

Directory of Open Access Journals (Sweden)

Azyumardi Azra

2016-06-01

Full Text Available With a brief foundation that covers some reviews of world literature on education and politics, the study points out the significance of developing a certain model of democracy education in the diverse country, Indonesia. The paper aims to establish the development and the excavation of democracy in Indonesia by presenting historical explanation on how Indonesian muslim scholars from UIN Syarif Hidayatullah Jakarta developed a suitable model of Indonesian civic education, which considers the elements of diversity as strengthening elements for democracy. Different from Shanker’s view (1996 on the global challenge of civic education, this study shows the successful experience of Indonesian Muslim in the development and application of civic education as a compulsory subject in Islamic education institutions, namely Public Islamic Higher Education (PTKIN and pesantren. Finally, it recommends further development and emphasizes the vital influence on rooting civic education in Pesantren since it will positively play an important role to strengthen the evolving democracy in Indonesia by integrating Islamic and Indonesian values. Abstrak Dengan melakukan review singkat terhadap beberapa literatur internasional tentang pendidikan dan politik, studi ini menunjukkan pengembangan model khusus  pendidikan demokrasi di Indonesia sebagai negara multi etnis. Tulisan ini bertujuan untuk menggambarkan perkembangan dan pengembangan demokrasi di Indonesia dengan pemaparan historis  tentang bagaimana muslim Indonesia khususnya di UIN jakarta dalam mengembangkan model Civic Education yang tepat, yang mempertimbangkan  elemen keberagamaan sebagai penguat demokrasi. Berbeda dari pendapat Shanker(1996 tentang tantangan global terhadap pendidikan kewarganegaraan, studi ini menggambarkan pengalaman sukses muslim Indonesia dalam mengembangkan pendidikan kewarganegaraan sebagai mata kuliah wajib di institusi pendidikan Islam dengan nama Perguruan Tinggi Keagaamaan

Public education programme for nuclear contingency planning in Hong Kong

International Nuclear Information System (INIS)

Wong, M. C.; Li, S. W.

2002-01-01

Two nuclear power stations on the coast of southern China are situated some 50 kilometers to the northeast of Hong Kong. Although the stations are far away from Hong Kong, the construction and operation of the nuclear power stations have generated public anxiety locally, in particular, after the Chernobyl accident in 1986. A comprehensive contingency plan which takes into account such concerns of the public has been implemented in Hong Kong. Cooperation by the public is vital to the effective implementation of any contingency plan. Understanding of the basics of radiation protection as well as the contingency plan will help the public to appreciate the situation and react in a rational manner. A public education program to promote awareness of the contingency plan has been implemented in Hong Kong. In particular, a Virtual Exhibition Hall on radiation has been developed and launched in February 2002 for access by the public via Internet. A video and a set of web pages will be launched in the later part of 2002 to inform and educate the public on matters related to nuclear accident response in Hong Kong. This paper describes the public education programme in Hong Kong to promote public awareness and understanding of the nuclear contingency plan

Analysing public relations education through international standards: The Portuguese case

OpenAIRE

Gonçalves, Gisela Marques Pereira; Spínola, Susana de Carvalho; Padamo, Celma

2013-01-01

By using international reports on PR education as a benchmark we analyse the status of PR higher education in Portugal. Despite differences among the study programs, the findings reveal that the standard five courses recommendation by the Commission on Public Relations Education (CPRE) are a part of Portuguese undergraduate curriculum. This includes 12 of the 14 content field guidelines needed to achieve the ideal master's program. Data shows, however, the difficulty of positioning public rel...

Benefits and Costs of For-Profit Public Education

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Alex Molnar

2001-04-01

Full Text Available As a policy initiative, for-profit operation of public schools has not lived up to the claims of its proponents. An examination of issues such as teaching methods, academic achievement, autonomy, local control, and the image and influence of for-profit public schools suggests that "for-profits" are unlikely to succeed in the long term in improving the overall quality of public education. They do, however, seem capable of harming public schools.

Significance of the NCA's "Dialogue on Public Relations Education" Conference.

Science.gov (United States)

Kruckeberg, Dean; Paluszek, John L.

1999-01-01

Contends that the 1998 Summer Conference of the National Communication Association, and the massive formative research in preparation for it, were seminal in examining current public-relations practice and education, in advocating education norms for the future, and in contributing to a much-needed ecumenism among the diverse public-relations…

Determining and Analyzing Public Support for Gifted Education.

Science.gov (United States)

Karnes, Frances A.; Riley, Tracy L.

1997-01-01

Statewide support for gifted education was assessed through a public opinion telephone survey with 400 respondents in one state. Results indicated general support for specialized programs, except residential schools, for gifted children. Appropriate public relations strategies utilizing such survey results are suggested. (DB)

Public perception process of nuclear power risk and some enlightenment to public education for nuclear power acceptance

International Nuclear Information System (INIS)

Yang Bo

2013-01-01

This paper, based on the international research literatures on perception of risks, designs a conceptual model of public perception of nuclear power risk. In this model, it is considered that the public perception of nuclear power risk is a dynamic, complicate and closed system and is a process from subjective perception to objective risk. Based on the features of the public perception of nuclear power risk and multi-faceted dimension influences as discussed, suggestions for the public education for nuclear power acceptance are given in five aspects with indication that the public education for nuclear power acceptance plays an important role in maintaining the public perception of nuclear power risk system. (author)

Helping Struggling Teachers.

Science.gov (United States)

Tucker, Pamela

2001-01-01

About 5 to 15 percent of teachers in 2.7 million public-education classrooms are marginal or incompetent. Assistance plans offer structure, purpose, and remedial help. Plans have six components: definition of the problem, statement of objectives, intervention strategies, a timeline, data-collection procedures, and final judgment. (MLH)

The corruption bogey in South Africa: Is public education safe?

Directory of Open Access Journals (Sweden)

Erika Serfontein

2015-02-01

Full Text Available Corruption is a constant global phenomenon, which is becoming more complex and intense as competition for resources increases. It is even more so amongst those living in developing countries, particularly emerging economies such as South Africa. Acts of corruption directly contest the basic principles of South Africa's Constitution, which aims at establishing freedom and security for everyone and a democracy 'for the people, by the people'. The aim of this article is to determine whether South African public education is safe from the corruption 'bogey', where reflection is made on professional public school management, which is the responsibility of school principals. Our objectives include designing an education-specific definition of corruption to advance accountable and transparent leadership; establishing the degree to which corruption has infiltrated the public education sphere; and making recommendations to fight corruption in public schools at professional public school management level. Among other findings, we found that even though some principals actively advocate upholding high morals, their conduct proves differently.

Everyday Physical Education: Functional and Dysfunctional Consequences in Hungarian Public Education

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Vamos Ảgnes

2015-09-01

Full Text Available In Participation in physical education is considered to be a fundamental right of pupils all over the world. In Hungary, where the rich elite sports traditions of the country are paralleled by the population’s moderate physical activity, the challenge posed by non-communicable diseases and growing obesity figures among youth was addressed by the introduction of daily P.E. in public education starting in the 2012/13 academic year. The objective of the present paper is to discuss, based on empirical research, the intended and unintended consequences of this measure in an educational and social context using the qualitative analysis of the views of key stakeholders and the quantitative analysis of statistical data on the infrastructural and personal conditions of P.E. The results indicate that neither before nor after the enforcement of the Act on Public Education were the infrastructural and personal conditions of daily P.E. created and, in addition to the intended consequences, a number of unintended consequences have also been encountered by various stakeholders. The study can also be regarded as an attempt to reveal these dysfunctions in order to contribute to positive changes in the area.

Religious education in public schools

DEFF Research Database (Denmark)

Jensen, Tim

2017-01-01

With special attention to Denmark, this article discusses to what degree religious education in public school in the Scandinavian countries, often said to be among the frontrunners as regards non-confessional religious education, reflects and accommodates an increased religious pluralism as well...... the 'repoliticization' and 'securitization' of religion (with special regard to Islamophobia, Islam and immigrant Muslim minorities), concludes, inter alia, that parts of the RE curricula do not just include a wider variety of religions but also helps to counter, if not stop, changes that have to do with the new...... plurality of religions. The analysis indicates that religious education is meant to serve the promotion of social cohesion by way of promoting knowledge and understanding of the new multi-religious world, at the same time as it continues to promote and propagate, for example, Danish culture as Christian...

Educational Exchanges in Public Diplomacy: Russian and International Experience

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Alexey Dolinkiy

2014-01-01

Full Text Available Education exchanges are a key element of public diplomacy for most countries that considered effective in that domain of foreign policy activities. Education exchanges are attributed an important role in the post-war peace settlement between Germany and France and in determining the outcome of the Cold war. Relevant aspects of public diplomacy remain key elements of foreign policy instruments of the US, Germany and many other countries. Russia has been increasingly active in public diplomacy in the past decade and the role of education exchanges has been increasing which is also demonstrated by a growing number of expert publications on the subject. However the strategy, the quality of organization and the use of modern technologies remain at a relatively low level which leads to an inefficient use of resources. Priority issues that can be a core of Russia's public diplomacy (and foreign policy in general. Moreover, systemic work would be required to evaluate efficiency of current and complete projects which would allow determine effectiveness of programs and appropriateness of resources used. Education exchanges need to be targeted at both bringing international students to Russia and assisting Russian students to study internationally and professors to teach abroad. Finally, international best practices show that there is a need to maintain connections with international exchanges alumni and assist them to maintain connections with each other including with the use of modern technologies.

Privatization and Commercialization of Public Education: Consequences for Citizenship and Citizenship Education

Science.gov (United States)

Ichilov, Orit

2012-01-01

My purpose is to examine and evaluate the implementation of market ideology and practices in education through the prism of both modern democratic theory and the discourse of rights. I examine the essence and defining characteristics of public schooling in modern democratic theory, explore the democratic purposes of education, and the unique…

What Do the Public Know about Anatomy? Anatomy Education to the Public and the Implications

Science.gov (United States)

Taylor, Adam M.; Diggle, Peter; Wessels, Quenton

2018-01-01

Public knowledge of the anatomical "self" is lacking and evidence points towards a growing need for anatomy education to the wider public. The public were offered the opportunity to learn human anatomy and complete an anatomical knowledge survey afterwards. Sixty-three participants volunteered to attempt to place 20 anatomical structures…

Education as a Commodity: Who Owns the Online Content Your Teachers Create?

Science.gov (United States)

Axelson, Mary

2001-01-01

As the Internet becomes increasingly commercialized, the K-12 world will need to follow higher education's lead and define who owns a wealth of instructional information. Some companies are actively seeking to purchase teacher-created work. Teachers generally own what they create, but district policies should be in place. (MLH)

Vocational Study and Public Service Motivation: Disentangling the Socializing Effects of Higher Education

DEFF Research Database (Denmark)

Kjeldsen, Anne Mette

2012-01-01

Most studies of Public Service Motivation investigate differences in motivation between public and private sector employees, but how these differences emerge and evolve in a pre-entry setting is still puzzling. Based on cross-sectional survey data with 3,521 Danish students enrolled in different...... vocational studies and at different stages (years) of their educational programs, this article investigates the socializing effects of higher education into different levels of public service motivation. The analysis demonstrates that students’ levels of public service motivation at different stages...... of their educational programs depends on the field of study: The level of public service motivation among students in vocational studies aimed at jobs with core public service delivery stays the same during education, whereas the level of public service motivation among students in other fields increases substantively...

Analysis of the literature pertaining to the education of public health professionals

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Connie J Evashwick

2013-11-01

Full Text Available A well-educated workforce is essential to the infrastructure of a public health system. At the time when global focus on public health is increasing, a severe shortage of public health professionals is projected. A strong educational framework is imperative to ensure the capacity and capability of the worldwide public health workforce for the future. Frenk and Chen (2011 comment that academic public health has done far less than medicine or nursing to examine its pedagogy. The goal of this study is to examine the literature pertaining to the education of public health professionals in order to document the extent to which those preparing public health professionals think about what they teach, how they teach, and what the results of the instruction are. The specific objectives are to (1 identify relevant peer reviewed literature, (2 analyze that literature for content, (3 characterize the literature according to type of methodology, and (4 draw conclusions and implications to enhance future pedagogical efforts. The study searched three bibliographic sources for articles written in English between 2000-2012. The search of PubMed, Scopus, Education Full Text identified 576 unique articles. The articles were analyzed according to ten content themes and four format categories. The conclusions are that those teaching public health professionals devote considerable thought to what and how they teach, although original research and evaluation studies are fewer than descriptive reports of courses, programs and curricula. A journal devoted specifically to articles pertaining to education of public health professionals will encourage academicians to write articles sharing approaches to educating the public health workforce.

Privatization of Public Education: Panacea or Pandora's Box?

Science.gov (United States)

Stevenson, Kenneth R.

1999-01-01

The drive for privatizing public education comes from two different movements: load-shedding and outsourcing. Districts hope to reduce perceived labor problems, avoid managing "uninteresting" services, save money, and/or buy quick-fix education reform. Privatization of charter schools is becoming big business, but its cost-effectiveness…

Teaching International Public Relations: An Update Report among Educators

Science.gov (United States)

Mak, Angela Ka Ying

2017-01-01

Involvement in international and multicultural career-related practices is ever on the rise in a global economic and political society, especially in public relations. This article reported an update of examining the attributes of public relations educators and their institutions in teaching of international public relations (IPR) through an…

Social Justice and Education in the Public and Private Spheres

Science.gov (United States)

Power, Sally; Taylor, Chris

2013-01-01

This paper explores the complex relationship between social justice and education in the public and private spheres. The politics of education is often presented as a battle between left and right, the state and the market. In this representation, the public and the private spheres are neatly aligned on either side of the line of battle, and…

Education based thinking and behaving? Towards an identity perspective for studying education differentials in public opinion and political participation

NARCIS (Netherlands)

Spruyt, Bram; Kuppens, Toon

2015-01-01

Education based thinking and behaving? Towards and identity perspective for studying education differentials in public opinion and political participation Abstract Ever since scholars started studying public opinion and political behaviour, they have reported substantial educational differences.

[Learning outcomes in public health education in Poland according to international settlements].

Science.gov (United States)

Cianciara, Dorota

2009-01-01

The essential functions of the Polish public health system have never been officially defined and some approaches are visible. In the article existing foreign catalogues of essential public health functions (services) and core competences for public health professionals and students are presented. They were confronted with students' final skills in public health field of study, described in formal Polish educational standards. It was claimed that graduates' competencies in Poland do not cover the full range of public health functions and skills defined in different countries. In the 2nd cycle of study an emphasis is put down on education for the managers of health care. An urgent need of change of educational standards for public health field of study was underlined. This is closely related to the need of national debate on public health functions.

Comparing Academic Library Spending with Public Libraries, Public K-12 Schools, Higher Education Public Institutions, and Public Hospitals between 1998-2008

Science.gov (United States)

Regazzi, John J.

2012-01-01

This study compares the overall spending trends and patterns of growth of Academic Libraries with Public Libraries, K-12 schools, higher education institutions, and hospitals in the period of 1998 to 2008. Academic Libraries, while showing a growth of 13% over inflation for the period, far underperformed the growth of the other public institutions…

The Legacy of Public Work: Educating for Citizenship.

Science.gov (United States)

Boyte, Harry C.; Skelton, Nan

1997-01-01

The nation's educational system mirrors the dynamics of our marketplace democracy, recasting parents as self-interested consumers. Jane Addams' philosophy of education (enhancing people's productive capacities to benefit the commonweal) has been revived in Public Achievement, a work-centered, civic-earning program in St.Paul, Minnesota, that helps…

Public Administration Education in Europe: Continuity or Reorientation?

Science.gov (United States)

Hajnal, Gyorgy

2015-01-01

The article explores the changing patterns of disciplinary orientation in European public administration (PA) education. The study builds on an earlier research, which defined three distinct clusters of countries, based on their specific PA education tradition. It asks whether countries' movement away from the Legalist paradigm has continued since…

Applied Behavior Analysis: Current Myths in Public Education

Science.gov (United States)

Fielding, Cheryl; Lowdermilk, John; Lanier, Lauren L.; Fannin, Abigail G.; Schkade, Jennifer L.; Rose, Chad A.; Simpson, Cynthia G.

2013-01-01

The effective use of behavior management strategies and related policies continues to be a debated issue in public education. Despite overwhelming evidence espousing the benefits of the implementation of procedures derived from principles based on the science of applied behavior analysis (ABA), educators often indicate many common misconceptions…

Public Relations Education: 1983 Survey and Report.

Science.gov (United States)

Walker, Albert

1984-01-01

Provides results of a survey of public relations education at 30 colleges and universities with respect to an examination of 115 syllabi, course requirements and reading lists, and innovative practices. (PD)

The Gift of Education: How Indigenous Knowledges Can Transform the Future of Public Education

Science.gov (United States)

Jacob, Michelle M.; Sabzalian, Leilani; Jansen, Joana; Tobin, Tary J.; Vincent, Claudia G.; LaChance, Kelly M.

2018-01-01

This article advocates for the necessity of Indigenous Knowledges in furthering Indigenous self-determination in public schools, as well as furthering the broad aims of public education. Drawing attention to past efforts across the United States to transform the public school curriculum and analyzing data from testimonies given at Oregon State…

Higher Education Public Relations at the Year 2000: Assessing the Status of Public Relations at Colleges and Universities.

Science.gov (United States)

Peyronel, Anthony C.

2000-01-01

Discusses the importance of higher education public relations professionals playing a key role in institutional decision making and not being limited to the role of communication technician or information processor. Reviews studies on relationships between higher education and the media and between public relations professionals and…

Closing Reflections: Public Policy, Advocacy, and Special Educators

Science.gov (United States)

West, Jane E.; Shepherd, Katharine G.

2016-01-01

When the Higher Education Consortium for Special Education (HECSE) convened in January 2016 in Washington, we celebrated both IDEA's and HECSE's 40th anniversaries. As we reflected on those two anniversaries, the convictions that generated this special issue became increasingly evident: the irrevocable significance of the impact of public policy…

New challenges in public health education and training in the Slovak Republic

Directory of Open Access Journals (Sweden)

Gabriel Gulis

2009-06-01

Full Text Available

Background: The Slovak Republic joined the European Union (EU on May 1st 2004. The public health system
of the country is under continuous transition including public health education and training. The aim of the presented paper is to describe and discuss how far the transition of public health education of the country
went during last time period.

Methods: Web site review, documentation search and curriculum content analysis were the main methods
employed within presented paper.

Results: There are 7 universities offering public health education on bachelor, master and doctoral level.
Among them 6 could be found in list of accredited universities of the Ministry of Education by Accreditation
Committee of the Government of the Slovak Republic. The three levels of education are fully harmonized with
the Bologna principles. The Accreditation Committee of the Government of the Slovak Republic describes very detailed aims of a public health education program including recommended study subjects. Universities add to additional, mostly clinical medicine or hygiene subjects to recommend study subjects leaving likely very
little time for research at universities.

Conclusions: Despite large progress further effort is needed to clarify what is public health, what kind of subject should be included in curricula and on introduction of public health research at universities.

Short-Run Distributional Effects of Public Education Transfers to Tertiary Education Students in Seven European Countries

Science.gov (United States)

Callan, Tim; Smeeding, Tim; Tsakloglou, Panos

2008-01-01

Direct provision of public services can alter the balance of resources across income groups. We focus on the issues arising when taking account of the impact of publicly provided education services across the income distribution. We combine OECD information on spending per student in particular levels of the education system with micro data from…

Public Relations Education: Where is Pedagogy?

Science.gov (United States)

Coombs, W. Timothy; Rybacki, Karyn

1999-01-01

Uses data from a national survey and from the 1998 National Communication Association Summer Conference, both described elsewhere in this issue, to examine the strengths and weaknesses of public-relations pedagogy; to compare educator and practitioner perceptions of pedagogy; and to offer a set of concerns and recommendations. (SR)

Public Service Motivation and Socialization in Graduate Education

Science.gov (United States)

Bright, Leonard

2016-01-01

The purpose of this study is to explore the extent to which the characteristics of public administration degree programs are related to public service motivation (PSM) using a higher education socialization framework. Using a sample of approximately 500 students enrolled in 26 Master's degree programs across the country, this study confirms that…

Opportunities and Resources for Scientist Participation in Education and Public Outreach

Science.gov (United States)

Buxner, Sanlyn; CoBabe-Ammann, E.; Shipp, S.; Hsu, B.

2012-10-01

Active engagement of scientists in Education and Public Outreach (E/PO) activities results in benefits for both the audience and scientists. Most scientists are trained in research but have little formal training in education. The Planetary Science Education and Public Outreach (E/PO) Forum helps the Science Mission Directorate support scientists currently involved in E/PO and to help scientists who are interested in becoming involved in E/PO efforts find ways to do so through a variety of avenues. We will present current and future opportunities and resources for scientists to become engaged in education and public outreach. These include upcoming NASA SMD E/PO funding opportunities, professional development resources for writing NASA SMD E/PO proposals (webinars and other online tools), toolkits for scientists interested in best practices in E/PO (online guides for K-12 education and public outreach), EarthSpace (a community web space where instructors can find and share about teaching space and earth sciences in the undergraduate classroom, including class materials news and funding opportunities, and the latest education research), thematic resources for teaching about the solar system (archived resources from Year of the Solar System), and an online database of scientists interested in connecting with education programs. Learn more about the Forum and find resources at http://smdepo.org/.

Capitalism and Public Education in the United States

Science.gov (United States)

Schneller, Peter L.

2017-01-01

The United States democratic system includes characteristics of capitalism as well as socialism. Perhaps the most socialistic endeavor of the US is its K-12 public school system; in fact, US public schools are necessary for democracy to thrive and to create an educated and well-informed populace. However, capitalism and socialism are strange…

Putting Health Education on the Public Health Map in Canada--The Role of Higher Education

Science.gov (United States)

Vamos, Sandra; Hayos, Julia

2010-01-01

The health education profession has developed over recent years garnering national and international attention. Canada's evolving health education perspective emphasizing the concept of health literacy within the broader public health system reflects the need for trained, competent and skilled health educators designing, implementing and…

Mental Health: A Case for Spiritual Education in Public Schools.

Science.gov (United States)

Dennis, Dixie L.; Dennis, Brent G.

2002-01-01

Suggests a unique mental health prevention strategy that focuses on spiritual education in public schools, defining spirituality, describing the spirituality-mental health connection, highlighting educators' responsibility toward spiritual education, and offering specific activities and strategies for enhancing students' spirituality suitable for…

MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers : A study of hereditary nonpolyposis colorectal cancer families

NARCIS (Netherlands)

Vasen, HFA; Stormorken, A; Menko, FH; Nagengast, FM; Kleibeuker, JH; Griffioen, G; Taal, BG; Moller, P; Wijnen, JT

2001-01-01

Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and

MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.

NARCIS (Netherlands)

Vasen, H.F.; Stormorken, A.; Menko, F.H.; Nagengast, F.M.; Kleibeuker, J.H.; Griffioen, G.; Taal, B.G.; Moller, P.; Wijnen, J.T.

2001-01-01

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and

Rapidly progressive adenomatous polyposis in a patient with germline mutations in both the APC and MLH1 genes: the worst of two worlds.

NARCIS (Netherlands)

Scheenstra, R; Rijcken, FE; Koornstra, JJ; Hollema, H; Fodde, R; Menko, F.H.; Sijmons, RH; Bijleveld, CM; Kleibeuker, J.H.

2003-01-01

The two most common inherited forms of colorectal cancer are familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Simultaneous inheritance of both an APC gene mutation and a mismatch repair gene (for example, MLH1) mutation has never been described. In the present case

The nuclear power public education and information program in the Philippines

International Nuclear Information System (INIS)

Garcia, E.A.; Natera, E.S.

1996-01-01

The nuclear power public education and information program aims to present the beneficial uses of radiation and nuclear energy. Considering that there are pros and cons to the use of nuclear energy, the program aims to give the public an objective and balanced view of this source of energy. A decision to use or not to use nuclear energy, to be sound,must be based on an adequate and objective knowledge of the atom and nuclear energy. Executive Order 243 created the Nuclear Power Steering committee including subcommittee on Nuclear Power Public Education and Information. This subcommittee is tasked to formulate an effective nuclear power public education and information program. Said program must include training component for science teachers in the high school and college levels and shall also work for the inclusion of nuclear related subjects in all engineering curriculum. It shall coordinate with the University of the Philippines for the revival of the M.S. in Nuclear Engineering Program of the university. This paper will discuss a brief history of nuclear power public education and awareness programs and the present and projected activities of this subcommittee. (author)

Best Practices in NASA's Astrophysics Education and Public Outreach Projects

Science.gov (United States)

Hasan, H.; Smith, D.

2015-11-01

NASA's Astrophysics Education and Public Outreach (EPO) program has partnered scientists and educators since its inception almost twenty years ago, leading to authentic STEM experiences and products widely used by the education and outreach community. We present examples of best practices and representative projects. Keys to success include effective use of unique mission science/technology, attention to audience needs, coordination of effort, robust partnerships and publicly accessible repositories of EPO products. Projects are broadly targeted towards audiences in formal education, informal education, and community engagement. All NASA programs are evaluated for quality and impact. New technology is incorporated to engage young students being raised in the digital age. All projects focus on conveying the excitement of scientific discoveries from NASA's Astrophysics missions, advancing scientific literacy, and engaging students in science and technology careers.

Return on Investment in College Education. The Guardians Initiative: Reclaiming the Public Trust

Science.gov (United States)

Association of Governing Boards of Universities and Colleges, 2017

2017-01-01

"Return on Investment in College Education" is the second publication in a series of informational briefings developed as part of The Guardians Initiative: Reclaiming the Public Trust, an effort to educate and engage trustees as advocates on key issues in higher education. What is the return on investment (ROI) in college education?…

The Challenges and Future of Public Higher Education Leadership in Kenya

Science.gov (United States)

Odhiambo, George

2014-01-01

This article discusses some of the key challenges and points of tension pertaining to leadership in higher education in Kenya. Effective leadership approaches are discussed including an exploration of why effective leadership is more important in Kenyan public higher education now than ever. Given the complex context within which public higher…

Vitamin E Modifies High-Fat Diet-Induced Increase of DNA Strand Breaks, and Changes in Expression and DNA Methylation of Dnmt1 and MLH1 in C57BL/6J Male Mice

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Marlene Remely

2017-06-01

Full Text Available Obesity is associated with low-grade inflammation, increased ROS production and DNA damage. Supplementation with antioxidants might ameliorate DNA damage and support epigenetic regulation of DNA repair. C57BL/6J male mice were fed a high-fat (HFD or a control diet (CD with and without vitamin E supplementation (4.5 mg/kg body weight (b.w. for four months. DNA damage, DNA promoter methylation and gene expression of Dnmt1 and a DNA repair gene (MLH1 were assayed in liver and colon. The HFD resulted in organ specific changes in DNA damage, the epigenetically important Dnmt1 gene, and the DNA repair gene MLH1. Vitamin E reduced DNA damage and showed organ-specific effects on MLH1 and Dnmt1 gene expression and methylation. These results suggest that interventions with antioxidants and epigenetic active food ingredients should be developed as an effective prevention for obesity—and oxidative stress—induced health risks.

Vitamin E Modifies High-Fat Diet-Induced Increase of DNA Strand Breaks, and Changes in Expression and DNA Methylation of Dnmt1 and MLH1 in C57BL/6J Male Mice.

Science.gov (United States)

Remely, Marlene; Ferk, Franziska; Sterneder, Sonja; Setayesh, Tahereh; Kepcija, Tatjana; Roth, Sylvia; Noorizadeh, Rahil; Greunz, Martina; Rebhan, Irene; Wagner, Karl-Heinz; Knasmüller, Siegfried; Haslberger, Alexander

2017-06-14

Obesity is associated with low-grade inflammation, increased ROS production and DNA damage. Supplementation with antioxidants might ameliorate DNA damage and support epigenetic regulation of DNA repair. C57BL/6J male mice were fed a high-fat (HFD) or a control diet (CD) with and without vitamin E supplementation (4.5 mg/kg body weight (b.w.)) for four months. DNA damage, DNA promoter methylation and gene expression of Dnmt1 and a DNA repair gene ( MLH1 ) were assayed in liver and colon. The HFD resulted in organ specific changes in DNA damage, the epigenetically important Dnmt1 gene, and the DNA repair gene MLH1 . Vitamin E reduced DNA damage and showed organ-specific effects on MLH1 and Dnmt1 gene expression and methylation. These results suggest that interventions with antioxidants and epigenetic active food ingredients should be developed as an effective prevention for obesity-and oxidative stress-induced health risks.

ANDRILL Education and Public Outreach: A Legacy of the IPY

Science.gov (United States)

Rack, F. R.; Huffman, L. T.; Reed, J.; Harwood, D. M.; Berg, M.; Diamond, J.; Fox, A.; Dahlman, L. E.; Levy, R. H.

2009-12-01

ANDRILL field projects during the IPY included the McMurdo Ice Shelf (MIS) and Southern McMurdo Sound (SMS) drilling projects, and the Mackay Sea Valley (MSV) and Offshore New Harbor (ONH) seismic surveys. ANDRILL's international network of scientists, engineers, students and educators work together to convey an understanding of geoscience research and the process of science to non-technical audiences. ANDRILL education and public outreach (EPO) program goals are to: (1) promote environmental and polar science literacy for all audiences; (2) develop and disseminate engaging resources for formal and informal education; (3) develop and nurture a network of polar science educators; (4) spark the curiosity of students and the general public; (5) encourage students to pursue careers in science; (6) challenge misconceptions about scientific research; (7) provide professional development opportunities for educators; and, (8) encourage inquiry teaching in science education. During the IPY, ANDRILL established partnerships with several IPY projects to enhance science literacy and promote the IPY in formal and informal education and outreach venues. ANDRILL-led initiatives include the ARISE (ANDRILL Research Immersion for Science Educators) Program, Project Iceberg, the FLEXHIBIT (FLEXible exHIBIT; in partnership with Antarctica’s Climate Secrets/IPY Engaging Antarctica), and the Project Circle. ANDRILL partnerships developed with several museums and school districts for teacher professional development workshops and a variety of public events. A polar learning community was created from the ARISE participants and their many contacts, the Project Circle participants, and interested educators who contacted ANDRILL. EPO activities are continuing in the post-IPY period with additional funding. The ARISE program has been successful in building a team of educators and a network of international collaborations across grade levels and cultures. The ANDRILL website has expanded to

Training Public School Special Educators to Implement Two Functional Analysis Models

Science.gov (United States)

Rispoli, Mandy; Neely, Leslie; Healy, Olive; Gregori, Emily

2016-01-01

The purpose of this study was to investigate the efficacy and efficiency of a training package to teach public school special educators to conduct functional analyses of challenging behavior. Six public school educators were divided into two cohorts of three and were taught two models of functional analysis of challenging behavior: traditional and…

Public and Private School Principals' Knowledge of Special Education Law

Science.gov (United States)

Boyd, Marie Nicole

2018-01-01

The purpose of this study is to examine the knowledge of special education law held by public and private school principals as the law pertains to providing the appropriate services to students with disabilities. Numerous studies have investigated public school principals' level of preparation, training, and role within in special education law.…

Romanian accrual accounting experience in public higher education sector

OpenAIRE

Tiron Tudor, Adriana; Blidisel, Rodica

2007-01-01

The purpose of this paper is to present experiences from the use of accrual accounting information in the public higher education sector in Romania and, thus, to contribute to our understanding of the prospects for using that kind of accounting in public organizations.

Archeologi educatori. Attuali tendenze per un’archeologia educativa in Italia, tra heritage education e public archaeology / Archaeologists-educators. Contemporary trends for an educational archaeology in Italy, between heritage education and public archaeology

Directory of Open Access Journals (Sweden)

Marta Brunelli

2013-05-01

In Italy, in recent years there has been a perspective-shift in archaeological education and communication, showing how current educational activities for the many publics of archaeology have incorporated practices and approaches that belong to different disciplinary ambits, although partially overlapping: the heritage education field with its theoretical-pedagogical reflection (especially at European level as well as educational practices on the one hand; and the new ‘global’ approach to heritage, which is expressed by the public archaeology sector of Anglo-Saxon matrix. Actually a real ‘educational archaeology’ is emerging, i.e. an archaeological activity, not delegated to other mediators, but personally conducted by archaeologists with educational, social and cultural objectives and aims: first, to transmit knowledge and skills enabling visitors to understand the archaeological evidence and the meaning itself of the dig, of the archaeological sites and heritage; second, to implement innovative and diversified educational and communication strategies, able to reach wider audiences and, consequently, to meet the new demands of social inclusion and cultural participation; third, but not least, to reassert the meaning of archaeological heritage as well as of the discipline and its actors, as a shared value and a potential of growth for citizens, communities and society as a whole.

Public health education for midwives and midwifery students: a mixed methods study.

Science.gov (United States)

McNeill, Jenny; Doran, Jackie; Lynn, Fiona; Anderson, Gail; Alderdice, Fiona

2012-12-07

Current national and international maternity policy supports the importance of addressing public health goals and investing in early years. Health care providers for women during the reproductive and early postnatal period have the opportunity to encourage women to make choices that will impact positively on maternal and fetal health. Midwives are in a unique position, given the emphasis of the philosophy of midwifery care on building relationships and incorporating a holistic approach, to support women to make healthy choices with the aim of promoting health and preventing ill health. However, exploration of the educational preparation of midwives to facilitate public health interventions has been relatively limited. The aim of the study was to identify the scope of current midwifery pre registration educational provision in relation to public health and to explore the perspectives of midwives and midwifery students about the public health role of the midwife. This was a mixed methods study incorporating a survey of Higher Educational Institutions providing pre registration midwifery education across the UK and focus groups with midwifery students and registered midwives. Twenty nine institutions (53% response) participated in the survey and nine focus groups were conducted (59 participants). Public health education was generally integrated into pre registration midwifery curricula as opposed to taught as a discrete subject. There was considerable variation in the provision of public health topics within midwifery curricula and the hours of teaching allocated to them. Focus group data indicated that it was consistently difficult for both midwifery students and midwives to articulate clearly their understanding and definition of public health in relation to midwifery. There is a unique opportunity to impact on maternal and infant health throughout the reproductive period; however the current approach to public health within midwifery education should be reviewed to

Informing the educators: one of the keys to public acceptance

International Nuclear Information System (INIS)

Mattox, G.C.; Reynolds, A.B.; Brenizer, J.S.

1986-01-01

One of the most difficult barriers to overcome in the task of gaining greater public acceptance of nuclear power is the widespread lack of correct information about the true risks and benefits of nuclear energy. The news media are the most prevalent sources of information for the public but they are highly constrained by the limits of space, time, and reader/viewer interest span in being able to cover this complex subject with any degree of completeness, much less with any degree of accuracy. Another source of information for the general public is the educational system, and while it also has its limitations, they are somewhat different from those faced by the media, and the educational system is generally considered to be a more credible information source than the media. This paper report on three programs undertaken in 1985 and 1986 by the Virginia Section of the American Nuclear Society (ANS) in conjunction with the University of Virginia (UVA), the Virginia State Department of Education, and various nuclear industry participants. Each program had its unique features, successes, an failures. All-in-all, these programs have been reported as being quite successful in helping to reach the public through informing the educators

Public Ethics in Educational Organizations: How to Manage For Achieving Common Wealth

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Ana Prieto Sánchez

2007-04-01

Full Text Available The objective of this essay is to reflect about the rol that should be assumed by the management of the educational organizations, as public administration’s leaders, under a perspective of public ethics based on values, like fundamental pillars of how to achieve the common wealth. The method used was documentary, consulting authors as Aranguren (1996, Santana (2000, Arana (2000 y Camargo (1998. It could be concluded: the educational manager as ethics public leader, should encourage the social learning of values to change from a right ethics to a responsibility ethics, in order to obtain a social transformation. The education and the educational policies are the way to achieve the convivence and the common wealth, when they are practiced by the ethics manager, presents in the educational organizations.

Transforming public health education in India through networking and collaborations: opportunities and challenges.

Science.gov (United States)

Sharma, Anjali; Zodpey, Sanjay P

2013-01-01

A competent and motivated health workforce is indispensable to achieve the best health outcomes possible through given available resources and circumstances. However, apart from the shortages and unequal distribution, the workforce has fallen short of responding to the public health challenges of 21 st century also because of primarily the traditional training of health professionals. Although, health professionals have made enormous contributions to health and development over the past century, the 20 th century educational strategies are unfit to tackle 21 st century challenges. One of the key recommendations of the Lancet Commission on Education of Health Professionals is to improve health through reforms of professional education by establishing networks and partnerships which takes advantage of information and communication linkages. The primary goal of this manuscript is to highlight the potential of networks and partnerships in advancing the agenda of educational reforms to revitalize public health education in India. It outlines the current status and expanding scope of public health education in India, existing networks of public health professionals and public health education institutions in the country, and opportunities, advantages and challenges for such networks. Although, we have networks of individuals and institutions in the country, there potential to bring about change has still not being utilized fully and effectively. Immediate collaborative efforts could be directed towards designing and adaptation of competency driven curriculum frameworks suitable of addressing public health challenges of 21 st century, shifting the current focus of curriculum to multidisciplinary public health outlook, developing accreditation mechanisms for both the programs and institutions, engaging in creating job opportunities and designing career pathways for public health professionals in public and private sector. These efforts could certainly be facilitated

AMASYA PUBLIC EDUCATION CENTER WORKS EXAMPLE: YASSIÇAL BROADCLOTH WEAVINGS

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Hurrem Sinem SANLI

2015-09-01

Full Text Available Public education aims to gain adults the skills and knowledge towards interpretation of free times of social and cultural activities. With public education, people living in the region especially women contribute to production. In Amasya, there are courses provided for women in Public Education Centers and it is made sure that they attend theses courses. In this study, a section of said center and Yassıçal broadcloth weavings are analyzed. Motifs and product examples in Yassıçal weavings are examined. These motifs are Eminem, Tekke peşkürü, Suleyman, Sinekli, Mehmet Dede, Kara viran, Çift mekik and Deveci kesmesi. This traditional motifs began to weave again. A variety of woven products; living room sets, veil, curtains, runners, bags, doll clothes and women's clothes are produced by traniees.

Integrating education, training and communication for public involvement in EIA

International Nuclear Information System (INIS)

Oprea, Irina; Oprea, Marcel; Guta, Cornelia; Guta, Vasilica

2003-01-01

We are going towards a globalized world, this involving the integration of every activity and every person. The public involvement in the development process is evident, taking into account that any objective will affect the people and the negative feedback could influence the result of the investment. Generally the public could be influenced by amplification of negative evaluated consequences, resulting psychosocial effects leading to illness or anxieties. This problem will be resolved by the public access to information provided by experts. A real-time interactive communication system is proposed as an open tool in order to facilitate decision-making by access to rapid and reliable information. The main task of the system is to collect, process, display and exchange the information relative to environmental impact assessment (EIA), to provide assistance, to receive specific opinions, being also proposed for public understanding of the field. The education and training integration will mitigate the barriers, which may inhibit the interaction and communication process. To increase learning will assure specialists-public interaction and a good information flow for knowledge exchange. The paper will outline key approaches in reaching agreement on the people educational process importance. The impact of development will be available to the public revealing the positive consequences, such as increased employment and income. An effective way to avoid negative reactions consists of the extensive consultation to identify the concerns and needs of the public, the access to suggestive and attractive programs for education and training. The system is developed as a modern information module, integrated into complex international management systems. It can be placed everywhere, everybody could access the facilities for education, world experience and training. Providing a real-time response to citizen concerns, the system represents an economic and rapid way to mitigate the

Interactive Education in Public Administration (2): Strategies for Teachers

Science.gov (United States)

Brock, Jonathan; Alford, John

2015-01-01

The previous article ("Interactive education in public administration (1): The role of teaching 'objects'") described the benefits of "moving from behind the lectern" to engage in interactive teaching in public policy and administration, and the central role of "objects" in that process. But teaching…

Intercultural competency in public health: a call for action to incorporate training into public health education

Directory of Open Access Journals (Sweden)

Julia eFleckman

2015-09-01

Full Text Available Due to increasing national diversity, programs addressing cultural competence have multiplied in U.S. medical training institutions. Little progress has been made to translate cultural competency training from the clinical setting into the public health setting where the focus is on population-based health, preventative programming, and epidemiological and behavioral research. The need for culturally relevant public health programming and culturally sensitive public health research is more critical than ever. Awareness of differing cultural roles needs to be included in all processes of planning, implementation and evaluation. In focusing on community-based health program planning and research, cultural competence implies that it is possible for public health professionals to completely know another culture, whereas intercultural competence implies it is a dual-sided process. Public health professionals need a commitment toward intercultural competence and skills that demonstrate flexibility, openness and self-reflection so that cultural learning is possible. In this article, the authors recommend a number of elements to develop, adapt and strengthen intercultural competence education in public health educational institutions.

Public education in cancer prevention.

Science.gov (United States)

Van Parijs, L G

1986-01-01

Life-style is now recognized as a main determinant of cancer risk. Public education is an important component of cancer control programmes and has been shown to be effective in leading to life-style changes. Four basic types of education programmes are reviewed: for increasing the public's awareness of cancer, for changing specific risk behaviour (such as stopping smoking), for learning self-examination skills (such as breast self-examination), and for promoting early cancer detection in the community.To change human behaviour it is best to approach the risk habit through the same forces that develop and sustain the habit. Simply giving information of an association between specific habits and cancer, even if repeated several times, will lead to increased public awareness and encourage some to make a minimal effort to change their behaviour, but in general the new habit does not persist and continuing and intensifying this approach are ineffective. An alternative strategy utilizes socially active forces to support the prevention practice and remove possible barriers to action. For example, an antismoking programme should create a favourable social image of the non-smoker. Although a culturally and socially relevant mass media campaign can influence knowledge and beliefs and induce people to participate in a screening activity, this needs to be supplemented over a period of time by personal contact methods, such as group discussions, telephone conversations and home visits, in order to promote a regular screening habit. Contrary to popular opinion, mass communication methods can be expensive on a per person cost-effectiveness basis because of low participation rates and weakness in sustaining healthy behaviour.

Public health education in South Asia: a basis for structuring a master degree course.

Science.gov (United States)

Karkee, Rajendra

2014-01-01

Countries in South Asian Association for Regional Cooperation (SAARC) lack enough public health workforces to address their poor public health situation. Recently, there have been efforts to develop capacity building in public health in these countries by producing competent public health workforce through public health institutes and schools. Considering the wide nature of public health, the public health education and curricula should be linked with skills, knowledge, and competencies needed for public health practice and professionalism. The 3 domains of public health practice and the 10 essential public health services provide an operational framework to explore this link between public health practice and public health education. This framework incorporates five core areas of public health education. A master degree course in public health can be structured by incorporating these core areas as basic and reinforcing one of these areas as an elective followed by a dissertation work.

Facilitating Corporate Entrepreneurship in Public Sector Higher Education Institutions: A Conceptual Model

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Javed Nayyar Malik

2012-06-01

Full Text Available This paper develops a conceptual model of public sector corporate entrepreneurship for the state government higher education institutions. The proposed model is intended to depict the main antecedents that relate to corporate entrepreneurship within the public sector higher education institution  and the impact of corporate entrepreneurship on public sector HEI’s performance, as well as factors influencing its continuous performance.

Meat and fish consumption, APC gene mutations and hMLH1 expression in colon and rectal cancer: a prospective cohort study (the Netherlands)

NARCIS (Netherlands)

Luchtenborg, M.; Weijenberg, M.P.; Goeij, de A.F.P.M.; Wark, P.A.; Brink, M.; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruine, de A.P.; Goldbohm, R.A.; Veer, van 't P.; Brandt, van den P.A.

2005-01-01

Objective:The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. Methods:The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer

Privatization or Public Investment in Education? Research & Policy Brief

Science.gov (United States)

Adamson, Frank

2016-01-01

Policymakers worldwide are trying to figure how best to organize, govern, and support their education systems. They must manage multiple goals, such as workforce development, nurturing knowledgeable citizens, and ensuring educational opportunity. Some countries approach these issues with a public investment in teacher professionalization and a…

Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC).

Science.gov (United States)

Vilkin, Alex; Niv, Yaron

2011-04-01

Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence.

Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome.

Directory of Open Access Journals (Sweden)

Abram Bunya Kamiza

Full Text Available Lynch syndrome, caused by germline mutations in mismatch repair genes, is a predisposing factor for colorectal cancer (CRC. This retrospective cohort study investigated the risk factors associated with the development of CRC in patients with MLH1 and MSH2 germline mutations.In total, 301 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A Cox proportional hazard model was used to calculate the hazard ratios (HRs and 95% confidence intervals (CIs to determine the association between the risk factors and CRC development. A robust sandwich covariance estimation model was used to evaluate family dependence.Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09-2.34; however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41-0.88. The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16-2.55 and 0.54 (95% CI = 0.34-0.83 among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07-2.27 than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06-6.58 compared with those with blood group type O.The present study revealed that Hakka ethnicity, manual occupation, and blood group type B were associated with an increased CRC risk, whereas regular physical activity was associated with a decreased CRC risk in MLH1 and MSH2 germline mutation carriers.

Assessing the professional development needs of public health educators in light of changing competencies.

Science.gov (United States)

Demers, Anne Roesler; Mamary, Edward

2008-10-01

Because of the need for a well-trained public health workforce, professional competencies have been recently revised by the Institute of Medicine and the National Health Educator Competencies Update Project. This study compared the self-identified training needs of public health educators with the updated competencies and assessed employer support for continuing education. A convenience sample of public health educators was recruited from an e-mail list of San Jose State University master of public health alumni. Respondents completed a Web-based survey that elicited information on emerging trends in public health education, training needs, and employer support for continuing education. Concerns about funding cuts and privatization of resources emerged as a theme. Key trends reported were an increase in information technology, the need for policy advocacy skills, and the importance of a lifespan approach to health issues. Primary areas for training were organization development, evaluation, and management. Although most employers were reported to support continuing education, less than two-thirds of respondents were reimbursed for expenses. These findings have implications for both research and practice. Innovative technologies should be developed to address health education professionals' training needs, and emerging themes should be incorporated into curricula for students.

Public education and misinformation on brain death in mainstream media.

Science.gov (United States)

Lewis, Ariane; Lord, Aaron S; Czeisler, Barry M; Caplan, Arthur

2016-09-01

We sought to evaluate the caliber of education mainstream media provides the public about brain death. We reviewed articles published prior to July 31, 2015, on the most shared/heavily trafficked mainstream media websites of 2014 using the names of patients from two highly publicized brain death cases, "Jahi McMath" and "Marlise Muñoz." We reviewed 208 unique articles. The subject was referred to as being "alive" or on "life support" in 72% (149) of the articles, 97% (144) of which also described the subject as being brain dead. A definition of brain death was provided in 4% (9) of the articles. Only 7% (14) of the articles noted that organ support should be discontinued after brain death declaration unless a family has agreed to organ donation. Reference was made to well-known cases of patients in persistent vegetative states in 16% (34) of articles and 47% (16) of these implied both patients were in the same clinical state. Mainstream media provides poor education to the public on brain death. Because public understanding of brain death impacts organ and tissue donation, it is important for physicians, organ procurement organizations, and transplant coordinators to improve public education on this topic. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Are Public Libraries Improving Quality of Education? When the Provision of Public Goods Is Not Enough. Policy Research Working Paper 7429

Science.gov (United States)

Rodriguez-Lesmes, Paul; Trujillo, Jose Daniel; Valderrama, Daniel

2015-01-01

This paper analyzes the relation between public, education-related infrastructure and the quality of education in schools. The analysis uses a case study of the establishment of two large, high-quality public libraries in low-income areas in Bogotá, Colombia. It assesses the impact of these libraries on the quality of education by comparing…

Public Schools, Hawaii, 2009, Hawaii Department of Education

Data.gov (United States)

U.S. Environmental Protection Agency — Locations represent Hawaii's public schools. List of schools was furnished by the Hawaii Department of Education (DOE). Locations were developed by the US EPA Region...

NASA Astrophysics Education and Public Outreach: The Impact of the Space Telescope Science Institute Office of Public Outreach

Science.gov (United States)

Smith, Denise Anne; Jirdeh, Hussein; Eisenhamer, Bonnie; Villard, Ray; Green, Joel David

2015-08-01

As the science operations center for the Hubble Space Telescope and the James Webb Space Telescope, the Space Telescope Science Institute (STScI) is uniquely positioned to captivate the imagination and inspire learners of all ages in humanity’s quest to understand fundamental questions about our universe and our place in it. This presentation will provide an overview of the impact of the STScI’s Office of Public Outreach’s efforts to engage students, educators, and the public in exploring the universe through audience-based news, education, and outreach programs.At the heart of our programs lies a tight coupling of scientific, education, and communications expertise. By partnering scientists and educators, we assure current, accurate science content and education products and programs that are classroom-ready and held to the highest pedagogical standards. Likewise, news and outreach programs accurately convey cutting-edge science and technology in a way that is attuned to audience needs. The combination of Hubble’s scientific capabilities, majestic imagery, and our deep commitment to create effective programs to share Hubble science with the education community and the public, has enabled the STScI Office of Public Outreach programs to engage 6 million students and ½ million educators per year, and 24 million online viewers per year. Hubble press releases generate approximately 5,000 online news articles per year with an average circulation of 125 million potential readers per press release news story. We will also share how best practices and lessons learned from this long-lived program are already being applied to engage a new generation of explorers in the science and technology of the James Webb Space Telescope.

Teachers' Salaries in Public Education: Between Myth and Fact

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Nir, Adam E.; Naphcha, Melly

2007-01-01

Purpose: The purpose of research is to attempt to determine to what extent the salary level of teachers working in public educational systems is connected with the trend towards privatization considering that privatization has become nowadays a prominent phenomenon in educational systems around the world. Design/methodology/approach: A secondary…

The Possibility of Public Education in an Instrumentalist Age

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Higgins, Chris

2011-01-01

In our increasingly instrumentalist culture, debates over the privatization of schooling may be beside the point. Whether we hatch some new plan for chartering or funding schools, or retain the traditional model of government-run schools, the ongoing instrumentalization of education threatens the very possibility of public education. Indeed, in…

Impact of OpenCourseWare Publication on Higher Education Participation and Student Recruitment

Directory of Open Access Journals (Sweden)

Stephen Carson

2012-10-01

Full Text Available The free and open publication of course materials (OpenCourseWare or OCW was initially undertaken by Massachusetts Institute of Technology (MIT and other universities primarily to share educational resources among educators (Abelson, 2007. OCW, however, and more in general open educational resources (OER1, have also provided well-documented opportunities for all learners, including the so-called “informal learners” and “independent learners” (Carson, 2005; Mulder, 2006, p. 35. Universities have also increasingly documented clear benefits for specific target groups such as secondary education students and lifelong learners seeking to enter formal postsecondary education programs.In addition to benefitting learners, OCW publication has benefitted the publishing institutions themselves by providing recruiting advantages. Finally enrollment figures from some institutions indicate that even in the case of the free and open publication of materials from online programs, OCW does not negatively affect enrollment. This paper reviews evaluation conducted at Massachusetts Institute of Technology, Johns Hopkins Bloomberg School of Public Health (JHSPH, and Open Universiteit Nederland (OUNL concerning OCW effects on higher education participation and student recruitment.

Intercultural Competency in Public Health: A Call for Action to Incorporate Training into Public Health Education.

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Fleckman, Julia M; Dal Corso, Mark; Ramirez, Shokufeh; Begalieva, Maya; Johnson, Carolyn C

2015-01-01

Due to increasing national diversity, programs addressing cultural competence have multiplied in U.S. medical training institutions. Although these programs share common goals for improving clinical care for patients and reducing health disparities, there is little standardization across programs. Furthermore, little progress has been made to translate cultural competency training from the clinical setting into the public health setting where the focus is on population-based health, preventative programming, and epidemiological and behavioral research. The need for culturally relevant public health programming and culturally sensitive public health research is more critical than ever. Awareness of differing cultures needs to be included in all processes of planning, implementation and evaluation. By focusing on community-based health program planning and research, cultural competence implies that it is possible for public health professionals to completely know another culture, whereas intercultural competence implies it is a dual-sided process. Public health professionals need a commitment toward intercultural competence and skills that demonstrate flexibility, openness, and self-reflection so that cultural learning is possible. In this article, the authors recommend a number of elements to develop, adapt, and strengthen intercultural competence education in public health educational institutions.

Sex education in the pedagogical practice of public school teachers

Directory of Open Access Journals (Sweden)

Camila Borges Rufino

2013-12-01

Full Text Available This descriptive study was performed with 29 teachers from three public state schools in Goiânia, Goiás state. The teachers answered a semi-structured questionnaire that aimed at verifying the pedagogical practice in sex education, difficulties related to the theme, and the need for training. Most teachers were male (69% and aged between 25 and 35 years (74%. Half held a graduate degree (54% in human sciences (49%. Nearly all teachers find difficulties in working the topic (89% and need training (93%. Contents on sexuality were not addressed in the Political Pedagogical Projects (76% and the biology program aimed at teaching the theme (55%, a reality that disagrees with the National Curricular Standards, which is based on transversality. Partnerships between health and education must be established, particularly between the Family Health Strategy the higher education institutions, providing public school teachers with the necessary didactic-pedagogical support to address sexuality in the classroom. Descriptors: Sexuality; Schools; Nursing; Public Health.

Pedagogical Scholarship in Public Health: A Call for Cultivating Learning Communities to Support Evidence-Based Education.

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Merzel, Cheryl; Halkitis, Perry; Healton, Cheryl

Public health education is experiencing record growth and transformation. The current emphasis on learning outcomes necessitates attention to creating and evaluating the best curricula and learning methods for helping public health students develop public health competencies. Schools and programs of public health would benefit from active engagement in pedagogical research and additional platforms to support dissemination and implementation of educational research findings. We reviewed current avenues for sharing public health educational research, curricula, and best teaching practices; we identified useful models from other health professions; and we offered suggestions for how the field of public health education can develop communities of learning devoted to supporting pedagogy. Our goal was to help advance an agenda of innovative evidence-based public health education, enabling schools and programs of public health to evaluate and measure success in meeting the current and future needs of the public health profession.

The Imperative of Public Health Education: A Global Perspective

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White, Franklin

2013-01-01

This review positions public health as an endeavour that requires a high order of professionalism in addressing the health of populations; this requires investment in an educational capacity that is designed to meet this need. In the global context, the field has evolved enormously over the past half century, supported by institutions such as the World Bank, the World Health Organization and the Institute of Medicine. Operational structures are formulated by strategic principles, with educational and career pathways guided by competency frameworks, all requiring modulation according to local, national and global realities. Talented and well-motivated individuals are attracted by its multidisciplinary and transdisciplinary environment, and the opportunity to achieve interventions that make real differences to people's lives. The field is globally competitive and open to many professional backgrounds based on merit. Its competencies correspond with assessments of population needs, and the ways in which strategies and services are formulated. Thus, its educational planning is needs-based and evidence-driven. This review explores four public health education levels: graduate, undergraduate, continuing professional education and promotion of health literacy for general populations. The emergence of accreditation schemes is examined, focusing on their relative merits and legitimate international variations. The role of relevant research policies is recognized, along with the need to foster professional and institutional networks in all regions of the world. It is critically important for the health of populations that nations assess their public health human resource needs and develop their ability to deliver this capacity, and not depend on other countries to supply it. PMID:23969636

Financing Albanian Higher Education: Growth between the Public and Private Sectors

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Pere, Engjell; Minxhozi, Luljeta

2011-01-01

In many countries, reforms in higher education have follow-on effects on social and economic development. This article relates mainly to economic and financial issues regarding the development of higher education. Starting from the notable increase in demand for higher education and the budgetary constraints on public education financing, we argue…

The Politics of Race and Educational Disparities in Delaware's Public Schools

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Davis, Theodore J., Jr.

2017-01-01

Delaware has long played a pivotal role in the nation's struggle to end school segregation and promote educational equality. This article discusses racial disparities in educational achievement and outcomes by examining the state's political history and the politics of race in public education. This article explores educational disparities from a…

RRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes

NARCIS (Netherlands)

Domingo, E; Niessen, RC; Oliveira, C; Alhopuro, P; Moutinho, C; Espin, E; Armengol, M; Sijmons, RH; Kleibeuker, JH; Seruca, R; Aaltonen, LA; Imai, K; Yamamoto, H; Schwartz, S; Hofstra, RMW

2005-01-01

Recently, it was shown that the oncogenic activation of BRAF, a member of the RAS/RAF family of kinases, by the V600E mutation is characteristic for sporadic colon tumors with microsatellite instability. Further, it was shown to associate with the silencing of the mismatch repair (MMR) gene MLH1 by

Professional and Educational Initiatives, Supports, and Opportunities for Advanced Training in Public Health

OpenAIRE

Truong, Hoai-An; Patterson, Brooke Y.

2010-01-01

The United States is facing a public health workforce shortage and pharmacists have the opportunity and obligation to address this challenge in health care. There have been initiatives and supports from within and beyond the profession for the pharmacist's role in public health. This article identifies existing professional and educational initiatives for the pharmacist's expanded role in public health, as well as postgraduate and other advanced educational opportunities in public health. Rec...

Shaping public health education, research, and policy in the Arab ...

International Development Research Centre (IDRC) Digital Library (Canada)

Arab countries often face multifaceted health challenges, including gaps and ... play a critical role in filling this gap by educating the public health workforce as well as ... implement an alternative institutional model for public health based on a ...

[Survey on public health nursing education-in the comparison of nursing education courses, universities, advanced courses for public health nurse with junior nursing colleges, and public health nursing school].

Science.gov (United States)

Hirano, Kayoko; Ikeda, Nobuko; Kanagawa, Katuko; Shiomi, Sigeki; Suzuki, Akira; Hirayama, Tomoko; Furuya, Akie; Ymazaki, Kyoko; Yasumura, Seiji

2005-08-01

Changes in public health nursing education have been consideration. Theses changes include a dramatic increase in the number of public health nurses (PHNs) who have enrolled for nursing courses at university. This study was conducted to assess the current status and future of public health nursing education as perceived by teachers and students at three types of schools: universities offering nursing courses, advanced courses for PHNs with junior nursing colleges, and public health nursing schools. Questionnaires were distributed to teachers and students by mail. The questions that were sent to teachers asked which subjects were required to become a certified PHN, which lecture methods were employed to teach public health-particularly community health assessment methods, and what was the level of awareness of the activities of PHNs. Students were asked about their motivation to be a PHN, their understanding of public health, their views of public health activities and their images of PHNs. Responses were analyzed and differences between questionnaires from different schools were noted. These included the number of subjects and the total number of hours spent doing practical training and field experience in universities and the other types of schools, and the number of teachers. Differences also were noted among students at three types of schools about their age, methods of public health activities, knowledge about activities undertaken by PHNs, and their images of PHNs. No differences were observed among the schools with respect to the students' conceptual understanding of public health. Student age, practical training and field experience were found to contribute to their level of understanding of public health and public health nursing. It is thus necessary to consider the teaching methods employed by universities that administer nursing courses and the effectiveness of courses offered by graduate schools.

NASA Astrophysics Education and Public Outreach: Engaging Educators and Students in Exploring the Cosmic Frontier

Science.gov (United States)

Lawton, Brandon L.; Eisenhamer, Bonnie; Smith, Denise Anne; Jirdeh, Hussein; Summers, Frank; Darnell, John T.; Ryer, Holly

2015-08-01

NASA’s Frontier Fields is an ambitious three-year Great Observatories program that will expand our understanding of galaxy formation and evolution in the early universe. The program includes six deep-field observations of strong-lensing galaxy clusters that will be taken in parallel with six deep “blank fields.” The observations allow astronomers to look deeper into the universe than ever before, and potentially uncover galaxies that are as much as 100 times fainter than what the telescopes can typically observe. The Frontier Fields science program is ideal for informing audiences about scientific advances and topics in STEM. The study of galaxy properties, statistics, optics, and Einstein’s theory of general relativity naturally leverages off of the science returns of the Frontier Fields program. As a result, the Space Telescope Science Institute’s Office of Public Outreach (OPO) has initiated an E/PO project to follow the progress of the Frontier Fields.For over two decades, the Hubble E/PO program has sought to bring the wonders of the universe to the education community, the youth, and the public, and engage audiences in the adventure of scientific discovery. Program components include standards-based curriculum-support materials, exhibits and exhibit components, professional development workshops, and direct interactions with scientists. We are also leveraging our new social media strategy to bring the science program to the public in the form of an ongoing blog. The main underpinnings of the program’s infrastructure are scientist-educator development teams, partnerships, and an embedded program evaluation component. OPO is leveraging this existing infrastructure to bring the Frontier Fields science program to the education community and the public in a cost-effective way.This talk features the goals and current status of the Frontier Fields E/PO program, with a particular emphasis on our education goals and achievements. We also highlight OPO�

Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States

NARCIS (Netherlands)

F. Kastrinos (Fay); E.M. Stoffel (Elena); J. Balmana (Judith); E.W. Steyerberg (Ewout); R. Mercado (Rowena); S. Syngal (Sapna)

2008-01-01

textabstractBackground and Aims: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression. Methods: This is a

Mutations in APC, CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study

International Nuclear Information System (INIS)

Lüchtenborg, Margreet; Weijenberg, Matty P; Wark, Petra A; Saritas, A Merdan; Roemen, Guido MJM; Muijen, Goos NP van; Bruïne, Adriaan P de; Brandt, Piet A van den; Goeij, Anton FPM de

2005-01-01

The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics. In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. Mutations at the phosphorylation sites (codons 31, 33, 37, and 45) in the CTNNB1 gene were observed in tumours from only 5/464 patients. Tumours with truncating APC mutations and activating K-ras mutations in codons 12 and 13 occurred at similar frequencies (37% (245/656) and 36% (235/656), respectively). Seventeen percent of tumours harboured both an APC and a K-ras mutation (109/656). Nine percent of all tumours (58/656) lacked hMLH1 expression. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients harbouring tumours with an APC and/or K-ras mutation. CTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency

Mutations in APC, CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study

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de Bruïne Adriaan P

2005-12-01

Full Text Available Abstract Background The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1 and Ras (K-ras pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics. Methods In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. Results Mutations at the phosphorylation sites (codons 31, 33, 37, and 45 in the CTNNB1 gene were observed in tumours from only 5/464 patients. Tumours with truncating APC mutations and activating K-ras mutations in codons 12 and 13 occurred at similar frequencies (37% (245/656 and 36% (235/656, respectively. Seventeen percent of tumours harboured both an APC and a K-ras mutation (109/656. Nine percent of all tumours (58/656 lacked hMLH1 expression. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients harbouring tumours with an APC and/or K-ras mutation. Conclusion CTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency.

Partnering to Enhance Planetary Science Education and Public Outreach Programs

Science.gov (United States)

Dalton, H.; Shipp, S. S.; Shupla, C. B.; Shaner, A. J.; LaConte, K.

2015-12-01

The Lunar and Planetary Institute (LPI) in Houston, Texas utilizes many partners to support its multi-faceted Education and Public Outreach (E/PO) program. The poster will share what we have learned about successful partnerships. One portion of the program is focused on providing training and NASA content and resources to K-12 educators. Teacher workshops are performed in several locations per year, including LPI and the Harris County Department of Education, as well as across the country in cooperation with other programs and NASA Planetary Science missions. To serve the public, LPI holds several public events per year called Sky Fest, featuring activities for children, telescopes for night sky viewing, and a short scientist lecture. For Sky Fest, LPI partners with the NASA Johnson Space Center Astronomical Society; they provide the telescopes and interact with members of the public as they are viewing celestial objects. International Observe the Moon Night (InOMN) is held annually and involves the same aspects as Sky Fest, but also includes partners from Johnson Space Center's Astromaterials Research and Exploration Science group, who provide Apollo samples for the event. Another audience that LPI E/PO serves is the NASA Planetary Science E/PO community. Partnering efforts for the E/PO community include providing subject matter experts for professional development workshops and webinars, connections to groups that work with diverse and underserved audiences, and avenues to collaborate with groups such as the National Park Service and the Afterschool Alliance. Additional information about LPI's E/PO programs can be found at http://www.lpi.usra.edu/education. View a list of LPI E/PO's partners here: http://www.lpi.usra.edu/education/partners/.

Beyond Choice to New Public Schools: Withdrawing the Exclusive Franchise in Public Education. Policy Report No. 8.

Science.gov (United States)

Kolderie, Ted

A strategy for revitalizing public education by stimulating the creation of new public schools is proposed in this report. The proposed system goes beyond school choice and is based on the withdrawal of local districts' exclusive franchise to own and operate public schools. The proposal is based on the premise that the state must provide both…

Public sector accounting in the education syllabi of leading chartered accountant professional bodies: A comparative study

Directory of Open Access Journals (Sweden)

Ahmed Mohammadali-Haji

2016-05-01

Full Text Available Public sector accounting has emerged as an area of concern within the sphere of professional accounting education. The International Federation of Accountants (IFAC allows its member bodies to apply discretion in the application of public sector accounting education requirements. This study explored the nature and extent to which public sector accounting features in the education syllabi of the leading chartered accountant professional bodies that form part of the IFAC contingent. By following an explorative approach, the study identified international trends within the ambit of public sector accounting education and provides guidance for other professional bodies in assessing the nature and extent of their public sector accounting education requirements

Radical Servant Leadership: A New Practice of Public Education Leadership in the Post-Industrial Age

Science.gov (United States)

Letizia, Angelo

2014-01-01

Both secondary and postsecondary public education may offer one the last spaces for true democratic dialogue untainted by the market (Giroux, 2011). Public education however is under attack by "reformers" who seek to privatize it and transform it into a market good (Klein, 2007). Due to this, public education needs leaders who will fight…

Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families

International Nuclear Information System (INIS)

Thodi, Georgia; Fountzilas, George; Yannoukakos, Drakoulis; Fostira, Florentia; Sandaltzopoulos, Raphael; Nasioulas, George; Grivas, Anastasios; Boukovinas, Ioannis; Mylonaki, Maria; Panopoulos, Christos; Magic, Mirjana Brankovic

2010-01-01

Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort. Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines. Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years. The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect

Engaging Public Space: Art Education Pedagogies for Social Justice

Science.gov (United States)

Duncum, Paul

2011-01-01

Considering social justice to be founded on human rights, which, in turn, are grounded in freedom of thought, expression, and assembly, this essay reviews efforts by art educators to engage with public space as a form of social justice pedagogy. Public space, whether actual or virtual, is understood to be inherently devoted to contestation in the…

ACCRUAL ACCOUNTING EXPERIENCE IN THE ROMANIAN PUBLIC HIGHER EDUCATION SECTOR

OpenAIRE

Tiron Tudor, Adriana; Blidisel, Rodica

2007-01-01

The purpose of this paper is to present experiences from the use of accrual accounting information in the public higher education sector in Romania and, thus, to contribute to our understanding of the prospects for using that kind of accounting in public organizations.

The Burden of Urban Education: Public Schools in Massachusetts, 1870-1915.

Science.gov (United States)

Lazerson, Marvin

Confronted by a rapidly changing urban-industrial society, Massachusetts educators undertook reforms between 1870 and 1915 to make the public school a more relevant institution. Kindergarten, manual training, vocational education, evening schools, and citizenship education represented answers to problems arising from industrialism and urbanism.…

Digital Culture, Education and Public Sphere

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Luiz Roberto Gomes

2016-02-01

Full Text Available In the context of the so-called digital culture, this paper discusses the issue of education and the political implications of the distance learning expansion movement in Brazil. In addition to the advances in the democratization of the access to information through the mediation of information and communication technologies (ICTs, which should be recognized as an effort to spread a certain “political culture”, this does not necessarily mean, as Habermas (2003b recalls, that the effective political participation of citizens is assured, especially in light of recurrent dislocation between the political public sphere and civil society. What are the interests behind the phenomenon of digitization of culture? And what is the purpose of education in this new cultural context? As an expression of contemporary social life, digital culture generates structural changes, not only in the form of transmission and access to culture, but also in the very concept and attitude towards culture, with decisive political implications for education. That leads us to think, for example, about the differences between the concepts of education present in the classical Greek Paideia culture, in the modern culture of Bildung, and in the contemporary educational model increasingly subservient to the ICTs we now have.

FINANCING PUBLIC INSTITUTIONS OF ACADEMIC EDUCATION IN SPAIN

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DRĂGUŞIN CRISTINA-PETRINA

2015-04-01

Full Text Available Currently, Spanish universities meet the educational needs of the students with a wide offer of courses and the opportunity to study at all levels. They appear as an attractive option in the context of the relatively low cost of living compared to other countries in the EU area and under conditions of a tax system controlled by the Government. Starting from the assumption that the financing model of the academic education public institutions represents the foundation of their modernization in the current society based on changes and evolution, in this paper we propose to bring into the light of the concerns of those who are interested, through a persuasive exhibit, the Spanish model and its specific features. To this end, our debate will begin with a description of the Spanish system of academic education under the decentralized model of financing imprint, continuing with the presentation of specific skills in terms of funding on the triptych template: state - autonomous communities - universities. Subsequently, our investigative approach will focus on detailing the tertiary education financing sources: public resources, private and patrimonial revenues. The end of our presentation will be intended for conclusions, through which we aim to advance our vision regarding the investigated problems. In fact, the paper is intended to be a precursor step in carrying out a comparative study between the academic education funding mechanism in Romania and the Spanish one.

Towards a pedagogy for patient and public involvement in medical education.

Science.gov (United States)

Regan de Bere, Sam; Nunn, Suzanne

2016-01-01

This paper presents a critique of current knowledge on the engagement of patients and the public, referred to here as patient and public involvement (PPI), and calls for the development of robust and theoretically informed strategies across the continuum of medical education. The study draws on a range of relevant literatures and presents PPI as a response process in relation to patient-centred learning agendas. Through reference to original research it discusses three key priorities for medical educators developing early PPI pedagogies, including: (i) the integration of evidence on PPI relevant to medical education, via a unifying corpus of literature; (ii) conceptual clarity through shared definitions of PPI in medical education, and (iii) an academically rigorous approach to managing complexity in the evaluation of PPI initiatives. As a response to these challenges, the authors demonstrate how activity modelling may be used as an analytical heuristic to provide an understanding of a number of PPI systems that may interact within complex and dynamic educational contexts. The authors highlight the need for a range of patient voices to be evident within such work, from its generation through to dissemination, in order that patients and the public are partners and not merely objects of this endeavour. To this end, this paper has been discussed with and reviewed by our own patient and public research partners throughout the writing process. © 2015 John Wiley & Sons Ltd.

The history of appearance of the Ministry of Public education in the domestic historiography

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