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MMR
Terms modified by MMR Selected AbstractsGait disturbance interpreted as cerebellar ataxia after MMR vaccination at 15 months of age: a follow-up studyACTA PAEDIATRICA, Issue 1 2000A-M Plesner Measles, mumps and rubella (MMR) vaccination was included in the Danish childhood vaccination programme in 1987. During the following 10-y period, 550 notification records of adverse events after MMR vaccination at 15 mo of age have been registered, and a total of 41 notifications have included "gait disturbance". This corresponds to a frequency of 8 per 100 000 doses of MMR vaccine used for 15-mo-old children. The symptoms and signs are characteristic of cerebellar ataxia. In 28 notifications, the descriptions by the doctors included only "gait disturbance", while in 13 an additional interpretation was included. Thirty-two parents (78%) filled in a questionnaire and 26 (63%) agreed to participate in a clinical follow-up study. The gait disturbance symptoms mainly occurred 7,14 d after the vaccination, and the duration was median 1,2 wk (range 1 d to more than 4 mo). One-third of the children had symptoms lasting more than 2 wk. Significantly more children with long duration of symptoms had some kind of complaint or clinical signs at the follow-up in 1997. Gait disturbance registered after MMR vaccination seems to be more frequent than hitherto reported. Most cases are mild and short-lasting and a longer duration of symptoms seems to be predictive of late sequelae. A clinical diagnosis of cerebellar ataxia after MMR and the exact frequency of this adverse event remains to be tested in prospective studies. [source] The epidemiology of autistic spectrum disorders: is the prevalence rising?DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2002Lorna Wing Abstract For decades after Kanner's original paper on the subject was published in 1943, autism was generally considered to be a rare condition with a prevalence of around 2,4 per 10,000 children. Then, studies carried out in the late 1990s and the present century reported annual rises in incidence of autism in pre-school children, based on age of diagnosis, and increases in the age-specific prevalence rates in children. Prevalence rates of up to 60 per 10,000 for autism and even more for the whole autistic spectrum were reported. Reasons for these increases are discussed. They include changes in diagnostic criteria, development of the concept of the wide autistic spectrum, different methods used in studies, growing awareness and knowledge among parents and professional workers and the development of specialist services, as well as the possibility of a true increase in numbers. Various environmental causes for a genuine rise in incidence have been suggested, including the triple vaccine for measles, mumps and rubella (MMR]. Not one of the possible environmental causes, including MMR, has been confirmed by independent scientific investigation, whereas there is strong evidence that complex genetic factors play a major role in etiology. The evidence suggests that the majority, if not all, of the reported rise in incidence and prevalence is due to changes in diagnostic criteria and increasing awareness and recognition of autistic spectrum disorders. Whether there is also a genuine rise in incidence remains an open question. MRDD Research Reviews 2002;8:151,161. © 2002 Wiley-Liss, Inc. [source] Aetiology in severe and mild mental retardation: a population-based study of Norwegian childrenDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 2 2000Petter Strømme MD PhD The aetiology of mental retardation (MR) was studied in a population-based series of Norwegian children derived from 30 037 children born between 1980 and 1985. The study included 178 children, 79 with severe MR (SMR) (IQ<50) and 99 with mild MR (MMR) (IQ 50 to 70). Aetiology was divided into two main groups: biopathological and unspecified. The biopathological group comprised 96% of SMR and 68% of MMR, and was subdivided into prenatal (70% and 51%), perinatal (4% and 5%), and postnatal damage (5% and 1%), and a group of undetermined timing of the damaging event (18% and 11%). Single-gene disorders accounted for 15 of the 63 children with genetic disorders, including X-linked recessive in six. During the course of the study, at least 27 (15%) children had their aetiological diagnosis revised. Gestational age <32 weeks, birthweight <1500g, and Apgar scores 0 to 2 at 1 and 5 minutes implied a significantly increased risk of MR, but contributed to only 4% of the children in the study. Decreased birthweight (1500 to 2499 g) and Apgar scores 3 to 6 at 1 and 5 minutes showed increased probability of MR. Despite extensive investigations, 4% of SMR and 32% of MMR were not identified with any biological markers and were considered as unspecified MR, several most probably representing the lower end of the normal IQ distribution in the population. [source] Elevated organochlorines in the brain,hypothalamic,pituitary complex of intersexual shovelnose sturgeonENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2006Brian T. Koch Abstract Organochlorine compounds (OCs), including polychlorinated biphenyls and organochlorine pesticides, were used on lands adjacent to the Middle Mississippi River (MMR; USA) from 1930 through 1988, and they continue to occur in MMR fish. These compounds are estrogenic and/or antiandrogenic, and they alter hormone production and reception within the brain and gonads of male fish, resulting in intersexuality and/or suppressed gonadal development. To assess how OCs affect reproduction of MMR fish, we quantified OC accumulation, intersexuality, and gonadal development in male shovelnose sturgeon (Scaphirhynchus platorynchus) throughout the MMR during the spring of 2003. Gonads were observed for intersexual characteristics, weighed to calculate the gonadosomatic index (GSI), and examined histologically. Tissue accumulation of OCs was quantified in gonads, brain,hypothalamic,pituitary (BHP) complex, and fillets. Four of 48 mature males were identified macroscopically as intersexuals, and a fifth was found through histology (a 10.4% incidence). Intersexuals accumulated higher concentrations of OCs in the BHP complex compared with those of mature males. In addition, GSI and OC accumulation within the BHP complex, gonads, and fillets of mature males were negatively related. Exposure to OCs before or during sexual differentiation likely induces intersexuality in MMR shovelnose sturgeon, and exposure throughout gonadal maturation inhibits gonadal development. [source] Using spatial models and kriging techniques to optimize long-term ground-water monitoring networks: a case studyENVIRONMETRICS, Issue 5-6 2002Kirk Cameron Abstract In a pilot project, a spatial and temporal algorithm (geostatistical temporal,spatial or GTS) was developed for optimizing long-term monitoring (LTM) networks. Data from two monitored ground-water plumes were used to test the algorithm. The primary objective was to determine the degree to which sampling, laboratory analysis, and/or well construction resources could be pared without losing key statistical information concerning the plumes. Optimization of an LTM network requires an accurate assessment of both ground-water quality over time and trends or other changes in individual monitoring wells. Changes in interpolated concentration maps over time indicate whether ground-water quality has improved or declined. GTS separately identifies temporal and spatial redundancies. Temporal redundancy may be reduced by lengthening the time between sample collection. Spatial redundancy may be reduced by removing wells from the network which do not significantly impact assessment of ground-water quality. Part of the temporal algorithm in GTS involves computation of a composite temporal variogram to determine the least redundant overall sampling interval. Under this measure of autocorrelation between sampling events, the lag time at which the variogram reaches a sill is the sampling interval at which same-well measurements lack correlation and are therefore non-redundant. The spatial algorithm assumes that well locations are redundant if nearby wells offer nearly the same statistical information about the underlying plume. A well was considered redundant if its removal did not significantly change: (i) an interpolated map of the plume; (ii) the local kriging variances in that section of the plume; and (iii) the average global kriging variance. To identify well redundancy, local kriging weights were accumulated into global weights and used to gauge each well's relative contribution to the interpolated plume map. By temporarily removing that subset of wells with the lowest global kriging weights and re-mapping the plume, it was possible to determine how many wells could be removed without losing critical information. Test results from the Massachusetts Military Reserve (MMR) indicated that substantial savings in sampling, analysis and operational costs could be realized by utilizing GTS. Annual budgetary savings that would accrue were estimated at between 35 per cent and 5 per cent for both LTM networks under study.Copyright © 2002 John Wiley & Sons, Ltd. [source] DNA base repair , recognition and initiation of catalysisFEMS MICROBIOLOGY REVIEWS, Issue 6 2009Bjørn Dalhus Abstract Endogenous DNA damage induced by hydrolysis, reactive oxygen species and alkylation modifies DNA bases and the structure of the DNA duplex. Numerous mechanisms have evolved to protect cells from these deleterious effects. Base excision repair is the major pathway for removing base lesions. However, several mechanisms of direct base damage reversal, involving enzymes such as transferases, photolyases and oxidative demethylases, are specialized to remove certain types of photoproducts and alkylated bases. Mismatch excision repair corrects for misincorporation of bases by replicative DNA polymerases. The determination of the 3D structure and visualization of DNA repair proteins and their interactions with damaged DNA have considerably aided our understanding of the molecular basis for DNA base lesion repair and genome stability. Here, we review the structural biochemistry of base lesion recognition and initiation of one-step direct reversal (DR) of damage as well as the multistep pathways of base excision repair (BER), nucleotide incision repair (NIR) and mismatch repair (MMR). [source] Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor , resistant cellsGENES, CHROMOSOMES AND CANCER, Issue 2 2008Swati Biswas The mutational inactivation of transforming growth factor , receptor type II (TGFBR2) occurs in ,30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. © 2007 Wiley-Liss, Inc. [source] Mutations in the ataxia telangiectasia and rad3-related,checkpoint kinase 1 DNA damage response axis in colon cancersGENES, CHROMOSOMES AND CANCER, Issue 12 2007Kriste A. Lewis In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior. Screening for ATR mutations in 48 tumors was performed using denaturing high-performance liquid chromatography (DHPLC) and confirmed with sequencing analysis. The CHEK1 exon 7 A(9) region was sequenced in 20 of the 27 (74%) tumors with high frequency of microsatellite instability (MSI-H). Univariate and multivariate analyses were used to examine associations with clinical outcomes. Frequent mutations in MSI-H colon cancers were identified within the ATR (37%)/CHEK1(5%) damage response pathway. Stage and MSI status both independently predicted overall survival (OS) and disease-free survival (DFS). ATR status was not associated with stage, but was associated with a trend toward improved DFS: 0/9 cancers recurred in MSI-H cases harboring ATR mutations vs. 4/18 recurrences in MSI-H cases without ATR mutations. This suggests that ATR mutations may affect clinical behavior and response to therapy in MSI-H colon cancers. © 2007 Wiley-Liss, Inc. [source] Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)GENES, CHROMOSOMES AND CANCER, Issue 2 2005Heleen van der Klift A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories. © 2005 Wiley-Liss, Inc. [source] DNA mismatch repair protein expression and microsatellite instability in primary mucosal melanomas of the head and neckHISTOPATHOLOGY, Issue 6 2007C Marani Aims:, To examine the expression of DNA mismatch repair (MMR) proteins and the presence of microsatellite instability (MSI) in seven primary mucosal melanomas of the head and neck (MMHN). Methods and results:, Haematoxylin and eosin staining and immunohistochemical analysis for routine diagnostic markers and for MMR proteins were performed. Six cases were examined for MSI. Four cases were monomorphous and three cases were pleomorphic type MMHN. Melanocytic markers were positive in all cases. Immunoreactivity for MMR proteins was weak in normal epithelium. The neoplastic tissue in six cases showed positivity for all MMR proteins with different percentages. One case showed weak positivity for hMSH2 and hMSH6 and no immunoreactivity for hMLH1 or hPMS2. Staining intensity was higher in tumour cells than in matched normal mucosa in three cases for hMSH2 and hMLH1 and in two cases for hPMS2. None of the examined cases showed MSI. Conclusions:, Expression of hMSH2 and hMLH1 proteins was up-regulated in three cases, whereas in two cases that of hPMS2 was increased. hMSH6 expression was comparable to that of normal cells in all cases. The percentage of positive neoplastic cells and the intensity of staining seemed to be greater in pleomorphic melanomas. Six cases were MMR-proficient and microsatellite stable. [source] Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristicsHUMAN MUTATION, Issue 5 2009Sven Arnold Abstract Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm in vitro, splicing aberrations associated with mismatch repair (MMR) variants identified in familial colon cancer patients. Six programs were used to predict the effect of 13 MLH1 and 6 MSH2 gene variants on pre-mRNA splicing. mRNA from cycloheximide-treated lymphoblastoid cell lines of variant carriers was screened for splicing aberrations. Tumors of variant carriers were tested for microsatellite instability and MMR protein expression. Variant segregation in families was assessed using Bayes factor causality analysis. Amino acid alterations were examined for evolutionary conservation and physicochemical properties. Splicing aberrations were detected for 10 variants, including a frameshift as a minor cDNA product, and altered ratio of known alternate splice products. Loss of splice sites was well predicted by splice-site prediction programs SpliceSiteFinder (90%) and NNSPLICE (90%), but consequence of splice site loss was less accurately predicted. No aberrations correlated with ESE predictions for the nine exonic variants studied. Seven of eight missense variants had normal splicing (88%), but only one was a substitution considered neutral from evolutionary/physicochemical analysis. Combined with information from tumor and segregation analysis, and literature review, 16 of 19 variants were considered clinically relevant. Bioinformatic tools for prediction of splicing aberrations need improvement before use without supporting studies to assess variant pathogenicity. Classification of mismatch repair gene variants is assisted by a comprehensive approach that includes in vitro, tumor pathology, clinical, and evolutionary conservation data. Hum Mutat 0, 1,14, 2009. © 2009 Wiley-Liss, Inc. [source] Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome,HUMAN MUTATION, Issue 2 2009Marietta E. Kovacs Abstract Several different genetic alterations in the etiology of Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30,50%) of clinicopathologically well-defined HNPCC families, suggesting the presence of other predisposing mechanisms. In a set of probands from 27 Lynch syndrome families who lacked evidence of a germline mutation in either the MSH2 or MLH1 gene, we performed genomic deletion screening with the use of multiplex ligation-dependent probe amplification (MLPA) and sequencing. We used immunohistochemistry (IHC) and microsatellite instability (MSI) analyses on samples of the probands of all families. Comparative analysis of mRNA transcripts was performed on blood leukocyte,derived samples from mutation carriers and noncarrier controls. We report that large germline deletions encompassing the last exons of the TACSTD1 gene, upstream of MSH2, cosegregate with the HNPCC phenotype in 19% (5/27) of families tested. The tumors of the carriers show high-level MSI and MSH2 protein loss. We show that these deletions, by removing the transcriptional termination sequences of the upstream gene, give rise to multiple TACSTD1/MSH2 fusion transcripts. Our results provide evidence that deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Thus, analysis of the 3, region of the TACSTD1 gene should be included in the routine mutation screening protocols for HNPCC. Hum Mutat 30, 197,203, 2009. © 2009 Wiley-Liss, Inc. [source] Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes,HUMAN MUTATION, Issue 11 2007Jianghua Ou Abstract Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is caused by DNA variations in the DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and PMS2. Many of the mutations identified result in premature termination of translation and thus in loss-of-function of the encoded mutated protein. These DNA variations are thought to be pathogenic mutations. However, some patients carry other DNA mutations, referred to as unclassified variants (UVs), which do not lead to such a premature termination of translation; it is not known whether these contribute to the disease phenotype or merely represent rare polymorphisms. This is a major problem which has direct clinical consequences. Several criteria can be used to classify these UVs, such as: whether they segregate with the disease within pedigrees, are absent in control individuals, show a change of amino acid polarity or size, provoke an amino acid change in a domain that is evolutionary conserved and/or shared between proteins belonging to the same protein family, or show altered function in an in vitro assay. In this review we discuss the various functional assays reported for the HNPCC-associated MMR proteins and the outcomes of these tests on UVs identified in patients diagnosed with or suspected of having HNPCC. We conclude that a large proportion of MMR UVs are likely to be pathogenic, suggesting that missense variants of MMR proteins do indeed play a role in HNPCC. Hum Mutat 28(11), 1047,1054, 2007. © 2007 Wiley-Liss, Inc. [source] Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue,,HUMAN MUTATION, Issue 3 2004Jens Plaschke Abstract Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6 -deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations. © 2004 Wiley-Liss, Inc. [source] MMR and IBD: The only thing we have to fear is,fear itselfINFLAMMATORY BOWEL DISEASES, Issue 4 2001Subra Kugathasan M.D. No abstract is available for this article. [source] MR linear contact detection algorithmINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 1 2006A. Munjiza Abstract Large-scale discrete element simulations, as well as a whole range of related problems, involve contact of a large number of separate bodies and an efficient and robust contact detection algorithm is necessary. There has been a number of contact detection algorithms with total detection time proportional to N ln(N) (where N is the total number of separate bodies) reported in the past. In more recent years algorithms with total CPU time proportional to N have been developed. In this work, a novel contact detection algorithm with total detection time proportional to N is proposed. The performance of the algorithm is not influenced by packing density, while memory requirements are insignificant. The algorithm is applicable to systems comprising bodies of a similar size. The algorithm is named MR (Munjiza,Rougier: Munjiza devised the algorithm, Rougier implemented it). In the second part of the paper the algorithm is extended to particles of different sizes. The new algorithm is called MMR (multi-step MR) algorithm. Copyright © 2005 John Wiley & Sons, Ltd. [source] Mismatch repair system decreases cell survival by stabilizing the tetraploid G1 arrest in response to SN-38INTERNATIONAL JOURNAL OF CANCER, Issue 12 2010Mandar Ramesh Bhonde Abstract The role of the mismatch repair (MMR) system in correcting base,base mismatches is well established; its involvement in the response to DNA double strand breaks, however, is less clear. We investigated the influence of the essential component of MMR, the hMLH1 protein, on the cellular response to DNA-double strand breaks induced by treatment with SN-38, the active metabolite of topoisomerase I inhibitor irinotecan, in a strictly isogenic cell system (p53wt, hMLH1+/p53wt, hMLH1,). By using hMLH1 expressing clones or cells transduced with the hMLH1-expressing adenovirus as well as siRNA technology, we show that in response to SN-38-induced DNA damage the MMR proficient (MMR+) cells make: (i) a stronger G2/M arrest, (ii) a subsequent longer tetraploid G1 arrest, (iii) a stronger activation of Chk1 and Chk2 kinases than the MMR deficient (MMR,) counterparts. Both Cdk2 and Cdk4 kinases contribute to the basal tetraploid G1 arrest in MMR+ and MMR, cells. Although the Chk1 kinase is involved in the G2/M arrest, neither Chk1 nor Chk2 are involved in the enhancement of the tetraploid G1 arrest. The long-lasting tetraploid G1 arrest of MMR+ cells is associated with their lower clonogenic survival after SN-38 treatment, the abrogation of the tetraploid G1 arrest resulted in their better clonogenic survival. These data show that the stabilization of the tetraploid G1 arrest in response to double strand breaks is a novel function of the MMR system that contributes to the lesser survival of MMR+ cells. [source] Mismatch repair expression in testicular cancer predicts recurrence and survivalINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Alfredo Velasco Abstract We investigated mismatch repair (MMR) gene expression in testicular cancer as a molecular marker for clinical outcome (recurrence, response to chemotherapy and death) using protein expression and specific genetic alterations associated with the presence or absence of MMR activity. One hundred sixty-two cases of paraffin-embedded testis cancer specimens were subjected to immunohistochemical analysis using monoclonal antibody for MLH1 and MSH2 MMR proteins and genetic analysis using specific polymorphic markers. The degree of MMR immunoreactivity and genetic instability in the form of loss of heterozygosity (LOH) and/or microsatellite instability (MSI) were determined by comparing matched normal and tumor tissue. The degree of immunohistochemical staining for MMR expression was associated with a shorter time to tumor recurrence, resistance to chemotherapy and death. Furthermore, clinical relapse and cancer specific death was also associated with tumors exhibiting a high degree of MSI, p = 0.01 and 0.04, respectively. In contrast, LOH was not associated with recurrence, resistance to chemotherapy or death. Therefore, MMR expression defines testis cancers with distinct molecular properties and clinical behavior, such that tumors with decreased MMR immunostaining and/or increased frequency of MSI have a shorter time to recurrence and death despite chemotherapy. © 2007 Wiley-Liss, Inc. [source] Beta2-microglobulin mutations in microsatellite unstable colorectal tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2007Matthias Kloor Abstract Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the ,2 -microglobulin (,2m) gene. To examine the implications of ,2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of ,2m mutations in MSI-H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of ,2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of ,2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. ,2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of ,2m expression may promote local progression of colorectal MSI-H tumors. However, no ,2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional ,2m may be necessary for distant metastasis formation in CRC patients. © 2007 Wiley-Liss, Inc. [source] Diethylstilbestrol effects and lymphomagenesis in Mlh1 -deficient miceINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Omar Kabbarah Abstract Inherited defects in DNA mismatch repair (MMR) predispose to a variety of malignancies in humans and in mouse knockout models. In humans, hemizygosity for one of several DNA MMR genes greatly increases an individual's risk for colon and endometrial carcinoma. Hemizygous mice develop gastrointestinal tumors at a low to moderate frequency. Homozygous nulls have higher rates of gastrointestinal tumors and are particularly susceptible to lymphoma. In an effort to model endometrial carcinoma associated with mutation in MMR, we treated mice carrying knockout alleles for Mlh1 or Msh2 with the synthetic estrogen diethylstilbestrol (DES), a known promoter of uterine endometrial carcinoma. The C57BL/6 mice carrying DNA MMR mutations failed to develop endometrial carcinomas. However, the Mlh1 -deficient mice treated with DES tended to become moribund at an early age and had very early onset of lymphoma. Comparison of DES-treated and untreated Mlh1,/, animals suggests the combination of Mlh1 deficiency and DES exposure accelerates lymphomagenesis. © 2005 Wiley-Liss, Inc. [source] Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from ThailandINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Upama Liengswangwong Abstract The liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) is a major liver cancer in Northeast Thailand. The molecular basis of this ICC is poorly understood. To address possible roles of the DNA mismatch repair (MMR) system in ICC carcinogenesis, a fluorescence-labeling PCR/laser scanning technique with high sensitivity was employed to analyze genomic instability in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in 24 fresh and 13 formalin-fixed, paraffin-embedded tissues of ICC and their corresponding normal parts. Microsatellite instability (MSI) was assessed in nDNA, using 12 highly polymorphic loci including 5 Bethesda markers. These loci were mainly related to major MMR genes, hMSH2 and hMLH1. Also 3 (C)n and/or (C)n(A)n repeat instability at 1 noncoding region in the displacement-loop (D-loop) and 2 coding sequences in NADH dehydrogenase subunit 1 and subunit 5 gene in mtDNA were analyzed. MSI was only detected in 1 (2.7%), 6 (16.7%), 1 (2.9%), 1 (2.9%) or 2 (6.3%) out of 37, 36, 35, 35 or 32 cases at BAT-25, D2S123, D3S1611, D11S904 or D17S250, respectively. LOH was found at D3S1298, D3S1561, D5S346 and TP53 in 4 (18.2%) out of 22, 2 (18.2%) out of 11, 6 (33.3%) out of 18 and 3 (12.5%) out of 24 informative cases, respectively. In mtDNA, none except a single case out of the 37 (2.7%) exhibited repeat sequence instability in the D-loop. We conclude that the liver fluke infection-associated ICC in Thailand is classified as low frequency MSI or microsatellite stable type and that DNA MMR system, through hMSH2 and hMLH1 gene mutations, does not play a major role in its carcinogenesis. © 2003 Wiley-Liss, Inc. [source] Evidence for an age-related influence of microsatellite instability on colorectal cancer survivalINTERNATIONAL JOURNAL OF CANCER, Issue 6 2002Susan M. Farrington Abstract It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p , 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. © 2002 Wiley-Liss, Inc. [source] Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithmJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2009Ossama Abbas Sebaceous gland neoplasms such as adenoma, epithelioma, and carcinoma are uncommon cutaneous tumors. Although sporadic, their occurrence is clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that include gastrointestinal and genitourinary cancers. MTS is usually the result of germline mutation in one or more of the DNA mismatch repair (MMR) genes. MMR genes commonly implicated include MSH -2 and MLH -1 and, more recently, MSH -6. Recent evidence suggests that immunohistochemistry is very sensitive and effective in detecting these defects in cutaneous tumors in MTS. In addition, the genetic instability of cutaneous and visceral tumors in MTS caused by the defects in MMR genes can also be detected, using polymerase chain reaction (PCR)-based techniques, for microsatellite instability (MSI). Given that some sebaceous neoplasms represent cutaneous markers of MTS, what should we as dermatopathologists be advocating? Should we be looking for absence/loss of MMRs in all sebaceous neoplasms? When should we recommend assaying for MSI? This review attempts to address all of these issues with a view to streamlining the work-up of a patient presenting for the first time with a sebaceous neoplasm and no prior personal or family history of internal malignancies. [source] MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeresAGING CELL, Issue 1 2009Paula Martinez Summary Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerase-deficient mice. In particular, progressively shorter telomeres at successive generations of MSH2,/,Terc,/,- mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2,/,Terc,/, mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway. [source] Maternal Mortality in Rural India: A Hospital Based, 10 Year Retrospective AnalysisJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 4 2001Dr. Kavita Verma Abstract Objectives: To estimate the maternal mortality ratio (MMR) in Ludhiana, a city of Northern India in order to determine the causes associated with MMR and to suggest ways to reduce it. Methods: Retrospective analysis of the mortality records of obstetrics cases in Christian Medical College, Ludhiana, India. Results: The mean MMR for the 10 year period was 785 per 100,000 live births. Of the total 116 reported maternal deaths, 44 (41.9%) were due to induced septic abortion. The reasons were unwanted pregnancy in 22 (50%) and 11 (25%) were female feticide. Conclusions: In our hospital based analysis, MMR was very high. Most maternal deaths are preventable by intervention at the appropriate time and it is important for health professionals, policy makers and politicians to implement the introduction of programs for reducing maternal mortality. Special emphasis should be placed on antenatal care, the establishment of a registration system and measures to abolish illegal abortion. [source] Best-practice recommendations for estimating interaction effects using moderated multiple regressionJOURNAL OF ORGANIZATIONAL BEHAVIOR, Issue 6 2010Herman Aguinis An interaction effect indicates that a relationship is contingent upon the values of another (moderator) variable. Thus, interaction effects describe conditions under which relationships change in strength and/or direction. Understanding interaction effects is essential for the advancement of the organizational sciences because they highlight a theory's boundary conditions. We describe procedures for estimating and interpreting interaction effects using moderated multiple regression (MMR). We distill the technical literature for a general readership of organizational science researchers and include specific best-practice recommendations regarding actions researchers can take before and after data collection to improve the accuracy of MMR-based conclusions regarding interaction effects. Copyright © 2010 John Wiley & Sons, Ltd. [source] An ultra-wideband bandpass filter using hybrid structure of microstrip and CPWMICROWAVE AND OPTICAL TECHNOLOGY LETTERS, Issue 10 2009Xun Luo Abstract An ultra-wideband (UWB) bandpass filter is proposed based on the hybrid structure of microstrip and coplanar waveguide (CPW). First, the detached-mode resonator is formed on the CPW layer, which composes a quarter-wavelength (,/4) multiple-mode resonator (MMR) with a short-stub and a ,/4 single-mode resonator. Then, two ,/4 microstrip open-stubs on the top side of the common substrate are introduced for bandwidth enhancement to meet the UWB passband limit. Quasi-elliptic function response and UWB operation are achieved. The simulated and measured results show an excellent agreement. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 2470,2473, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24658 [source] A novel compact ultrawideband (UWB) bandpass filter using multiple-mode resonatorMICROWAVE AND OPTICAL TECHNOLOGY LETTERS, Issue 7 2009D. Chen Abstract In this letter, a novel compact ultrawideband (UWB) bandpasss filter (BPF) using the proposed multiple-mode resonator (MMR) is presented. The MMR is composed of a conventional microstrip hairpin resonator of which the two arms are connected by a section of microstrip line and a short-circuited point located in the middle of the hairpin resonator. Its first three resonant modes can be utilized to construct the UWB band. The tapped feeding structure has been used to realize desired tight couplings for designing the UWB BPF. The filter has been investigated numerically and experimentally. Both the simulated and measured results show that the filter has good performance, such as compact size, low-insertion loss, small group delay variation, and improved out-of-band performances. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 1662,1664, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24424 [source] Microsatellite instability and alteration of E2F-4 gene in adenosquamous and squamous cell carcinomas of the stomachPATHOLOGY INTERNATIONAL, Issue 9 2000Dong Kyun Woo Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) is a form of genomic instability underlying the tumorigenesis of various human neoplasms. To evaluate the roles of MSI in the pathogenesis of gastric carcinomas with squamous differentiation, 17 primary stomach cancer patients (15 adenosquamous and two squamous cell carcinomas) were examined for MSI frequency using five microsatellite markers and the criteria for MSI recommended by the National Cancer Institute Workshop. The molecular causes and consequences of MSI in these neoplasms were further researched through the immunohistochemistry of MMR proteins and the mutational analysis of cancer-associated genes targeted by MSI, respectively. Two of the 17 (12%) cases demonstrated MSI at the most examined loci and were classified as having high level MSI (MSI-H). These tumors also exhibited frame-shift mutations at mononucleotide repeats in the target genes, including TGF,RII, IGFIIR, BAX, and hMSH6. It is interesting to note that the mutations of the serine (AGC)13 repeats within the E2F-4 gene were found only in the squamous cell carcinoma portions of them, whereas such alterations were not detected in any of the adenocarcinomatous portions. This suggests that E2F-4 might be implicated in the transformation of adenocarcinoma into squamous cell carcinoma and further studies are needed to understand its role in squamous differentiation. [source] Prevalence of allergic symptoms among children with diabetes mellitus type 1 of different socioeconomic statusPEDIATRIC DIABETES, Issue 4pt2 2008Kyriaki Karavanaki Abstract:, The aim of the study was to assess the possible associations between allergies and type 1 diabetes mellitus (DM1), stratified by social class. We studied 127 children with DM1 with a median age of 10.8 yr and 150 controls of comparable age and sex distribution. The parents completed questionnaires on their education and occupation and on their children's history of allergic symptoms, breast-feeding, viral infections, and measles,mumps,rubella (MMR) vaccination. Lower family's social class was more frequently encountered among the DM1 families than in the controls (OR = 0.56, 95% CI: 0.35,0.92). The occurrence of any allergic symptoms among children with DM1 (35.45%) was not significantly different from the controls (38.78%), neither in the total group (OR = 0.87, 95% CI: 0.52,1.45) nor in the stratified analysis by social class. Similar findings were observed regarding the different types of allergic symptoms. In the univariate analysis, breast-feeding, the experience of viral infections, and MMR vaccination were found to be protective of DM1 presentation in both upper and lower social classes. In the multiple logistic regression analysis, the experience of more than 2 infections/yr (OR = 0.12, 95% CI: 0.04,0.34), the origin from middle and upper social classes (OR = 0.42, 95% CI: 0.22,0.80) and breast-feeding (OR = 0.58, 95% CI: 0.31,1.07) were protective of DM1 occurrence. In children with DM1, the presence of allergic symptoms was not associated with the development of DM1. Among the environmental factors, the origin from middle or upper social classes, breast-feeding, the experience of viral infections, and MMR vaccination were found to have a protective effect on DM1 presentation. [source] | |||||||||||||||||||||||||||||||||||||||||||