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Sample records for recurrent p14arf mutations

  1. Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation

    DEFF Research Database (Denmark)

    Robertson, Lindsay B; Armstrong, Georgina N; Olver, Bianca D

    2010-01-01

    There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline m...

  2. Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line

    International Nuclear Information System (INIS)

    Vaskivuo, Liisa; Rysae, Jaana; Koivuperae, Johanna; Myllynen, Paeivi; Vaskivuo, Tommi; Chvalova, Katerina; Serpi, Raisa; Savolainen, Eeva-Riitta; Puistola, Ulla; Vaehaekangas, Kirsi

    2006-01-01

    p14 ARF tumor suppressor protein regulates p53 by interfering with mdm2-p53 interaction. p14 ARF is activated in response to oncogenic stimuli but little is known of the responses of endogenous p14 ARF to different types of cellular stress or DNA damage. Azidothymidine (AZT) is being tested in several clinical trials as an enhancer of anticancer chemotherapy. However, the knowledge of the relationship between AZT and cellular pathways, e.g. p53 pathway, is very limited. In this study, we show that AZT, cisplatin (CDDP) and docetaxel (DTX) all induce unique molecular responses in OVCAR-3 ovarian carcinoma cells carrying a mutated p53, while in A2780, ovarian carcinoma and MCF-7 breast carcinoma cells with wild type p53, all of these drugs cause similar p53 responses. We found that endogenous p14 ARF protein in OVCAR-3 cells is down-regulated by DTX but induced by AZT and a short CDDP pulse treatment. In HT-29 colon carcinoma cells with a mutated p53, all treatments down-regulated p14 ARF protein. Both CDDP and AZT increased the expression of p14ARF mRNA in OVCAR-3 cells. Differences in cell death induced by these drugs did not explain the differences in protein and mRNA expressions. No increase in the level of either c-Myc or H-ras oncoproteins was seen in OVCAR-3 cells after AZT or CDDP-treatment. These results suggest that p14 ARF can respond to DNA damage without oncogene activation in cell lines without functional p53

  3. p53-Induced Apoptosis Occurs in the Absence of p14ARF in Malignant Pleural Mesothelioma

    Directory of Open Access Journals (Sweden)

    Sally Hopkins-Donaldson

    2006-07-01

    Full Text Available Malignant pleural mesotheliomas (MPMs are usually wild type for the p53 gene but contain homozygous deletions in the INK4A locus that encodes p14ARF, an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of p14ARF expression and the presence of SV40 large T antigen (L-Tag result in p53 inactivation in MPM. We did not detect SV40 L-Tag mRNA in either MPM cell lines or primary cultures, treatment of p14ARF-deficient cells with cisplatin (CDDP increased both total and phosphorylated p53 and enhanced p53 DNA-binding activity. On incubation with CDDP, levels of positively regulated p53 transcriptional targets p21WAF, PIG3, MDM2, Bax, PUMA increased in p14ARF-deficient cells, whereas negatively regulated survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14ARF-deficient cells, treatment with p53-specific siRNA rendered them more CDDP-resistant. p53 was also activated by: 1 inhibition of MDM2 (using nutlin-3; 2 transient overexpression of p14ARF; and 3 targeting of survivin using antisense oligonucleotides. However, it is noteworthy that only survivin downregulation sensitized cells to CDDP-induced apoptosis. These results suggest that p53 is functional in the absence of p14ARF in MPM and that targeting of the downstream apoptosis inhibitor survivin can sensitize to CDDP-induced apoptosis.

  4. High promoter hypermethylation frequency of p14/ARF in supratentorial PNET but not in medulloblastoma.

    Science.gov (United States)

    Inda, M M; Muñoz, J; Coullin, P; Fauvet, D; Danglot, G; Tuñón, T; Bernheim, A; Castresana, J S

    2006-04-01

    Medulloblastoma (MB) is the most common primitive neuroectodermal tumour (PNET) of the central nervous system. Although supratentorial PNET (sPNET) and MB are histologically similar, their clinical behaviour differs, sPNET being more aggressive than MB. The aim of this study was to determine whether sPNET and MB are genetically different entities. We investigated 32 PNET primary tumour samples (23 MB and nine sPNET) and four PNET cell lines, for the presence of CDKN2A homozygous deletions at exon 1-alpha of p16/INK4 and exon 1-beta of p14/ARF, and promoter hypermethylation of both genes. No homozygous deletion of either p16/INK4 or p14/ARF was demonstrated in any of the PNET primary tumour samples. Methylation of p16/INK4 was found in one of six sPNET and in one of 23 MB, while p14/ARF methylation was observed in three of six sPNET and in three of 21 MB. No methylation of p16/INK4 or p14/ARF was found in any of the PNET cell lines analysed. The three MB cell lines did not show p16/INK4 expression, and only the MB Daoy cell line (homozygously deleted at CDKN2A) presented loss of p14/ARF expression. Our results in this limited series of central PNET show that p14/ARF is frequently involved in PNET carcinogenesis, with a higher frequency, but not statistically significant, for sPNET than for MB.

  5. A novel proapoptotic gene PANO encodes a post-translational modulator of the tumor suppressor p14ARF

    Energy Technology Data Exchange (ETDEWEB)

    Watari, Akihiro; Li, Yang; Higashiyama, Shinji; Yutsudo, Masuo, E-mail: yutsudo@biken.osaka-u.ac.jp

    2012-02-01

    The protein p14ARF is a known tumor suppressor protein controlling cell proliferation and survival, which mainly localizes in nucleoli. However, the regulatory mechanisms that govern its activity or expression remain unclear. Here, we report that a novel proapoptotic nucleolar protein, PANO, modulates the expression and activity of p14ARF in HeLa cells. Overexpression of PANO enhances the stability of p14ARF protein by protecting it from degradation, resulting in an increase in p14ARF expression levels. Overexpression of PANO also induces apoptosis under low serum conditions. This effect is dependent on the nucleolar localization of PANO and inhibited by knocking-down p14ARF. Alternatively, PANO siRNA treated cells exhibit a reduction in p14ARF protein levels. In addition, ectopic expression of PANO suppresses the tumorigenicity of HeLa cells in nude mice. These results indicate that PANO is a new apoptosis-inducing gene by modulating the tumor suppressor protein, p14ARF, and may itself be a new candidate tumor suppressor gene.

  6. Hypermethylation of the 5′ CpG island of the p14ARF flanking exon 1β in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression

    Directory of Open Access Journals (Sweden)

    Nyiraneza Christine

    2012-06-01

    Full Text Available Abstract Background It has been suggested that inactivation of p14ARF, a tumor suppressor central to regulating p53 protein stability through interaction with the MDM2 oncoprotein, abrogates p53 activity in human tumors retaining the wild-type TP53 gene. Differences in expression of tumor suppressor genes are frequently associated with cancer. We previously reported on a pattern of restricted p53 immunohistochemical overexpression significantly associated with microsatellite instability (MSI, low TP53 mutation frequency, and MDM2 overexpression in colorectal cancers (CRCs. In this study, we investigated whether p14ARF alterations could be a mechanism for disabling the p53 pathway in this subgroup of CRCs. Results Detailed maps of the alterations in the p14ARF gene were determined in a cohort of 98 CRCs to detect both nucleotide and copy-number changes. Methylation-specific PCR combined with bisulfite sequencing was used to evaluate the prevalence and distribution of p14ARF methylation. p14ARF alterations were then correlated with MSI status, TP53 mutations, and immunohistochemical expression of p53 and MDM2. The frequency of p14ARF mutations was extremely low (1/98; 1%, whereas coexistence of methylated and unmethylated alleles in both tumors and normal colon mucosa was common (91/98; 93%. Only seven of ninety-eight tumors (7% had a distinct pattern of methylation compared with normal colon mucosa. Evaluation of the prevalence and distribution of p14ARF promoter methylation in a region containing 27 CpG sites in 35 patients showed a range of methylated CpG sites in tumors (0 to 25 (95% CI 1 to 13 versus 0 to 17 (95% CI 0 to 2 in adjacent colon mucosa (P = 0.004. Hypermethylation of the p14ARF promoter was significantly correlated with the restricted p53 overexpression pattern (P = 0.03, and MDM2 overexpression (P = 0.02, independently of MSI phenotype. Although no significant correlation between p14ARF methylation and TP53 mutational

  7. Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors.

    Science.gov (United States)

    Eymin, Béatrice; Gazzeri, Sylvie; Brambilla, Christian; Brambilla, Elisabeth

    2002-04-18

    Pathways involving p53 and pRb tumor suppressor genes are frequently deregulated during lung carcinogenesis. Through its location at the interface of these pathways, Mdm2 can modulate the function of both p53 and pRb genes. We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein. Using Immunohistochemistry (IHC), Mdm2 was overexpressed as compared to normal lung in 31% (60 out of 192) of all tumors analysed, whatever their histological types. Western blotting was performed on 28 out of the 192 tumoral samples. Overexpression of p85/90, p74/76 and p57 Mdm2 isoforms was detected in 18% (5 out of 28), 25% (7 out of 28) and 39% (11 out of 28) of the cases respectively. Overall, overexpression of at least one isoform was observed in 14 out of 28 (50%) lung tumors and concomittant overexpression of at least two isoforms in 7 out of 28 (25%) cases. A good concordance (82%) was observed between immunohistochemical and Western blot data. Interestingly, a highly significant inverse relationship was detected between p14(ARF) loss and Mdm2 overexpression either in NSCLC (P=0.0089) or in NE lung tumors (P1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm2 (P=0.0021). Taken together, these data strongly suggest that p14(ARF)and Mdm2 act on common pathway(s) to regulate p53 and/or pRb-dependent or independent functions and that the Mdm2 : p14(ARF) ratio might act as a rheostat in modulating the activity of both proteins.

  8. Pokemon enhances proliferation, cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF-MDM2-p53 pathway.

    Science.gov (United States)

    Zhao, Yi; Yao, Yun-hong; Li, Li; An, Wei-fang; Chen, Hong-zen; Sun, Li-ping; Kang, Hai-xian; Wang, Sen; Hu, Xin-rong

    2014-12-01

    Pokemon has been showed to directly suppress p14(ARF) expression and also to overexpress in multiple cancers. However, p14(ARF)-MDM2-p53 pathway is usually aberrant in colorectal cancer (CRC). The aim is to confirm whether Pokemon plays a role in CRC and explore whether Pokemon works through p14(ARF)-MDM2-p53 pathway in CRC. Immunohistochemistry for Pokemon, p14(ARF) and Mtp53 protein was applied to 45 colorectal epitheliums (CREs), 42 colorectal adenomas (CRAs) and 66 CRCs. Pokemon was knocked down with RNAi technique in CRC cell line Lovo to detect mRNA expression of p14(ARF) with qRT-PCR, cell proliferation with CCK8 assay, and cell cycle and apoptosis with flowcytometry analysis. The protein expression rates were significantly higher in CRC (75.8%) than in CRE (22.2 %) or CRA (38.1%) for Pokemon and higher in CRC (53.0%) than in CRE (0) or CRA (4.8%) for Mtp53, but not significantly different in CRC (86.4 %) versus CRE (93.3%) or CRA (90.5 %) for p14(ARF). Higher expression rate of Pokemon was associated with lymph node metastasis and higher Duke's stage. After knockdown of Pokemon in Lovo cells, the mRNA level of p14(ARF) was not significantly changed, the cell proliferation ability was decreased by 20.6%, cell cycle was arrested by 55.7% in G0/G1 phase, and apoptosis rate was increased by 19.0%. Pokemon enhanced the oncogenesis of CRC by promoting proliferation, cell cycle progression and anti-apoptosis activity of CRC cells independently of p14(ARF)-MDM2-p53 pathway. This finding provided a novel idea for understanding and further studying the molecular mechanism of Pokemon on carcinogenesis of CRC.

  9. Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Sonaglio V

    2013-06-01

    Full Text Available Viviane Sonaglio,1 Ana C de Carvalho,2 Silvia R C Toledo,3,4 Carolina Salinas-Souza,3,4 André L Carvalho,5 Antonio S Petrilli,3 Beatriz de Camargo,6 André L Vettore21Pediatrics Department, A C Camargo Hospital, São Paulo, Brazil; 2Biological Science Department, Federal University of São Paulo, Diadema, Brazil; 3Department of Pediatrics, Pediatric Oncology Institute, GRAACC/Federal University of São Paulo, São Paulo, Brazil; 4Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil; 5Department of Head and Neck Surgery, PIO XII Foundation, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; 6Research Program Pediatric Oncology Program, CPNq, Instituto Nacional do Cancer, Rio de Janeiro, BrazilAbstract: Osteosarcoma (OS is the eighth most common form of childhood and adolescence cancer. Approximately 10%–20% of patients present metastatic disease at diagnosis and the 5-year overall survival remains around 70% for nonmetastatic patients and around 30% for metastatic patients. Metastatic disease at diagnosis and the necrosis grade induced by preoperative treatment are the only well-established prognostic factors for osteosarcoma. The DNA aberrant methylation is a frequent epigenetic alteration in humans and has been described as a molecular marker in different tumor types. This study evaluated the DNA aberrant methylation status of 18 genes in 34 OS samples without previous chemotherapy treatment and in four normal bone specimens and compared the methylation profile with clinicopathological characteristics of the patients. We were able to define a three-gene panel (AIM1, p14ARF, and ESR1 in which methylation was correlated with OS cases. The hypermethylation of p14ARF showed a significant association with the absence of metastases at diagnoses, while ESR1 hypermethylation was marginally associated with worse overall survival. This study demonstrated that aberrant promoter methylation is a common event

  10. Involvement of Bmi-1 gene in the development of gastrointestinal stromal tumor by regulating p16Ink4A/p14ARF gene expressions: An in vivo and in vitro study.

    Science.gov (United States)

    Wang, Jiang-Li; Wu, Jiang-Hong; Hong, Cai; Wang, Ya-Nong; Zhou, Ye; Long, Zi-Wen; Zhou, Ying; Qin, Hai-Shu

    2017-12-01

    This study was conducted in order to explore the role that Bmi-1 plays during the development of a gastrointestinal stromal tumor (GIST) by regulation of the p16 Ink4A and p14 ARF expressions. Eighty-six patients diagnosed with GIST were selected to take part in this experiment. The Bmi-1 protein expressions in GIST and adjacent normal tissues were detected using immunohistochemistry and further analyzed by using photodensitometry. To monitor and track the progression of the GIST, a 3-year follow-up was conducted for all affected patients. After cell transfection, the GIST cells were assigned into the control group (without transfection), the negative control (NC) group (transfected with Bmi-1-Scramble plasmid), and the Bmi-1 shRNA group (transfected with the pcDNA3.1-Bmi-1 shRNA plasmid). Protein and mRNA expressions collected from Bmi-1, p16 lnk4A , P14 ARF , cyclin D1, and CDK4 were measured using both the RT-qPCR and western blotting methods Cell senescence was assessed and obtained by using the β-Galactosidase (β-Gal) activity assay. The use of a Soft agar colony formation assay and CCK-8 assay were performed in order to detect the cell growth and subsequent proliferation. Cell invasion and migration were analyzed using the Transwell assay and scratch test. Bmi-1 in the GIST tissues was found to be significantly higher and the p16 lnk4A and P14 ARF expressions were lower than those in the adjacent normal tissues. Bmi-1 was negatively correlated with p16 lnk4A and P14 ARF expressions according to the correlation analysis. Bmi-1 expression was associated with the TNM stage, postoperative recurrence, metastasis, tumor size, and the 5-year survival rate. Area under ROC curve was calculated at 0.884, and sensitivity, specificity, and accuracy of Bmi-1 predicting the GIST were 67.44%, 97.67%, and 65.12%, respectively. Patients exhibiting a high Bmi-1 expression in the GIST tissues had lower survival rates than those with low Bmi-1 expression. In comparison with

  11. Recurrent LDL-receptor mutation causes familial ...

    African Journals Online (AJOL)

    1995-05-05

    May 5, 1995 ... 3. eaudet . New. Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in ... amplification refractory mutation system (ARMS)" and single- strand conformation .... Location. Afrikaner. Mixed race. ApaLl.

  12. Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Schlecht, Nicolas F; Ben-Dayan, Miriam; Anayannis, Nicole; Lleras, Roberto A; Thomas, Carlos; Wang, Yanhua; Smith, Richard V; Burk, Robert D; Harris, Thomas M; Childs, Geoffrey; Ow, Thomas J; Prystowsky, Michael B; Belbin, Thomas J

    2015-01-01

    Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P < 0.05; ROC area under the curve = 0.96, 95% CI: 0.91–1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95% CI: 0.82–0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products

  13. Recurrent APC gene mutations in Polish FAP families

    Directory of Open Access Journals (Sweden)

    Pławski Andrzej

    2007-12-01

    Full Text Available Abstract The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.

  14. Recurrent and founder mutations in the PMS2 gene.

    Science.gov (United States)

    Tomsic, J; Senter, L; Liyanarachchi, S; Clendenning, M; Vaughn, C P; Jenkins, M A; Hopper, J L; Young, J; Samowitz, W; de la Chapelle, A

    2013-03-01

    Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2. © 2012 John Wiley & Sons A/S.

  15. Detecting negative selection on recurrent mutations using gene genealogy

    Science.gov (United States)

    2013-01-01

    Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their

  16. Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

    Science.gov (United States)

    Behjati, Sam; Tarpey, Patrick S; Sheldon, Helen; Martincorena, Inigo; Van Loo, Peter; Gundem, Gunes; Wedge, David C; Ramakrishna, Manasa; Cooke, Susanna L; Pillay, Nischalan; Vollan, Hans Kristian M; Papaemmanuil, Elli; Koss, Hans; Bunney, Tom D; Hardy, Claire; Joseph, Olivia R; Martin, Sancha; Mudie, Laura; Butler, Adam; Teague, Jon W; Patil, Meena; Steers, Graham; Cao, Yu; Gumbs, Curtis; Ingram, Davis; Lazar, Alexander J; Little, Latasha; Mahadeshwar, Harshad; Protopopov, Alexei; Al Sannaa, Ghadah A; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Zhang, Jianhua; Ravi, Vinod; Torres, Keila E; Khatri, Bhavisha; Halai, Dina; Roxanis, Ioannis; Baumhoer, Daniel; Tirabosco, Roberto; Amary, M Fernanda; Boshoff, Chris; McDermott, Ultan; Katan, Matilda; Stratton, Michael R; Futreal, P Andrew; Flanagan, Adrienne M; Harris, Adrian; Campbell, Peter J

    2014-04-01

    Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

  17. Calmodulin Mutations Associated with Recurrent Cardiac Arrest in Infants

    Science.gov (United States)

    Crotti, Lia; Johnson, Christopher N.; Graf, Elisabeth; De Ferrari, Gaetano M.; Cuneo, Bettina F.; Ovadia, Marc; Papagiannis, John; Feldkamp, Michael D.; Rathi, Subodh G.; Kunic, Jennifer D.; Pedrazzini, Matteo; Wieland, Thomas; Lichtner, Peter; Beckmann, Britt-Maria; Clark, Travis; Shaffer, Christian; Benson, D. Woodrow; Kääb, Stefan; Meitinger, Thomas; Strom, Tim M.; Chazin, Walter J.; Schwartz, Peter J.; George, Alfred L.

    2013-01-01

    Background Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on two unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results We ascertained two unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The two parent-child trios were investigated using exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in two genes encoding calmodulin. We discovered three heterozygous de novo mutations in either CALM1 or CALM2, two of the three human genes encoding calmodulin, in the two probands and in two additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several fold reductions in calcium binding affinity. Conclusions Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy. PMID:23388215

  18. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P.; Cheng, Elaine; Davis, Matthew J.; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton-Regester, Ken; Capatana, Ana; Holman, Edna C.; Bosenberg, Marcus; Sznol, Mario; Kluger, Harriet M.; Brash, Douglas E.; Stern, David F.; Materin, Miguel A.; Lo, Roger S.; Mane, Shrikant; Ma, Shuangge; Kidd, Kenneth K.; Hayward, Nicholas K.; Lifton, Richard P.; Schlessinger, Joseph; Boggon, Titus J.; Halaban, Ruth (Yale-MED); (UCLA); (Queens)

    2012-10-11

    We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1{sup P29S}) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1{sup P29S} showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

  19. Recurrent Hyperparathyroidism Due to a Novel CDC73 Splice Mutation.

    Science.gov (United States)

    Hattangady, Namita Ganesh; Wilson, Tremika Le-Shan; Miller, Barbra Sue; Lerario, Antonio Marcondes; Giordano, Thomas James; Choksi, Palak; Else, Tobias

    2017-08-01

    The recognition of hereditary causes of primary hyperparathyroidism (pHPT) is important because clinical care and surveillance differ significantly between sporadic and hereditary pHPT. In addition, the increasing number of genetic tests poses a challenge to classify mutations as benign or pathogenic. Functional work-up of variants remains a mainstay to provide evidence for pathogenicity. We describe a 52-year-old male patient with recurrent pHPT since age 35 years. Despite several neck surgeries with complete parathyroidectomy, he experienced persistent pHPT, necessitating repeated surgery for a forearm autotransplant, which finally resulted in unmeasurable parathyroid hormone (PTH) levels. Genetic testing revealed a new CDC73 variant (c.238-8G>A [IVS2-8G>A]), initially classified as a variant of uncertain significance. Parathyroid tissue from the initial surgeries showed loss of heterozygosity. Using an RT-PCR approach, we show that the mutation leads to the use of a cryptic splice site in peripheral mononuclear cells. In addition, a minigene approach confirms the use of the cryptic splice site in a heterologous cell system. The novel c.238-8G>A CDC73 variant activates a cryptic splice site, and the functional data provided justify the classification as a likely pathogenic variant. Our results underscore the importance of functional work-up for variant classification in the absence of other available data, such as presence in disease-specific databases, other syndromic clinical findings, or family history. In addition, the presented case exemplifies the importance to consider a hereditary condition in young patients with pHPT, particularly those with multi-gland involvement. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  20. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

    DEFF Research Database (Denmark)

    Nilbert, Mef; Wikman, Friedrik P; Hansen, Thomas V O

    2009-01-01

    mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably...... higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667......+2_1667_+8TAAATCAdelinsATTT was identified in 14/58 (24%) MLH1 mutant families. The Danish Lynch syndrome population thus demonstrates that MSH6 mutations and recurrent/founder mutations have a larger contribution than previously recognized, which implies that the MSH6 gene should be included in routine diagnostics...

  1. Recurrent occurrences of CDKL5 mutations in patients with epileptic encephalopathy.

    Science.gov (United States)

    Yamamoto, Toshiyuki; Shimojima, Keiko; Kimura, Nobusuke; Mogami, Yukiko; Usui, Daisuke; Takayama, Rumiko; Ikeda, Hiroko; Imai, Katsumi

    2015-01-01

    The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration.

  2. Rapid detection of RB1 recurrent mutations in retinoblastoma by ...

    Indian Academy of Sciences (India)

    In about half of the patients, one mutation is inherited via the germinal cells, while in the .... mutational hot spots in the RB1 gene, making genetic testing complex and challenging ... by direct sequencing. High normal background in sequenc-.

  3. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

    NARCIS (Netherlands)

    M. Remke (Marc); E.A. Ramaswamy; M. Peacock (Munro); D.J.H. Shih (David J.); C. Koelsche (Christian); P.A. Northcott (Paul A.); N. Hill (Nadia); S. Cavalli (Silvia); M. Kool (Marcel); X. Wang (Xin); S. Mack (Stephen); M. Barszczyk (Mark); A.S. Morrissy (A. Sorana); X. Wu (Xiaochong); S. Agnihotri (Sameer); P. Luu (Phan); D. Jones (David); L. Garzia (Livia); A.M. Dubuc (Adrian); N. Zhukova (Nataliya); R. Vanner (Robert); J.M. Kros (Johan); P.J. French (Pim); E.G. van Meir (Erwin); R. Vibhakar (Rajeev); K. Zitterbart (Karel); J.A. Chan (Jennifer); L. Bognár (László); A. Klekner (Almos); B. Lach (Boleslaw); S. Jung (Shin); F. Saad (Fred); L.M. Liau (Linda); S. Albrecht (Steffen); M. Zollo (Maurizio); M.K. Cooper (Michael); R.C. Thompson (Reid); O. Delattre (Olivier); F. Bourdeaut (Franck); F.F. Doz (François); M. Garami (Miklós); P. Hauser (Peter); C.G. Carlotti (Carlos); T.E. Van Meter (Timothy); L. Massimi (Luca); D. Fults (Daniel); L.W. Pomeroy (Laura); T. Kumabe (Toshiro); Y.S. Ra (Young Shin); J.R. Leonard (Jeffrey); S.K. Elbabaa (Samer); J. Mora (Jaume); J.B. Rubin (Joshua); Y.-J. Cho (Yoon-Jae); R.E. McLendon (Roger); D.D. Bigner (Darell); C.G. Eberhart (Charles); M. Fouladi (Maryam); R.J. Wechsler-Reya (Robert); R. Faria (Rui); S.E. Croul (Sidney); A. Huang (Anding); E. Bouffet (Eric); C.E. Hawkins (Cynthia); M. Dirks (Maaike); W.A. Weiss (William); U. Schüller (Ulrich); A. Pollack (Aaron); P. Rutkowski (Piotr); D. Meyronet (David); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); N. Jabado (Nada); M. Perek-Polnik (Marta); W.A. Grajkowska (Wieslawa); S.-K. Kim (Seung-Ki); J.T. Rutka (James); E. Malkin (Elissa); U. Tabori (Uri); S.M. Pfister (Stefan); A. Korshunov (Andrey); A. von Deimling (Andreas); M.D. Taylor (Michael)

    2013-01-01

    textabstractTelomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought

  4. The Association of Factor V Leiden Mutation with Recurrent Pregnancy Loss

    International Nuclear Information System (INIS)

    Kashif, M.; Saeed, A.

    2015-01-01

    Objective: To determine the association of factor V Leiden mutation with recurrent pregnancy loss. Methods: The case-control study was conducted at the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to June 2012, and comprised women of 18 to 45 years of age who had a history of recurrent pregnancy loss, and controls with no history of pregnancy loss. All the subjects belonged to Punjabi ethnic group. Three ml blood was taken from cases and controls and deoxyribonucleic acid was extracted. In order to identify Factor V Leiden mutation, polymerase chain reaction method was utilised combined with the amplification refractory mutation system. Data was analysed using SPSS 17. Results: Of the 112 subjects, 56(50 percent) were in each of the two groups. The presence of factor V Leiden mutation among the cases was 3(5.4 percent) while it was absent among the controls. The mutation was significantly associated with recurrent pregnancy loss (p=0.017).Recurrent pregnancy loss was higher in cases than controls (p=0.001). Conclusion: Factor V Leiden mutation was significantly associated with recurrent pregnancy loss. It should be considered one of the causes of recurrent pregnancy loss. (author)

  5. Soft sweeps III: the signature of positive selection from recurrent mutation.

    Directory of Open Access Journals (Sweden)

    Pleuni S Pennings

    2006-12-01

    Full Text Available Polymorphism data can be used to identify loci at which a beneficial allele has recently gone to fixation, given that an accurate description of the signature of selection is available. In the classical model that is used, a favored allele derives from a single mutational origin. This ignores the fact that beneficial alleles can enter a population recurrently by mutation during the selective phase. In this study, we present a combination of analytical and simulation results to demonstrate the effect of adaptation from recurrent mutation on summary statistics for polymorphism data from a linked neutral locus. We also analyze the power of standard neutrality tests based on the frequency spectrum or on linkage disequilibrium (LD under this scenario. For recurrent beneficial mutation at biologically realistic rates, we find substantial deviations from the classical pattern of a selective sweep from a single new mutation. Deviations from neutrality in the level of polymorphism and in the frequency spectrum are much less pronounced than in the classical sweep pattern. In contrast, for levels of LD, the signature is even stronger if recurrent beneficial mutation plays a role. We suggest a variant of existing LD tests that increases their power to detect this signature.

  6. Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

    Science.gov (United States)

    Tenedini, E; Bernardis, I; Artusi, V; Artuso, L; Roncaglia, E; Guglielmelli, P; Pieri, L; Bogani, C; Biamonte, F; Rotunno, G; Mannarelli, C; Bianchi, E; Pancrazzi, A; Fanelli, T; Malagoli Tagliazucchi, G; Ferrari, S; Manfredini, R; Vannucchi, A M; Tagliafico, E

    2014-01-01

    With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3+T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score. PMID:24150215

  7. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

    DEFF Research Database (Denmark)

    Johansson, Peter; Aoude, Lauren G; Wadt, Karin

    2016-01-01

    Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole......, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors......-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature...

  8. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    Science.gov (United States)

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  9. Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood

    NARCIS (Netherlands)

    Zeharia, Avraham; Shaag, Avraham; Houtkooper, Riekelt H.; Hindi, Tareq; de Lonlay, Pascale; Erez, Gilli; Hubert, Laurence; Saada, Ann; de Keyzer, Yves; Eshel, Gideon; Vaz, Frédéric M.; Pines, Ophry; Elpeleg, Orly

    2008-01-01

    Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using

  10. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

    Science.gov (United States)

    Piazza, Rocco; Valletta, Simona; Winkelmann, Nils; Redaelli, Sara; Spinelli, Roberta; Pirola, Alessandra; Antolini, Laura; Mologni, Luca; Donadoni, Carla; Papaemmanuil, Elli; Schnittger, Susanne; Kim, Dong-Wook; Boultwood, Jacqueline; Rossi, Fabio; Gaipa, Giuseppe; De Martini, Greta P; di Celle, Paola Francia; Jang, Hyun Gyung; Fantin, Valeria; Bignell, Graham R; Magistroni, Vera; Haferlach, Torsten; Pogliani, Enrico Maria; Campbell, Peter J; Chase, Andrew J; Tapper, William J; Cross, Nicholas C P; Gambacorti-Passerini, Carlo

    2013-01-01

    Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. PMID:23222956

  11. Confirmation of the recurrent ACVR1 617G>A mutation in South ...

    African Journals Online (AJOL)

    Objective. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition in which progressive ossification of fibrous tissue, tendons and ligaments leads to severe physical handicap. Most affected individuals who have been studied have a recurrent 617G>A mutation in the ACVR1/ALK2 gene that codes for activin ...

  12. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

    NARCIS (Netherlands)

    Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana; Blume, Carolin; Sellner, Leopold; Jauch, Anna; Sill, Martin; Kater, Arnon P.; te Raa, G. Doreen; Geisler, Christian; van Oers, Marinus; Dietrich, Sascha; Dreger, Peter; Ho, Anthony D.; Paruzynski, Anna; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno; Zenz, Thorsten

    2013-01-01

    Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were

  13. Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

    DEFF Research Database (Denmark)

    Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana

    2013-01-01

    Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were...

  14. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.

    Science.gov (United States)

    Kiel, Mark J; Velusamy, Thirunavukkarasu; Betz, Bryan L; Zhao, Lili; Weigelin, Helmut G; Chiang, Mark Y; Huebner-Chan, David R; Bailey, Nathanael G; Yang, David T; Bhagat, Govind; Miranda, Roberto N; Bahler, David W; Medeiros, L Jeffrey; Lim, Megan S; Elenitoba-Johnson, Kojo S J

    2012-08-27

    Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.

  15. Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma.

    Science.gov (United States)

    Lim, Weng Khong; Ong, Choon Kiat; Tan, Jing; Thike, Aye Aye; Ng, Cedric Chuan Young; Rajasegaran, Vikneswari; Myint, Swe Swe; Nagarajan, Sanjanaa; Nasir, Nur Diyana Md; McPherson, John R; Cutcutache, Ioana; Poore, Gregory; Tay, Su Ting; Ooi, Wei Siong; Tan, Veronique Kiak Mien; Hartman, Mikael; Ong, Kong Wee; Tan, Benita K T; Rozen, Steven G; Tan, Puay Hoon; Tan, Patrick; Teh, Bin Tean

    2014-08-01

    Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.

  16. Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.

    Science.gov (United States)

    Bahi-Buisson, Nadia; Villeneuve, Nathalie; Caietta, Emilie; Jacquette, Aurélia; Maurey, Helene; Matthijs, Gert; Van Esch, Hilde; Delahaye, Andrée; Moncla, Anne; Milh, Mathieu; Zufferey, Flore; Diebold, Bertrand; Bienvenu, Thierry

    2012-07-01

    Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. Copyright © 2012 Wiley Periodicals, Inc.

  17. Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases.

    Science.gov (United States)

    Li, Yingmei; Liu, Boxiang; Connolly, Ian David; Kakusa, Bina Wasunga; Pan, Wenying; Nagpal, Seema; Montgomery, Stephen B; Hayden Gephart, Melanie

    2018-03-29

    When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n = 4 [7.7%]) but a high number of EGFR mutations (n = 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  18. Unexpected identification of a recurrent mutation in the DLX3 gene causing amelogenesis imperfecta.

    Science.gov (United States)

    Kim, Y-J; Seymen, F; Koruyucu, M; Kasimoglu, Y; Gencay, K; Shin, T J; Hyun, H-K; Lee, Z H; Kim, J-W

    2016-05-01

    To identify the molecular genetic aetiology of a family with autosomal dominant amelogenesis imperfecta (AI). DNA samples were collected from a six-generation family, and the candidate gene approach was used to screen for the enamelin (ENAM) gene. Whole-exome sequencing and linkage analysis with SNP array data identified linked regions, and candidate gene screening was performed. Mutational analysis revealed a mutation (c.561_562delCT and p.Tyr188Glnfs*13) in the DLX3 gene. After finding a recurrent DLX3 mutation, the clinical phenotype of the family members was re-examined. The proband's mother had pulp elongation in the third molars. The proband had not hair phenotype, but her cousin had curly hair at birth. In this study, we identified a recurrent 2-bp deletional DLX3 mutation in a new family. The clinical phenotype was the mildest one associated with the DLX3 mutations. These results will advance the understanding of the functional role of DLX3 in developmental processes. © 2016 The Authors. Oral Diseases Published by John Wiley & Sons Ltd.

  19. Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.

    Science.gov (United States)

    Rostami, Elham; Witt Nyström, Petra; Libard, Sylwia; Wikström, Johan; Casar-Borota, Olivera; Gudjonsson, Olafur

    2017-11-01

    Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

  20. R102W mutation in the RS1 gene responsible for retinoschisis and recurrent glaucoma

    Directory of Open Access Journals (Sweden)

    Xiu-Feng Huang

    2014-02-01

    Full Text Available AIM: To identify the mutations in RS1 gene associated with typical phenotype of X-linked juvenile retinoschisis (XLRS and a rare condition of concomitant glaucoma.METHODS: Complete ophthalmic examinations were performed in the proband. The coding regions of the RS1 gene that encode retinoschisin were amplified by polymerase chain reaction and directly sequenced.RESULTS: The proband showed a typical phenotype of XLRS with large peripheral retinal schisis in both eyes, involving the macula and combined with foveal cystic change, reducing visual acuity. A typical phenotype of recurrent glaucoma with high intraocular pressure (IOP and reduced visual field was also demonstrated with the patient. Mutation analysis of RS1 gene revealed R102W (c.304C>T mutations in the affected male, and his mother was proved to be a carrier with the causative mutation and another synonymous polymorphism (c.576C>CT.CONCLUSION: We identified the genetic variations of a Chinese family with typical phenotype of XLRS and glaucoma. The severe XLRS phenotypes associated with R102W mutations reveal that the mutation determines a notable alteration in the function of the retinoschisin protein. Identification of the disease-causing mutation is beneficial for future clinical references.

  1. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Hurtado, A M; Chen-Liang, T-H; Przychodzen, B; Hamedi, C; Muñoz-Ballester, J; Dienes, B; García-Malo, M D; Antón, A I; Arriba, F de; Teruel-Montoya, R; Ortuño, F J; Vicente, V; Maciejewski, J P; Jerez, A

    2015-01-01

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring

  2. Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond.

    Science.gov (United States)

    Rosenquist, Richard; Rosenwald, Andreas; Du, Ming-Qing; Gaidano, Gianluca; Groenen, Patricia; Wotherspoon, Andrew; Ghia, Paolo; Gaulard, Philippe; Campo, Elias; Stamatopoulos, Kostas

    2016-09-01

    Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management. In selected entities, a predominantly mutated gene is identified in almost all cases (e.g. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma and hairy-cell leukemia), while for the vast majority of lymphomas a quite diverse mutation pattern is observed, with a limited number of frequently mutated genes followed by a seemingly endless tail of genes with mutations at a low frequency. Herein, the European Expert Group on NGS-based Diagnostics in Lymphomas (EGNL) summarizes the current status of this ever-evolving field, and, based on the present evidence level, segregates mutations into the following categories: i) immediate impact on treatment decisions, ii) diagnostic impact, iii) prognostic impact, iv) potential clinical impact in the near future, or v) should only be considered for research purposes. In the coming years, coordinated efforts aiming to apply targeted next-generation sequencing in large patient series will be needed in order to elucidate if a particular gene mutation will have an immediate impact on the lymphoma classification, and ultimately aid clinical decision making. Copyright© Ferrata Storti Foundation.

  3. Recurrent papillary craniopharyngioma with BRAF V600E mutation treated with dabrafenib: case report.

    Science.gov (United States)

    Himes, Benjamin T; Ruff, Michael W; Van Gompel, Jaimie J; Park, Sean S; Galanis, Evanthia; Kaufmann, Timothy J; Uhm, Joon H

    2018-04-27

    The authors present the case of a man with a papillary craniopharyngioma, first diagnosed at 47 years of age, who experienced multiple recurrences. Review of the pathologic specimen from his first resection demonstrated the BRAF V600E mutation. With his most recent recurrence following previous surgery and radiotherapy, at 52 years of age, the decision was made to initiate treatment with the BRAF V600E inhibitor dabrafenib. Imaging following initiation of dabrafenib demonstrated reduction in tumor size. He remained on dabrafenib therapy for approximately 1 year and continued to demonstrate a good clinical result. At that time the decision was made to discontinue dabrafenib therapy and follow up with serial imaging. After more than 1 year of follow-up since stopping dabrafenib, the patient has continued to do well with no radiographic evidence of tumor progression and continues to be monitored with frequent interval imaging.

  4. EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.

    Science.gov (United States)

    Danhauser, Katharina; Haack, Tobias B; Alhaddad, Bader; Melcher, Marlen; Seibt, Annette; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

    2016-06-01

    Mitochondrial aminoacyl tRNA synthetases are essential for organelle protein synthesis. Genetic defects affecting the function of these enzymes may cause pediatric mitochondrial disease. Here, we report on a child with fatal neonatal lactic acidosis and recurrent hypoglycemia caused by mutations in EARS2, encoding mitochondrial glutamyl-tRNA synthetase 2. Brain ultrasound revealed agenesis of corpus callosum. Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species (ROS) production, and altered mitochondrial morphology. Our report further illustrates the clinical spectrum of the severe neonatal-onset form of EARS2 mutations. Moreover, in this case the live-cell parameters appeared to be more sensitive to mitochondrial dysfunction compared to standard diagnostics, which indicates the potential relevance of fibroblast studies in children with mitochondrial diseases.

  5. Novel and recurrent MYO7A mutations in Usher syndrome type 1 and type 2.

    Science.gov (United States)

    Rong, Weining; Chen, Xue; Zhao, Kanxing; Liu, Yani; Liu, Xiaoxing; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Sheng, Xunlun; Zhao, Chen

    2014-01-01

    Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.

  6. Novel and recurrent MYO7A mutations in Usher syndrome type 1 and type 2.

    Directory of Open Access Journals (Sweden)

    Weining Rong

    Full Text Available Usher syndrome (USH is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.

  7. Novel alpha-galactosidase A mutation in a female with recurrent strokes.

    Science.gov (United States)

    Tuttolomondo, Antonino; Duro, Giovanni; Miceli, Salvatore; Di Raimondo, Domenico; Pecoraro, Rosaria; Serio, Antonia; Albeggiani, Giuseppe; Nuzzo, Domenico; Iemolo, Francesco; Pizzo, Federica; Sciarrino, Serafina; Licata, Giuseppe; Pinto, Antonio

    2012-11-01

    Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human alpha-galactosidase A gene have been determined and to date, several disease-causing alpha-galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  8. Recurrent hyperparathyroidism and a novel nonsense mutation in a patient with hyperparathyriodism-jaw tumor syndrome.

    Science.gov (United States)

    Abdulla, Amer G; O'Leary, Erin M; Isorena, Jennifer P; Diaz, Miguel Fernando Palma; Yeh, Michael W

    2013-01-01

    To present the case of a hyperparathyroidism-jaw tumor (HPT-JT) patient with a novel nonsense mutation of the CDC73 gene. We present the case of a patient with a history of three prior maxillectomies and two prior parathyroidectomies who presented with recurrent primary hyperparathyroidism (PHPT). We also briefly review the literature pertaining to HPT-JT. Genetic analysis revealed a novel nonsense mutation (c.85G>T; pGlu29) in exon 1 of CDC73. The patient's son underwent genetic testing for a CDC73 mutation and was found to be negative. HPT-JT is a rare condition characterized by PHPT and benign tumors of the mandible and maxilla. Up to 15% of HPT-JT patients with PHPT have parathyroid carcinoma. HPT-JT is associated with an inactivating mutation of CDC73, a gene that codes for the tumor suppressor protein parafibromin. This report expands our understanding of the genetics underlying this rare disorder and emphasizes the importance of early detection in order to prevent hypercalcemic complications such as parathyroid carcinoma.

  9. Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival.

    Science.gov (United States)

    Yap, Kai Lee; Kiyotani, Kazuma; Tamura, Kenji; Antic, Tatjana; Jang, Miran; Montoya, Magdeline; Campanile, Alexa; Yew, Poh Yin; Ganshert, Cory; Fujioka, Tomoaki; Steinberg, Gary D; O'Donnell, Peter H; Nakamura, Yusuke

    2014-12-15

    Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. ©2014 American Association for Cancer Research.

  10. Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.

    Science.gov (United States)

    Ockenga, J; Stuhrmann, M; Ballmann, M; Teich, N; Keim, V; Dörk, T; Manns, M P

    2000-08-01

    We investigated whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and cationic trypsinogen gene are associated with recurrent acute, or chronic idiopathic pancreatitis. Twenty patients with idiopathic pancreatitis (11 women, nine men; mean age, 30 yr) were studied for the presence of a CFTR mutation by screening the genomic DNA for more than 30 mutations and variants in the CFTR gene. Selected mutations of the cationic trypsinogen gene were screened by Afl III restriction digestion or by a mutation-specific polymerase chain reaction (PCR). In each patient exons 1, 2, and 3 of the cationic trypsinogen gene were sequenced. Patients with a CFTR mutation underwent evaluation of further functional electrophysiological test (intestinal current measurement). No mutation of the cationic trypsinogen gene was detected. A CFTR mutation was detected in 6/20 (30.0%) patients. Three patients (15.0%) had a cystic fibrosis (CF) mutation on one chromosome (deltaF508, I336K, Y1092X), which is known to cause phenotypical severe cystic fibrosis. One patient was heterozygous for the 5T allele. In addition, two possibly predisposing CFTR variants (R75Q, 1716G-->A) were detected on four patients, one of these being a compound heterozygous for the missense mutation I336K and R75Q. No other family member (maternal I336K; paternal R75Q; sister I1336K) developed pancreatitis. An intestinal current measurement in rectum samples of patients with a CFTR mutation revealed no CF-typical constellations. CFTR mutations are associated with recurrent acute, or chronic idiopathic pancreatitis, whereas mutations of the cationic trypsinogen mutation do not appear to be a frequent pathogenetic factor.

  11. A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation.

    Science.gov (United States)

    Connallon, Tim; Clark, Andrew G

    2012-04-01

    Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection.

  12. A case of recurrent encephalopathy with SCN2A missense mutation.

    Science.gov (United States)

    Fukasawa, Tatsuya; Kubota, Tetsuo; Negoro, Tamiko; Saitoh, Makiko; Mizuguchi, Masashi; Ihara, Yukiko; Ishii, Atsushi; Hirose, Shinichi

    2015-06-01

    Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A, which encodes the Na(+) channel Nav1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  13. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    DEFF Research Database (Denmark)

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations...... subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s)....

  14. Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation?

    Directory of Open Access Journals (Sweden)

    Verhoeven WMA

    2011-05-01

    Full Text Available Willem MA Verhoeven1,2, Jos IM Egger1,3,4, Berry PH Kremer5, Boudewijn JHB de Pont1, Carlo LM Marcelis61Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands; 2Erasmus University Medical Centre, Department of Psychiatry, Rotterdam, The Netherlands; 3Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands; 5Department of Neurology, University Medical Centre Groningen, The Netherlands; 6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsAbstract: At present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A→G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric

  15. Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk

    Energy Technology Data Exchange (ETDEWEB)

    Passos-Bueno, M.R.; Takata, R.I.; Rapaport, D.; Bakker, E.; Kneppers, A.L.J.; Dunnen, J.T. den; Ommen, J.B. van

    1992-11-01

    In about 65% of the cases of Duchenne muscular dystrophy (DMD) a partial gene deletion or duplication in the dystrophin gene can be detected. These mutations are clustered at two hot spots: 30% at the hot spot in the proximal part of the gene and about 70% at a more distal hot spot. Unexpectedly the authors observed a higher frequency of proximal gene rearrangements among proved germ line' mosaic cases. Of the 24 mosaic cases they are aware of, 19 (79%) have a proximal mutation, while only 5 (21%) have a distal mutation. This finding indicates that the mutations at the two hot spots in the dystrophin gene differ in origin. Independent support for the different mosaicism frequency was found by comparing the mutation spectra observed in isolated cases of DMD and familial cases (ratio 1:1). The authors conclude from these data that proximal deletions most likely occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Finally, the findings have important consequences for the calculation of recurrence-risk estimates according to the site of the deletion: a [open quote]proximal[close quote] new mutant has an increased recurrence risk of approximately 30%, and a [open quote]distal[close quote] new mutant has a decreased recurrence risk of approximately 4%. 28 refs., 2 figs., 2 tabs.

  16. [Recurrent vascular access trombosis associated with the prothrombin mutation G20210A in a adult patient in haemodialysis].

    Science.gov (United States)

    Quintana, L F; Coll, E; Monteagudo, I; Collado, S; López-Pedret, J; Cases, A

    2005-01-01

    Vascular access-related complications are a frequent cause of morbidity in haemodialysis patients and generate high costs. We present the case of an adult patient with end-stage renal disease and recurrent vascular access thrombosis associated with the prothrombin mutation G20210A and renal graft intolerance. The clinical expression of this heterozygous gene mutation may have been favoured by inflammatory state, frequent in dialysis patients. In this patient, the inflammatory response associated with the renal graft intolerance would have favored the development of recurrent vascular access thrombosis in a adult heterozygous for prothrombin mutation G20210A. In the case of early dysfunction of haemodialysis vascular access and after ruling out technical problems, it is convenient to carry out a screening for thrombophilia.

  17. Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation.

    Science.gov (United States)

    Shibata, Yusuke; Yamazaki, Masanori; Takei, Masahiro; Uchino, Shinya; Sakurai, Akihiro; Komatsu, Mitsuhisa

    2015-01-01

    Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant hereditary tumor syndrome characterized by synchronous or metachronous occurrence of primary hyperparathyroidism (PHPT), ossifying fibroma of the maxilla and/or mandible, renal tumor and uterine tumors. Early diagnosis of this syndrome is essential because it is associated with increased risk of parathyroid cancer. A 30-year-old man with urolithiasis had severe hypercalcemia (15.0 mg/dL after correction) induced by inappropriate parathyroid hormone (PTH) secretion (intact PTH 1390 pg/mL), indicating severe PHPT. An underlying parathyroid tumor was surgically removed and was histologically confirmed to be an adenoma. However, PHPT due to another parathyroid tumor reoccurred two years after the surgery. Although no HPT-JT-associated manifestations other than PHPT were detected, HPT-JT was strongly suspected based on the exclusion of multiple endocrine neoplasia (MEN) and the young age of disease occurrence. Genetic analysis revealed a novel nonsense mutation (p.Arg91X; c.271C>T) in exon 3 of the causative gene, CDC73, which encodes the tumor suppressor protein parafibromin. The residual parathyroid glands were all removed without autotransplantation of parathyroid gland taking into consideration prospective parathyroid carcinogenesis. The resected parathyroid tumor was also an adenoma. The present case highlights that HPT-JT should be considered and CDC73 mutation analysis should be performed, especially in cases of early-onset PHPT, recurrent PHPT, PHPT with polyglandular parathyroid involvement, and PHPT presenting with severe hypercalcemia even if there is no positive family history.

  18. A 3-plex methylation assay combined with the FGFR3 mutation assay sensitively detects recurrent bladder cancer in voided urine

    DEFF Research Database (Denmark)

    Kandimalla, Raju; Masius, Roy; Beukers, Willemien

    2013-01-01

    is to determine the sensitivity and specificity of a urine assay for the diagnosis of recurrences in patients with a previous primary NMIBC G1/G2 by using cystoscopy as the reference standard. Experimental Design: We selected eight CpG islands (CGI) methylated in bladder cancer from our earlier genome-wide study......Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as useful biomarkers. FGFR3 mutations are present in 60% to 70% of non–muscle invasive bladder cancer (NMIBC). Low-grade bladder cancer recurs in more than 50% of patients. The aim of this study......, and nonmalignant urines (n = 130). Results: The 3-plex assay identified recurrent bladder cancer in voided urine with a sensitivity of 74% in the validation set. In combination with the FGFR3 mutation assay, a sensitivity of 79% was reached (specificity of 77%). Sensitivity of FGFR3 and cytology was 52% and 57...

  19. Case Report: Exome sequencing reveals recurrent RETSAT mutations and a loss-of-function POLDIP2 mutation in a rare undifferentiated tongue sarcoma [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Jason Y. K. Chan

    2018-04-01

    Full Text Available Soft tissue sarcoma of the tongue represents a very rare head and neck cancer with connective tissue features, and the genetics underlying this rare cancer are largely unknown. There are less than 20 cases reported in the literature thus far. Here, we reported the first whole-exome characterization (>×200 depth of an undifferentiated sarcoma of the tongue in a 31-year-old male. Even with a very good sequencing depth, only 19 nonsynonymous mutations were found, indicating a relatively low mutation rate of this rare cancer (lower than that of human papillomavirus (HPV-positive head and neck cancer. Yet, among the few genes that are somatically mutated in this HPV-negative undifferentiated tongue sarcoma, a noticeable deleterious frameshift mutation (with a very high allele frequency of >93% of a gene for DNA replication and repair, namely POLDIP2 (DNA polymerase delta interacting protein 2, and two recurrent mutations of the adipogenesis and adipocyte differentiation gene RETSAT (retinol saturase, were identified. Thus, somatic events likely affecting adipogenesis and differentiation, as well as potential stem mutations to POLDIP2, may be implicated in the formation of this rare cancer. This identified somatic whole-exome sequencing profile appears to be distinct from that of other reported adult sarcomas from The Cancer Genome Atlas, suggesting a potential unique genetic profile for this rare sarcoma of the tongue. Interestingly, this low somatic mutation rate is unexpectedly found to be accompanied by multiple tumor protein p53 and NOTCH1 germline mutations of the patient’s blood DNA. This may explain the very early age of onset of head and neck cancer, with likely hereditary predisposition. Our findings are, to our knowledge, the first to reveal a unique genetic profile of this very rare undifferentiated sarcoma of the tongue.

  20. Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA aneuploidy and p53 mutation as supportive evidence of malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Ostrowski, M.L. [Department of Pathology and Laboratory Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Department of Pathology and Laboratory Medicine, Houston, TX (United States). Methodist Hospital; Johnson, M.E. [Department of Orthopedic Surgery, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Truong, L.D.; Hicks, M.J.; Spjut, H.J. [Department of Pathology and Laboratory Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Smith, F.E. [Department of Oncology, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States)

    1999-11-01

    We report a rare case of malignant chondroblastoma, which presented in a 47-year-old man as a recurrent tumor, 18 years following wide excision of a typical pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large, lytic, destructive lesion of the right pelvic bones and femur, with a pathologic fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary metastases. Biopsy tissue showed typical features of chondroblastoma, but also increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the original tumor, and, most significantly, abnormal mitotic figures. Immunohistochemical studies of the recurrent tumor revealed p53 mutation and extensive proliferative activity, and flow cytometric studies showed DNA aneuploidy, none of which was present in the original tumor. The patient received chemotherapy and radiation, but died of disease eight months after presentation. We also review chondroblastoma in general, to assign this unusual lesion to a tumor subtype. (orig.)

  1. Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

    Directory of Open Access Journals (Sweden)

    Novakovic Srdjan

    2008-09-01

    Full Text Available Abstract Background Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations. The current study was aimed at establishing the mutation spectrum of BRCA1/2 in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families. Methods The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the BRCA1/2 screening were: (i probands with at least two first degree relatives with breast and ovarian cancer; (ii probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family. Results Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A BRCA1/2 mutation was found in 56 (39%. Two novel large deletions covering consecutive exons of BRCA1 were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the BRCA1 gene and IVS16-2A>G in the BRCA2 gene. The IVS16-2A>G in the BRCA2 gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the BRCA1/2 positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of

  2. Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.

    Science.gov (United States)

    Sundquist, Kristina; Wang, Xiao; Svensson, Peter J; Sundquist, Jan; Hedelius, Anna; Larsson Lönn, Sara; Zöller, Bengt; Memon, Ashfaque A

    2015-11-25

    Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.

  3. Evidence in Latin America of recurrence of V388M, a phenylketonuria mutation with high in vitro residual activity

    Energy Technology Data Exchange (ETDEWEB)

    Desviat, L.R.; Perez, B.; De Lucca, M. [Universidad Autonoma de Madrid, (Spain)] [and others

    1995-08-01

    Phenylketonuria mutation V388M is frequent in the Iberian Peninsula. In vitro, the V388M mutant enzyme has similar immunoreactive protein and phenylalanine hydroxylase mRNA and had 43% residual activity, which correlates well with the mild phenotype exhibited by the homozygous patients. In Spain it has been detected in 5.7% of the mutant alleles and is always associated with haplotype 1.7. This mutation is also present in high frequency in some Latin American countries (Brazil, 9% Chile, 13%). It is interesting that in Chile most of the alleles bearing this mutation carry haplotype 4.3, although in Brazil it is found only on the background of haplotype 1.7. The origin of V388M in Spain on haplotype 1.7 and in Chile on haplotype 4.3 is clearly different. Recurrence is the most plausible explanation, because the mutation involves a CpG dinucleotide, and a recombination event transferring the mutation from haplotype 1 to 4 is unlikely. 29 refs., 2 figs., 3 tabs.

  4. Combined mutation and rearrangement screening by quantitative PCR high-resolution melting: is it relevant for hereditary recurrent Fever genes?

    Directory of Open Access Journals (Sweden)

    Nathalie Pallares-Ruiz

    2010-11-01

    Full Text Available The recent identification of genes implicated in hereditary recurrent fevers has allowed their specific diagnosis. So far however, only punctual mutations have been identified and a significant number of patients remain with no genetic confirmation of their disease after routine molecular approaches such as sequencing. The possible involvement of sequence rearrangements in these patients has only been examined in familial Mediterranean fever and was found to be unlikely. To assess the existence of larger genetic alterations in 3 other concerned genes, MVK (Mevalonate kinase, NLRP3 (Nod like receptor family, pyrin domain containing 3 and TNFRSF1A (TNF receptor superfamily 1A, we adapted the qPCR-HRM method to study possible intragenic deletions and duplications. This single-tube approach, combining both qualitative (mutations and quantitative (rearrangement screening, has proven effective in Lynch syndrome diagnosis. Using this approach, we studied 113 unselected (prospective group and 88 selected (retrospective group patients and identified no intragenic rearrangements in the 3 genes. Only qualitative alterations were found with a sensitivity similar to that obtained using classical molecular techniques for screening punctual mutations. Our results support that deleterious copy number alterations in MVK, NLRP3 and TNFRSF1A are rare or absent from the mutational spectrum of hereditary recurrent fevers, and demonstrate that a routine combined method such as qPCR-HRM provides no further help in genetic diagnosis. However, quantitative approaches such as qPCR or SQF-PCR did prove to be quick and effective and could still be useful after non contributory punctual mutation screening in the presence of clinically evocative signs.

  5. E2F-dependent induction of p14ARF during cell cycle re-entry in human T cells

    DEFF Research Database (Denmark)

    del Arroyo, Ana Gutierrez; El Messaoudi, Selma; Clark, Paula A

    2007-01-01

    The ARF protein, encoded by alternate exon usage within the CDKN2A locus, provides a link between the retinoblastoma (pRb) and p53 tumor suppressor pathways. Agents that disable pRb or otherwise impinge on the E2F family of transcription factors induce expression of ARF, resulting in stabilization...... of p53 and activation of p53-regulated genes. However, in some cell types ARF is not induced upon cell cycle re-entry, as expected of a conventional E2F target gene, leading to the suggestion that the ARF promoter only responds to supra-physiological or aberrant levels of E2F. These properties have...

  6. A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family

    Directory of Open Access Journals (Sweden)

    Yi-Hua Yao

    2018-03-01

    Full Text Available AIM: To identify the mutations of MYOC, OPTN, CYP1B1 and WDR36 in a large Chinese family affected by juvenile open angle glaucoma (JOAG. METHODS: Of 114 members of one family were recruited in this study. Blood samples from twelve members of this pedigree were collected for further research. As a control, 100 unrelated subjects were recruited from the same hospital. The exon and flanking intron sequences of candidate genes were amplified using the polymerase chain reaction and direct DNA sequencing. RESULTS: The proband (III:10 was a seventy-three years old woman with binocular JOAG at the age of 31. A recurrent heterozygous mutation (c.1099G>A of MYOC was identified in the three JOAG patients and another suspect. This transition was located in the first base pair of codon 367 (GGA>AGA in exon 3 of MYOC and was predicted to be a missense substitution of glycine to arginine (p.G367R in myocilin. Mutations in OPTN, CYP1B1 or WDR36 were not detected in this study. The G367R mutation was not present in unaffected family members or in 100 ethnically matched controls. Other variants of the coding regions of candidate genes were not detected in all participants. To date, this family was the largest to have been identified as carrying a certain MYOC mutation in China, further evidence of a founder effect for the G367R MYOC mutant was provided by our data. CONCLUSION: A MYOC c.1099G>A mutation in an autosomal dominant JOAG family is identified and the characteristic phenotypes among the patients are summarized. Genetic testing could be utilized in high-risk populations and be helpful not only for genetic counseling, but also for early diagnosis and treatment of affected patients or carriers of inherited JOAG.

  7. Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation

    Directory of Open Access Journals (Sweden)

    Chad J. Cooper

    2014-01-01

    Full Text Available Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL, eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL. Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

  8. Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck.

    Science.gov (United States)

    Poi, M J; Yen, T; Li, J; Song, H; Lang, J C; Schuller, D E; Pearl, D K; Casto, B C; Tsai, M D; Weghorst, C M

    2001-01-01

    The INK4a-ARF locus is located on human chromosome 9p21 and is known to encode two functionally distinct tumor-suppressor genes. The p16(INK4a) (p16) tumor-suppressor gene product is a negative regulator of cyclin-dependent kinases 4 and 6, which in turn positively regulate progression of mammalian cells through the cell cycle. The p14(ARF) tumor-suppressor gene product specifically interacts with human double minute 2, leading to the subsequent stabilization of p53 and G(1) arrest. Previous investigations analyzing the p16 gene in squamous cell carcinomas of the head and neck (SCCHNs) have suggested the predominate inactivating events to be homozygous gene deletions and hypermethylation of the p16 promoter. Somatic mutational inactivation of p16 has been reported to be low (0-10%, with a combined incidence of 25 of 279, or 9%) and to play only a minor role in the development of SCCHN. The present study examined whether this particular mechanism of INK4a/ARF inactivation, specifically somatic mutation, has been underestimated in SCCHN by determining the mutational status of the p16 and p14(ARF) genes in 100 primary SCCHNs with the use of polymerase chain reaction technology and a highly sensitive, nonradioactive modification of single-stranded conformational polymorphism (SSCP) analysis termed "cold" SSCP. Exons 1alpha, 1beta, and 2 of INK4a/ARF were amplified using intron-based primers or a combination of intron- and exon-based primers. A total of 27 SCCHNs (27%) exhibited sequence alterations in this locus, 22 (22%) of which were somatic sequence alterations and five (5%) of which were a single polymorphism in codon 148. Of the 22 somatic alterations, 20 (91%) directly or indirectly involved exon 2, and two (9%) were located within exon 1alpha. No mutations were found in exon 1beta. All 22 somatic mutations would be expected to yield altered p16 proteins, but only 15 of them should affect p14(ARF) proteins. Specific somatic alterations included microdeletions or

  9. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2

    DEFF Research Database (Denmark)

    Neilson, Derek E; Adams, Mark D; Orr, Caitlin M D

    2009-01-01

    a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore...... protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de...... novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude...

  10. Novel and recurrent mutations of WISP3 in two Chinese families with progressive pseudorheumatoid dysplasia.

    Directory of Open Access Journals (Sweden)

    Jing Sun

    Full Text Available BACKGROUND: The WNT1-inducible signaling pathway protein 3 (WISP3, which belongs to the CCN (cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed family, is a secreted cysteine-rich matricellular protein that is involved in chondrogenesis, osteogenesis and tumorigenesis. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230, an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism. METHODOLOGY/PRINCIPAL FINDINGS: Four PPD patients from two unrelated Chinese families were recruited for this study. The clinical diagnosis was confirmed by medical history, physical examinations, laboratory results and radiological abnormalities. WISP3 mutations were detected by direct DNA sequence analysis. In total, four different mutations were identified, which consisted of two missense mutations, one deletion and one insertion that spanned exons 3, 5 and 6 of the WISP3 gene. One of the missense mutations (c.342T>G/p.C114W and a seven-base pair frameshift deletion (c.716_722del/p.E239fs*16 were novel. The other missense mutation (c.1000T>C/p. S334P and the insertion mutation (c.866_867insA/p.Q289fs*31 had previously been identified in Chinese patients. All four cases had a compound heterozygous status, and their parents were heterozygous carriers of these mutations. CONCLUSIONS/SIGNIFICANCE: The results of our study expand the spectrum of WISP3 mutations that are associated with PPD and further elucidate the function of WISP3.

  11. Recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history.

    Science.gov (United States)

    Kang, Peter Choon Eng; Phuah, Sze Yee; Sivanandan, Kavitta; Kang, In Nee; Thirthagiri, Eswary; Liu, Jian Jun; Hassan, Norhashimah; Yoon, Sook-Yee; Thong, Meow Keong; Hui, Miao; Hartman, Mikael; Yip, Cheng Har; Mohd Taib, Nur Aishah; Teo, Soo Hwang

    2014-04-01

    Although the breast cancer predisposition genes BRCA1 and BRCA2 were discovered more than 20 years ago, there remains a gap in the availability of genetic counselling and genetic testing in Asian countries because of cost, access and inaccurate reporting of family history of cancer. In order to improve access to testing, we developed a rapid test for recurrent mutations in our Asian populations. In this study, we designed a genotyping assay with 55 BRCA1 and 44 BRCA2 mutations previously identified in Asian studies, and validated this assay in 267 individuals who had previously been tested by full sequencing. We tested the prevalence of these mutations in additional breast cancer cases. Using this genotyping approach, we analysed recurrent mutations in 533 Malaysian breast cancer cases with Malays, 3 BRCA1 and 2 BRCA2 mutations in Chinese and 1 BRCA1 mutation in Indians account for 60, 24 and 20 % of carrier families, respectively. By contrast, haplotype analyses suggest that a recurrent BRCA2 mutation (c.262_263delCT) found in 5 unrelated Malay families has at least 3 distinct haplotypes. Taken together, our data suggests that panel testing may help to identify carriers, particularly Asian BRCA2 carriers, who do not present with a priori strong family history characteristics.

  12. A woman with recurrent "infections" since birth--a new mevalonate kinase mutation

    NARCIS (Netherlands)

    Farber, C. M.; Wanders, J. A. W.; Goffard, J. C.; Parma, J.

    2011-01-01

    A tired 32-year-old woman complaining of tiredness was referred for work-up of a possible immune deficiency. She had a history of recurrent infections since birth, which usually responded to antibiotics within a few days. Her mother, a nurse, had reported that early charts had disappeared.

  13. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

    DEFF Research Database (Denmark)

    Muona, M.; Berkovic, S. F.; Dibbens, L. M.

    2015-01-01

    Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonicclonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo...

  14. Hepatitis B virus mutation may play a role in hepatocellular carcinoma recurrence: A systematic review and meta-regression analysis.

    Science.gov (United States)

    Zhou, Hua-ying; Luo, Yue; Chen, Wen-dong; Gong, Guo-zhong

    2015-06-01

    A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients. MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy. Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC. HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients. © 2015 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  15. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Shah, S.; Schrader, K.A.; Waanders, E.; Timms, A.E.; Vijai, J.; Miething, C.; Wechsler, J.; Yang, J.; Hayes, J.; Klein, R.J.; Zhang, J.; Wei, L.; Wu, G.; Rusch, M.; Nagahawatte, P.; Ma, J; Chen, S.C.; Song, G.; Cheng, J.; Meyers, P.; Bhojwani, D.; Jhanwar, S.; Maslak, P.; Fleisher, M.; Littman, J.; Offit, L.; Rau-Murthy, R.; Fleischut, M.H.; Corines, M.; Murali, R.; Gao, X.; Manschreck, C.; Kitzing, T.; Murty, V.V.; Raimondi, S.C.; Kuiper, R.P.; Simons, A.; Schiffman, J.D.; Onel, K.; Plon, S.E.; Wheeler, D.A.; Ritter, D.; Ziegler, D.S.; Tucker, K.; Sutton, R.; Chenevix-Trench, G.; Li, J.; Huntsman, D.G.; Hansford, S.; Senz, J.; Walsh, T.; Lee (Helen Dowling Instituut), M. van der; Hahn, C.N.; Roberts, K.G.; King, M.C.; Lo, S.M.; Levine, R.L.; Viale, A.; Socci, N.D.; Nathanson, K.L.; Scott, H.S.; Daly, M.; Lipkin, S.M.; Lowe, S.W.; Downing, J.R.; Altshuler, D.; Sandlund, J.T.; Horwitz, M.S.; Mullighan, C.G.; Offit, K.

    2013-01-01

    Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A

  16. Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

    NARCIS (Netherlands)

    A.L. Walz (Amy L.); A.H.A.G. Ooms (Ariadne ); S. Gadd (Samantha); D.S. Gerhard (Daniela S.); M.A. Smith (Malcolm A.); J.M. GuidryAuvil (Jamie M.); D. Meerzaman (Daoud); Q.-R. Chen (Qing-Rong); C. Hsu (ChihHao); C. Yan (Chunhua); C. Nguyen (Cu); Y. Hu (Ying); R. Bowlby (Reanne); D. Brooks (Denise); Y. Ma (Yussanne); A.A. Mungall (Andrew J.); R.A. Moore (Richard A.); J. Schein (Jacqueline); M.A. Marra (Marco A.); V. Huff (Vicki); J.S. Dome (Jeffrey); Y.-Y. Chi (Yueh-Yun); C.G. Mullighan (Charles); J. Ma (Jing); D.A. Wheeler (David A.); O.A. Hampton (Oliver A.); N. Jafari (Nadereh); N. Ross (Nicole); J.M. Gastier-Foster (Julie); E.J. Perlman (Elizabeth J.)

    2015-01-01

    textabstractWe report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/. 2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates

  17. A recurrent deletion mutation in OPA1 causes autosomal dominant optic atrophy in a Chinese family

    Science.gov (United States)

    Zhang, Liping; Shi, Wei; Song, Liming; Zhang, Xiao; Cheng, Lulu; Wang, Yanfang; Ge, Xianglian; Li, Wei; Zhang, Wei; Min, Qingjie; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-11-01

    Autosomal dominant optic atrophy (ADOA) is the most frequent form of hereditary optic neuropathy and occurs due to the degeneration of the retinal ganglion cells. To identify the genetic defect in a family with putative ADOA, we performed capture next generation sequencing (CNGS) to screen known retinal disease genes. However, six exons failed to be sequenced by CNGS in optic atrophy 1 gene (OPA1). Sequencing of those exons identified a 4 bp deletion mutation (c.2983-1_2985del) in OPA1. Furthermore, we sequenced the transcripts of OPA1 from the patient skin fibroblasts and found there is six-nucleotide deletion (c.2984-c.2989, AGAAAG). Quantitative-PCR and Western blotting showed that OPA1 mRNA and its protein expression have no obvious difference between patient skin fibroblast and control. The analysis of protein structure by molecular modeling suggests that the mutation may change the structure of OPA1 by formation of an alpha helix protruding into an existing pocket. Taken together, we identified an OPA1 mutation in a family with ADOA by filling the missing CNGS data. We also showed that this mutation affects the structural intactness of OPA1. It provides molecular insights for clinical genetic diagnosis and treatment of optic atrophy.

  18. Recurrent major depression, ataxia, and cardiomyopathy : association with a novel POLG mutation?

    NARCIS (Netherlands)

    Verhoeven, Willem M. A.; Egger, Jos I. M.; Kremer, Berry P. H.; de Pont, Boudewijn J. H. B.; Marcelis, Carlo L. M.

    2011-01-01

    At present, more than 100 disease mutations in mitochondrial DNA polymerase gamma (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being

  19. Recurrent major depression, ataxia, and cardiomyopathy: Association with a novel POLG mutation?

    NARCIS (Netherlands)

    W.M.A. Verhoeven (Wim); J.I.M. Egger (Jos); H.P.H. Kremer (Berry); B.J.H.B. de Pont (Boudewijn J.H.B.); C.L.M. Marcelis (Carlo)

    2011-01-01

    textabstractAt present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter

  20. cDNA Clones with Rare and Recurrent Mutations Found in Cancers | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at UT- MD Anderson Cancer Center has developed High-Throughput Mutagenesis and Molecular Barcoding (HiTMMoB)1,2 pipeline to construct mutant alleles open reading frame expression clones that are either recurrent or rare in cancers. These barcoded genes can be used for context-specific functional validation, detection of novel biomarkers (pathway activation) and targets (drug sensitivity).

  1. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.

    Science.gov (United States)

    Vilarinho, Sílvia; Sari, Sinan; Yilmaz, Güldal; Stiegler, Amy L; Boggon, Titus J; Jain, Dhanpat; Akyol, Gulen; Dalgic, Buket; Günel, Murat; Lifton, Richard P

    2016-06-01

    Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986). © 2016 by the American Association for the Study of Liver Diseases.

  2. Molecular genetic analysis of the F11 gene in 14 Turkish patients with factor XI deficiency: identification of novel and recurrent mutations and their inheritance within families.

    Science.gov (United States)

    Colakoglu, Seyma; Bayhan, Turan; Tavil, Betül; Keskin, Ebru Yılmaz; Cakir, Volkan; Gümrük, Fatma; Çetin, Mualla; Aytaç, Selin; Berber, Ergul

    2018-01-01

    Factor XI (FXI) deficiency is an autosomal bleeding disease associated with genetic defects in the F11 gene which cause decreased FXI levels or impaired FXI function. An increasing number of mutations has been reported in the FXI mutation database, most of which affect the serine protease domain of the protein. FXI is a heterogeneous disorder associated with a variable bleeding tendency and a variety of causative F11 gene mutations. The molecular basis of FXI deficiency in 14 patients from ten unrelated families in Turkey was analysed to establish genotype-phenotype correlations and inheritance of the mutations in the patients' families. Fourteen index cases with a diagnosis of FXI deficiency and family members of these patients were enrolled into the study. The patients' F11 genes were amplified by polymerase chain reaction and subjected to direct DNA sequencing analysis. The findings were analysed statistically using bivariate correlations, Pearson's correlation coefficient and the nonparametric Mann-Whitney test. Direct DNA sequencing analysis of the F11 genes revealed that all of the 14 patients had a F11 gene mutation. Eight different mutations were identified in the apple 1, apple 2 or serine protease domains, except one which was a splice site mutation. Six of the mutations were recurrent. Two of the mutations were novel missense mutations, p.Val522Gly and p.Cys581Arg, within the catalytic domain. The p.Trp519Stop mutation was observed in two families whereas all the other mutations were specific to a single family. Identification of mutations confirmed the genetic heterogeneity of FXI deficiency. Most of the patients with mutations did not have any bleeding complications, whereas some had severe bleeding symptoms. Genetic screening for F11 gene mutations is important to decrease the mortality and morbidity rate associated with FXI deficiency, which can be life-threatening if bleeding occurs in tissues with high fibrinolytic activity.

  3. Recurrent loss of sex is associated with accumulation of deleterious mutations in Oenothera.

    Science.gov (United States)

    Hollister, Jesse D; Greiner, Stephan; Wang, Wei; Wang, Jun; Zhang, Yong; Wong, Gane Ka-Shu; Wright, Stephen I; Johnson, Marc T J

    2015-04-01

    Sexual reproduction is nearly universal among eukaryotes. Theory predicts that the rarity of asexual eukaryotic species is in part caused by accumulation of deleterious mutations and heightened extinction risk associated with suppressed recombination and segregation in asexual species. We tested this prediction with a large data set of 62 transcriptomes from 29 species in the plant genus Oenothera, spanning ten independent transitions between sexual and a functionally asexual genetic system called permanent translocation heterozygosity. Illumina short-read sequencing and de novo transcript assembly yielded an average of 16.4 Mb of sequence per individual. Here, we show that functionally asexual species accumulate more deleterious mutations than sexual species using both population genomic and phylogenetic analysis. At an individual level, asexual species exhibited 1.8 × higher heterozygosity than sexual species. Within species, we detected a higher proportion of nonsynonymous polymorphism relative to synonymous variation within asexual compared with sexual species, indicating reduced efficacy of purifying selection. Asexual species also exhibited a greater proportion of transcripts with premature stop codons. The increased proportion of nonsynonymous mutations was also positively correlated with divergence time between sexual and asexual species, consistent with Muller's ratchet. Between species, we detected repeated increases in the ratio of nonsynonymous to synonymous divergence in asexual species compared with sexually reproducing sister taxa, indicating increased accumulation of deleterious mutations. These results confirm that an important advantage of sex is that it facilitates selection against deleterious alleles, which might help to explain the dearth of extant asexual species. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations.

    Science.gov (United States)

    Giefer, Matthew J; Lowe, Mark E; Werlin, Steven L; Zimmerman, Bridget; Wilschanski, Michael; Troendle, David; Schwarzenberg, Sarah Jane; Pohl, John F; Palermo, Joseph; Ooi, Chee Y; Morinville, Veronique D; Lin, Tom K; Husain, Sohail Z; Himes, Ryan; Heyman, Melvin B; Gonska, Tanja; Gariepy, Cheryl E; Freedman, Steven D; Fishman, Douglas S; Bellin, Melena D; Barth, Bradley; Abu-El-Haija, Maisam; Uc, Aliye

    2017-07-01

    To assess whether the age of onset was associated with unique features or disease course in pediatric acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Demographic and clinical information on children with ARP or CP was collected at INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) centers. The Cochran-Armitage trend test and Jonckheere-Terpstra test were used to examine for differences between pediatric age groups (pancreatitis, 111 (32%) were 6-11 years of age, and 102 (30%) were ≥12 years of age. Early-onset disease was associated with mutations in cationic trypsinogen (PRSS1) (P pancreatitis (P = .02), family history of CP (P chronic renal failure (P = .02). Later-onset disease was more commonly present with hypertriglyceridemia (P = .04), ulcerative colitis (P = .02), autoimmune diseases (P pancreatitis is associated strongly with PRSS1 or CTRC mutations and family history of pancreatitis. Children with later-onset disease are more likely to have nongenetic risk factors. Future studies are needed to investigate whether the disease course, response to therapy, or clinical outcomes differ relative to the timing of disease onset. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism.

    Science.gov (United States)

    Amselem, S; Sobrier, M L; Duquesnoy, P; Rappaport, R; Postel-Vinay, M C; Gourmelen, M; Dallapiccola, B; Goossens, M

    1991-01-01

    In addition to its classical effects on growth, growth hormone (GH) has been shown to have a number of other actions, all of which are initiated by an interaction with specific high affinity receptors present in a variety of tissues. Purification of a rabbit liver protein via its ability to bind GH has allowed the isolation of a cDNA encoding a putative human growth hormone receptor that belongs to a new class of transmembrane receptors. We have previously shown that this putative growth hormone receptor gene is genetically linked to Laron dwarfism, a rare autosomal recessive syndrome caused by target resistance to GH. Nevertheless, the inability to express the corresponding full-length coding sequence and the lack of a test for growth-promoting function have hampered a direct confirmation of its role in growth. We have now identified three nonsense mutations within this growth hormone receptor gene, lying at positions corresponding to the amino terminal extremity and causing a truncation of the molecule, thereby deleting a large portion of both the GH binding domain and the full transmembrane and intracellular domains. Three independent patients with Laron dwarfism born of consanguineous parents were homozygous for these defects. Two defects were identical and consisted of a CG to TG transition. Not only do these results confirm the growth-promoting activity of this receptor but they also suggest that CpG doublets may represent hot spots for mutations in the growth hormone receptor gene that are responsible for hereditary dwarfism. Images PMID:1999489

  6. High-resolution melting (HRM) assay for the detection of recurrent BRCA1/BRCA2 germline mutations in Tunisian breast/ovarian cancer families.

    Science.gov (United States)

    Riahi, Aouatef; Kharrat, Maher; Lariani, Imen; Chaabouni-Bouhamed, Habiba

    2014-12-01

    Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an increased risk for the development of breast and ovarian cancer. Given the large size of these genes the detection of such mutations represents a considerable technical challenge. Therefore, the development of cost-effective and rapid methods to identify these mutations became a necessity. High resolution melting analysis (HRM) is a rapid and efficient technique extensively employed as high-throughput mutation scanning method. The purpose of our study was to assess the specificity and sensitivity of HRM for BRCA1 and BRCA2 genes scanning. As a first step we estimate the ability of HRM for detection mutations in a set of 21 heterozygous samples harboring 8 different known BRCA1/BRCA2 variations, all samples had been preliminarily investigated by direct sequencing, and then we performed a blinded analysis by HRM in a set of 68 further sporadic samples of unknown genotype. All tested heterozygous BRCA1/BRCA2 variants were easily identified. However the HRM assay revealed further alteration that we initially had not searched (one unclassified variant). Furthermore, sequencing confirmed all the HRM detected mutations in the set of unknown samples, including homozygous changes, indicating that in this cohort, with the optimized assays, the mutations detections sensitivity and specificity were 100 %. HRM is a simple, rapid and efficient scanning method for known and unknown BRCA1/BRCA2 germline mutations. Consequently the method will allow for the economical screening of recurrent mutations in Tunisian population.

  7. Multiple Recurrent Paraganglioma in a Pediatric Patient with Germline SDH-B Mutation

    Directory of Open Access Journals (Sweden)

    Aidan McGowan

    2017-07-01

    Full Text Available Magnetic Resonance Imaging (MRI and fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET are recognized approaches for locating paragangliomas. Recently, gallium-68 DOTA-octreotate (DOTATATE scans have shown promise detecting neuroendocrine tumors missed by FDG-PET and MRI. 13-year-old male with SDH-B mutation presented with symptoms of paraganglioma and elevated catecholamines. MRI did not demonstrate the T2 hyper intense signal typical of paraganglioma and pheochromocytoma; FDG-PET scan did not reveal increased foci of uptake. DOTATATE scan revealed a signal consistent only with residual adrenal tissue. Resection of the right adrenal bed revealed paraganglioma. Following surgery, no further symptoms were reported and biochemical tests normalized.

  8. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

    Science.gov (United States)

    Yokoyama, Satoru; Woods, Susan L.; Boyle, Glen M.; Aoude, Lauren G.; MacGregor, Stuart; Zismann, Victoria; Gartside, Michael; Cust, Anne E.; Haq, Rizwan; Harland, Mark; Taylor, John C.; Duffy, David L.; Holohan, Kelly; Dutton-Regester, Ken; Palmer, Jane M.; Bonazzi, Vanessa; Stark, Mitchell S.; Symmons, Judith; Law, Matthew H.; Schmidt, Christopher; Lanagan, Cathy; O’Connor, Linda; Holland, Elizabeth A.; Schmid, Helen; Maskiell, Judith A.; Jetann, Jodie; Ferguson, Megan; Jenkins, Mark A.; Kefford, Richard F.; Giles, Graham G.; Armstrong, Bruce K.; Aitken, Joanne F.; Hopper, John L.; Whiteman, David C.; Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.; Newton-Bishop, Julia A.; Montgomery, Grant W.; Martin, Nicholas G.; Mann, Graham J.; Bishop, D. Timothy; Tsao, Hensin; Trent, Jeffrey M.; Fisher, David E.; Hayward, Nicholas K.; Brown, Kevin M.

    2012-01-01

    So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility. PMID:22080950

  9. Matched-pair analysis of a multi-institutional cohort reveals that epidermal growth factor receptor mutation is not a risk factor for postoperative recurrence of lung adenocarcinoma.

    Science.gov (United States)

    Matsumura, Yuki; Suzuki, Hiroyuki; Ohira, Tetsuya; Shiono, Satoshi; Abe, Jiro; Sagawa, Motoyasu; Sakurada, Akira; Katahira, Masato; Machida, Yuichiro; Takahashi, Satomi; Okada, Yoshinori

    2017-12-01

    It is unclear whether epidermal growth factor receptor (EGFR) mutation status is a risk factor for postoperative recurrence of surgically resected lung adenocarcinoma (ADC). Therefore, we conducted a multi-institutional study employing matched-pair analysis to compare recurrence-free survival (RFS) and overall survival (OS) of patients with lung ADC according to EGFR mutation status. We collected the records of 909 patients who underwent surgical resection for lung ADC between 2005 and 2012 at five participating institutions and were also examined their EGFR mutation status. For each patient with an EGFR mutation, we selected one with the wild-type EGFR sequence and matched them according to institution, age, gender, smoking history, pathological stage (pStage), and adjuvant treatment. We compared RFS and OS of the matched cohort. The patients were allocated into groups (n=181 each) with mutated or wild-type EGFR sequences. Both cohorts had identical characteristics as follows: institution, median age (68 years), men (85, 47%), ever smokers (77, 43%), and pStage (IA, 108, 60%; IB, 48, 27%; II, 14, 8%; III, 11, 6%). The 3- and 5-year RFS rates of patients with mutated or wild-type EGFR sequence were 79%, 68% and 77%, 68%, respectively (p=0.557). The respective OS rates were 92%, 81%, and 89%, 79% (p=0.574). Matched-pair and multi-institutional analysis reveals that an EGFR mutation was not a significant risk factor for recurrence of patients with surgically resected lung adenocarcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

    Science.gov (United States)

    Gripp, Karen W; Aldinger, Kimberly A; Bennett, James T; Baker, Laura; Tusi, Jessica; Powell-Hamilton, Nina; Stabley, Deborah; Sol-Church, Katia; Timms, Andrew E; Dobyns, William B

    2016-09-01

    Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Recurrent gastrointestinal hemorrhage in treatment with dasatinib in a patient showing SMAD4 mutation with acute lymphoblastic leukemia Philadelphia positive and juvenile polyposis hereditary hemorrhagic telangiectasia syndrome

    Directory of Open Access Journals (Sweden)

    Chiara Sartor

    2013-07-01

    Full Text Available We report a case of a patient affected by juvenile polyposis and hereditary hemorrhagic telangiectasia linked to a SMAD4 mutation who developed acute lymphoblastic leukemia positive for the Philadelphia chromosome translocation and with a complex karyotype. During the treatment with the tyrosine kinase inhibitor dasatinib the patient presented recurrent severe gastrointestinal hemorrhages linked to the genetic background and aggravated by thrombocytopenia.

  12. KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer.

    Science.gov (United States)

    Kohonen-Corish, Maija R J; Tseung, Jason; Chan, Charles; Currey, Nicola; Dent, Owen F; Clarke, Stephen; Bokey, Les; Chapuis, Pierre H

    2014-06-15

    Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer. © 2013 UICC.

  13. Recurrent and founder mutations in the Netherlands Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia

    NARCIS (Netherlands)

    van der Zwaag, P. A.; Cox, M. G. P. J.; van der Werf, C.; Wiesfeld, A. C. P.; Jongbloed, J. D. H.; Dooijes, D.; Bikker, H.; Jongbloed, R.; Suurmeijer, A. J. H.; van den Berg, M. P.; Hofstra, R. M. W.; Hauer, R. N. W.; Wilde, A. A. M.; van Tintelen, J. P.

    2010-01-01

    Background. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p. Arg79X mutation

  14. Recurrent and founder mutations in the Netherlands Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia

    NARCIS (Netherlands)

    van der Zwaag, P. A.; Cox, M. G. P. J.; van der Werf, C.; Wiesfeld, A. C. P.; Jongbloed, J. D. H.; Dooijes, D.; Bikker, H.; Jongbloed, R.; Suurmeijer, A. J. H.; van den Berg, M. P.; Hofstra, R. M. W.; Hauer, R. N. W.; Wilde, A. A. M.; van Tintelen, J. P.

    Background. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p. Arg79X mutation

  15. Mutation inactivation of Nijmegen breakage syndrome gene (NBS1 in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

    Directory of Open Access Journals (Sweden)

    Yan Wang

    Full Text Available Nijmegen breakage syndrome (NBS with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin, involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC. Eight missense NBS1 mutations were identified in six of 64 (9.4% HCCs and two of 18 (11.1% ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene.

  16. 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 ...

  17. A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma

    DEFF Research Database (Denmark)

    Wadt, Karin Anna Wallentin; Aoude, L G; Johansson, P

    2015-01-01

    ) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported...

  18. A Somatic HIF2α Mutation-Induced Multiple and Recurrent Pheochromocytoma/Paraganglioma with Polycythemia: Clinical Study with Literature Review.

    Science.gov (United States)

    Liu, Qiuli; Wang, Yan; Tong, Dali; Liu, Gaolei; Yuan, Wenqiang; Zhang, Jun; Ye, Jin; Zhang, Yao; Yuan, Gang; Feng, Qingxing; Zhang, Dianzheng; Jiang, Jun

    2017-03-01

    A syndrome known as pheochromocytomas (PCC)/paragangliomas (PGL) and polycythemia resulted from gain-of-function mutation of hypoxia-inducible factor 2α (HIF2α) has been reported recently. However, clinical features of this syndrome vary from patient to patient. In our study, we described the clinical features of the patient within 15-year follow-up with a literature review. The patient presented with "red face" since childhood and was diagnosed with polycythemia and pheochromocytoma in 2000, and then, tumor was removed at his age of 27 (year 2000). However, 13 years later (2013), he was diagnosed with multiple paragangliomas. Moreover, 2 years later (2015), another two paragangaliomas were also confirmed. Genetic analysis of hereditary PCC/PGL-related genes was conducted. A somatic heterozygous missense mutation of HIF2α (c.1589C>T) was identified at exon 12, which is responsible for the elevated levels of HIF2α and erythropoietin (EPO) and subsequent development of paragangaliomas. However, this mutation was only found in the tumors from three different areas, not in the blood. So far, 13 cases of PCC/PGL with polycythemia have been reported. Among them, somatic mutations of HIF2α at exon 12 are responsible for 12 cases, and only 1 case was caused by germline mutation of HIF2α at exon 9. The HIF2α mutation-induced polycythemia with PCC/PGL is a rare syndrome with no treatment for cure. Comprehensive therapies for this disease include removal of the tumors and intermittent phlebotomies; administration of medications to control blood pressure and to prevent complications or death resulted from high concentration of red blood cell (RBC). Genetic test is strongly recommended for patients with early onset of polycythemia and multiple/recurrent PCC/PGL.

  19. Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes

    Science.gov (United States)

    Léger, Sandy; Balguerie, Xavier; Goldenberg, Alice; Drouin-Garraud, Valérie; Cabot, Annick; Amstutz-Montadert, Isabelle; Young, Paul; Joly, Pascal; Bodereau, Virginie; Holder-Espinasse, Muriel; Jamieson, Robyn V; Krause, Amanda; Chen, Hongsheng; Baumann, Clarisse; Nunes, Luis; Dollfus, Hélène; Goossens, Michel; Pingault, Véronique

    2012-01-01

    The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci. PMID:22258527

  20. Whole-exome sequencing reveals a recurrent mutation in the cathepsin C gene that causes Papillon–Lefevre syndrome in a Saudi family

    Directory of Open Access Journals (Sweden)

    Yaser Mohammad Alkhiary

    2016-09-01

    Full Text Available Papillon–Lefevre syndrome (PALS is a rare, autosomal recessive disorder characterized by periodontitis and hyperkeratosis over the palms and soles. Mutations in the cathepsin C gene (CTSC have been recognized as the cause of PALS since the late 1990s. More than 75 mutations in CTSC have been identified, and phenotypic variability between different mutations has been described. Next generation sequencing is widely used for efficient molecular diagnostics in various clinical practices. Here we investigated a large consanguineous Saudi family with four affected and four unaffected individuals. All of the affected individuals suffered from hyperkeratosis over the palms and soles and had anomalies of both primary and secondary dentition. For molecular diagnostics, we combined whole-exome sequencing and genome-wide homozygosity mapping procedures, and identified a recurrent homozygous missense mutation (c.899G>A; p.Gly300Asp in exon 7 of CTSC. Validation of all eight family members by Sanger sequencing confirmed co-segregation of the pathogenic variant (c.899G>A with the disease phenotype. This is the first report of whole-exome sequencing performed for molecular diagnosis of PALS in Saudi Arabia. Our findings provide further insights into the genotype–phenotype correlation of CTSC pathogenicity in PALS.

  1. Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation.

    Science.gov (United States)

    Harms, Paul W; Collie, Angela M B; Hovelson, Daniel H; Cani, Andi K; Verhaegen, Monique E; Patel, Rajiv M; Fullen, Douglas R; Omata, Kei; Dlugosz, Andrzej A; Tomlins, Scott A; Billings, Steven D

    2016-03-01

    Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin 20 (CK20) is expressed in ~95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small-cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (10 Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high-confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping genetic changes

  2. Next Generation Sequencing of Cytokeratin 20-Negative Merkel Cell Carcinoma Reveals Ultraviolet Signature Mutations and Recurrent TP53 and RB1 Inactivation

    Science.gov (United States)

    Harms, Paul W.; Collie, Angela M. B.; Hovelson, Daniel H.; Cani, Andi K.; Verhaegen, Monique E.; Patel, Rajiv M.; Fullen, Douglas R.; Omata, Kei; Dlugosz, Andrzej A.; Tomlins, Scott A.; Billings, Steven D.

    2016-01-01

    Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin-20 (CK20) is expressed in approximately 95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (ten Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%)) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping

  3. Novel and recurrent NDP gene mutations in familial cases of Norrie disease and X-linked exudative vitreoretinopathy.

    Science.gov (United States)

    Pelcastre, Erika L; Villanueva-Mendoza, Cristina; Zenteno, Juan C

    2010-05-01

    To present the results of molecular analysis of the NDP gene in Mexican families with Norrie disease (ND) and X-linked familial exudative vitreoretinopathy (XL-FEVR). Two unrelated families with ND and two with XL-FEVR were studied. Clinical diagnosis was suspected on the basis of a complete ophthalmologic examination. Molecular methods included DNA isolation from peripheral blood leucocytes, polymerase chain reaction amplification and direct nucleotide sequencing analysis of the complete coding region and exon-intron junctions of NDP. Haplotype analysis using NDP-linked microsatellites markers was performed in both ND families. A novel Norrin missense mutation, p.Arg41Thr, was identified in two apparently unrelated families with ND. Haplotype analysis demonstrated that affected males in these two families shared the same ND-linked haplotype, suggesting a common origin for this novel mutation. The previously reported p.Arg121Trp and p.Arg121Gln Norrin mutations were identified in the two families with XL-FEVR. Our results expand the mutational spectrum in ND. This is the first report of ND resulting from mutation at arginine position 41 of Norrin. Interestingly, mutations at the same residue but resulting in a different missense change were previously described in subjects with XL-FEVR (p.Arg41Lys) or persistent fetal vasculature syndrome (p.Arg41Ser), indicating that the novel p.Arg41Thr change causes a more severe retinal phenotype. Preliminary data suggest a founder effect for the ND p.Arg41Thr mutation in these two Mexican families.

  4. A novel APOC2 gene mutation identified in a Chinese patient with severe hypertriglyceridemia and recurrent pancreatitis.

    Science.gov (United States)

    Jiang, Jingjing; Wang, Yuhui; Ling, Yan; Kayoumu, Abudurexiti; Liu, George; Gao, Xin

    2016-01-16

    The severe forms of hypertriglyceridemia are usually caused by genetic defects. In this study, we described a Chinese female with severe hypertriglyceridemia caused by a novel homozygous mutation in the APOC2 gene. Lipid profiles of the pedigree were studied in detail. LPL and HL activity were also measured. The coding regions of 5 candidate genes (namely LPL, APOC2, APOA5, LMF1, and GPIHBP1) were sequenced using genomic DNA from peripheral leucocytes. The ApoE gene was also genotyped. Serum triglyceride level was extremely high in the proband, compared with other family members. Plasma LPL activity was also significantly reduced in the proband. Serum ApoCII was very low in the proband as well as in the heterozygous mutation carriers. A novel mutation (c.86A > CC) was identified on exon 3 [corrected] of the APOC2 gene, which converted the Asp [corrected] codon at position 29 into Ala, followed by a termination codon (TGA). This study presented the first case of ApoCII deficiency in the Chinese population, with a novel mutation c.86A > CC in the APOC2 gene identified. Serum ApoCII protein might be a useful screening test for identifying mutation carriers.

  5. Mutations of the Birt–Hogg–Dubé gene in patients with multiple lung cysts and recurrent pneumothorax

    Science.gov (United States)

    Gunji, Yoko; Akiyoshi, Taeko; Sato, Teruhiko; Kurihara, Masatoshi; Tominaga, Shigeru; Takahashi, Kazuhisa; Seyama, Kuniaki

    2007-01-01

    Rationale Birt–Hogg–Dubé (BHD) syndrome, a rare inherited autosomal genodermatosis first recognised in 1977, is characterised by fibrofolliculomas of the skin, an increased risk of renal tumours and multiple lung cysts with spontaneous pneumothorax. The BHD gene, a tumour suppressor gene located at chromosome 17p11.2, has recently been shown to be defective. Recent genetic studies revealed that clinical pictures of the disease may be variable and may not always present the full expression of the phenotypes. Objectives We hypothesised that mutations of the BHD gene are responsible for patients who have multiple lung cysts of which the underlying causes have not yet been elucidated. Methods We studied eight patients with lung cysts, without skin and renal disease; seven of these patients have a history of spontaneous pneumothorax and five have a family history of pneumothorax. The BHD gene was examined using PCR, denaturing high‐performance liquid chromatography and direct sequencing. Main results We found that five of the eight patients had a BHD germline mutation. All mutations were unique and four of them were novel, including three different deletions or insertions detected in exons 6, 12 and 13, respectively and one splice acceptor site mutation in intron 5 resulting in an in‐frame deletion of exon 6. Conclusions We found that germline mutations of the BHD gene are involved in some patients with multiple lung cysts and pneumothorax. Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement. PMID:17496196

  6. CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays.

    Science.gov (United States)

    Legendre, Marine; Rodriguez-Ballesteros, Montserrat; Rossi, Massimiliano; Abadie, Véronique; Amiel, Jeanne; Revencu, Nicole; Blanchet, Patricia; Brioude, Frédéric; Delrue, Marie-Ange; Doubaj, Yassamine; Sefiani, Abdelaziz; Francannet, Christine; Holder-Espinasse, Muriel; Jouk, Pierre-Simon; Julia, Sophie; Melki, Judith; Mur, Sébastien; Naudion, Sophie; Fabre-Teste, Jennifer; Busa, Tiffany; Stamm, Stephen; Lyonnet, Stanislas; Attie-Bitach, Tania; Kitzis, Alain; Gilbert-Dussardier, Brigitte; Bilan, Frédéric

    2018-02-01

    CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

  7. Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype.

    Science.gov (United States)

    Lamers, Ideke J C; Reijnders, Margot R F; Venselaar, Hanka; Kraus, Alison; Jansen, Sandra; de Vries, Bert B A; Houge, Gunnar; Gradek, Gyri Aasland; Seo, Jieun; Choi, Murim; Chae, Jong-Hee; van der Burgt, Ineke; Pfundt, Rolph; Letteboer, Stef J F; van Beersum, Sylvia E C; Dusseljee, Simone; Brunner, Han G; Doherty, Dan; Kleefstra, Tjitske; Roepman, Ronald

    2017-11-02

    The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization. Copyright © 2017 American Society of Human Genetics. All rights reserved.

  8. Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.

    Science.gov (United States)

    Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L; Loh, Abigail; Wright, Graham D; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K; Choudhri, Asim F; Krüger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N; Mundlos, Stefan; Villarroel, Camilo E; Byers, Peter; Masri, Amira; Robertson, Stephen P; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-09-03

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  9. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika

    2012-11-15

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  10. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika; Merner, Nancy D.; Hodgkinson, Kathy A.; Houston, Jim; Syrris, Petros; Booth, Valerie; Connors, Sean; Pantazis, Antonios; Quarta, Giovanni; Elliott, Perry; McKenna, William; Young, Terry Lynn

    2012-01-01

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  11. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis.

    Science.gov (United States)

    Esteller, M; Toyota, M; Sanchez-Cespedes, M; Capella, G; Peinado, M A; Watkins, D N; Issa, J P; Sidransky, D; Baylin, S B; Herman, J G

    2000-05-01

    O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from the O6 position of guanine. O6-methylguanine mispairs with thymine during replication, and if the adduct is not removed, this results in conversion from a guanine-cytosine pair to an adenine-thymine pair. In vitro assays show that MGMT expression avoids G to A mutations and MGMT transgenic mice are protected against G to A transitions at ras genes. We have recently demonstrated that the MGMT gene is silenced by promoter methylation in many human tumors, including colorectal carcinomas. To study the relevance of defective MGMT function by aberrant methylation in relation to the presence of K-ras mutations, we studied 244 colorectal tumor samples for MGMT promoter hypermethylation and K-ras mutational status. Our results show a clear association between the inactivation of MGMT by promoter hypermethylation and the appearance of G to A mutations at K-ras: 71% (36 of 51) of the tumors displaying this particular type of mutation had abnormal MGMT methylation, whereas only 32% (12 of 37) of those with other K-ras mutations not involving G to A transitions and 35% (55 of 156) of the tumors without K-ras mutations demonstrated MGMT methylation (P = 0.002). In addition, MGMT loss associated with hypermethylation was observed in the small adenomas, including those that do not yet contain K-ras mutations. Hypermethylation of other genes such as p16INK4a and p14ARF was not associated with either MGMT hypermethylation or K-ras mutation. Our data suggest that epigenetic silencing of MGMT by promoter hypermethylation may lead to a particular genetic change in human cancer, specifically G to A transitions in the K-ras oncogene.

  12. Severe hypertriglyceridemia due to two novel loss-of-function lipoprotein lipase gene mutations (C310R/E396V) in a Chinese family associated with recurrent acute pancreatitis.

    Science.gov (United States)

    Lun, Yu; Sun, Xiaofang; Wang, Ping; Chi, Jingwei; Hou, Xu; Wang, Yangang

    2017-07-18

    Lipoprotein lipase (LPL) is widely expressed in skeletal muscles, cardiac muscles as well as adipose tissue and involved in the catabolism of triglyceride. Herein we have systematically characterized two novel loss-of-function mutations in LPL from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis. DNA sequencing revealed that the proband was a heterozygote carrying a novel c.T928C (p.C310R) mutation in exon 6 of the LPL gene. Another member of the family was detected to be a compound heterozygote who along with the c.T928C mutation also carried a novel missense mutation c.A1187T (p.E396V) in exon 8 of the LPL gene. Furthermore, COS-1 cells were transfected with lentiviruses containing the mutant LPL genes. While C310R markedly reduced the overall LPL protein level, COS-1 cells carrying E396V or double mutations contained similar overall LPL protein levels to the wild-type. The specific activity of the LPL mutants remained at comparable magnitude to the wild-type. However, few LPL were detected in the culture medium for the mutants, suggesting that both mutations caused aberrant triglyceride catabolism. More specifically, E396V and double mutations dampened the transport of LPL to the cell surface, while for the C310R mutation, reducing LPL protein level might be involved. By characterizing these two novel LPL mutations, this study has expanded our understanding on the pathogenesis of familial hypertriglyceridemia (FHTG).

  13. High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast-ovarian cancer prevention and control.

    Science.gov (United States)

    Laarabi, Fatima-Zahra; Ratbi, Ilham; Elalaoui, Siham Chafai; Mezzouar, Loubna; Doubaj, Yassamine; Bouguenouch, Laila; Ouldim, Karim; Benjaafar, Noureddine; Sefiani, Abdelaziz

    2017-06-02

    To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients. Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco. In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.

  14. SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

    NARCIS (Netherlands)

    J. Vogt (Julia); K. Bengesser (Kathrin); K.B.M. Claes (Kathleen B.M.); K. Wimmer (Katharina); V.-F. Mautner (Victor-Felix); R. van Minkelen (Rick); E. Legius (Eric); H. Brems (Hilde); M. Upadhyaya (Meena); J. Högel (Josef); C. Lazaro (Conxi); T. Rosenbaum (Thorsten); S. Bammert (Simone); L. Messiaen (Ludwine); D.N. Cooper (David); H. Kehrer-Sawatzki (Hildegard)

    2014-01-01

    textabstractBackground: Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The

  15. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation

    Science.gov (United States)

    Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun; Diplas, Bill H.; Yang, Rui; Killela, Patrick J.; Liang, Junbo; Meng, Qun; Ye, Zai-Yuan; Wang, Wei; Jiang, Xiao-Ting; Xu, Li; He, Xiang-Lei; Zhao, Zhong-Sheng; Xu, Wen-Juan; Wang, Hui-Ju; Ma, Ying-Yu; Xia, Ying-Jie; Li, Li; Zhang, Ru-Xuan; Jin, Tao; Zhao, Zhong-Kuo; Xu, Ji; Yu, Sheng; Wu, Fang; Wang, Si-Zhen; Jiao, Yu-Chen; Yan, Hai; Tao, Hou-Quan

    2015-01-01

    Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets. PMID:25843513

  16. A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa

    NARCIS (Netherlands)

    Van Schil, Kristof; Klevering, B. Jeroen; Leroy, Bart P.; Pott, Jan Willem R.; Bandah-Rozenfeld, Dikla; Zonneveld-Vrieling, Marijke N.; Sharon, Dror; den Hollander, Anneke I.; Cremers, Frans P. M.; De Baere, Elfride; Collin, Rob W. J.; van den Born, L. Ingeborgh

    PURPOSE. To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. METHODS. Homozygosity mapping, amplification-refractory mutation

  17. Recurrent vomiting and ethylmalonic aciduria associated with rare mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene

    DEFF Research Database (Denmark)

    Seidel, J.; Streck, S.; Bellstedt, K.

    2003-01-01

    blood spots. Neither of the frequent SCAD gene variants 625G>A and 511C>T was present, but direct sequencing of the promoter and coding regions of the SCAD gene revealed that the patient had mutations on both alleles: 417G>C (Trpl15Cys) and 1095G>T (Gln341His). Neither mutation has been described before...

  18. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions | Office of Cancer Genomics

    Science.gov (United States)

    We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases.

  19. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

    Science.gov (United States)

    Jiang, Y; Chen, H-C; Su, X; Thompson, P A; Liu, X; Do, K-A; Wierda, W; Keating, M J; Plunkett, W

    2016-09-02

    Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

  20. Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer

    Science.gov (United States)

    2018-05-31

    ATM Gene Mutation; ATR Gene Mutation; BARD1 Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; BRIP1 Gene Mutation; CHEK1 Gene Mutation; CHEK2 Gene Mutation; FANCA Gene Mutation; FANCC Gene Mutation; FANCD2 Gene Mutation; FANCF Gene Mutation; FANCM Gene Mutation; NBN Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; RAD51B Gene Mutation; RAD54L Gene Mutation; Recurrent Squamous Cell Lung Carcinoma; RPA1 Gene Mutation; Stage IV Squamous Cell Lung Carcinoma AJCC v7

  1. SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

    Science.gov (United States)

    2014-01-01

    Background Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. Results We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. Conclusions Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome. PMID:24958239

  2. Recurrent varicocele

    Directory of Open Access Journals (Sweden)

    Katherine Rotker

    2016-01-01

    Full Text Available Varicocele recurrence is one of the most common complications associated with varicocele repair. A systematic review was performed to evaluate varicocele recurrence rates, anatomic causes of recurrence, and methods of management of recurrent varicoceles. The PubMed database was evaluated using keywords "recurrent" and "varicocele" as well as MESH criteria "recurrent" and "varicocele." Articles were not included that were not in English, represented single case reports, focused solely on subclinical varicocele, or focused solely on a pediatric population (age <18. Rates of recurrence vary with the technique of varicocele repair from 0% to 35%. Anatomy of recurrence can be defined by venography. Management of varicocele recurrence can be surgical or via embolization.

  3. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia

    Science.gov (United States)

    Coutelier, Marie; Blesneac, Iulia; Monteil, Arnaud; Monin, Marie-Lorraine; Ando, Kunie; Mundwiller, Emeline; Brusco, Alfredo; Le Ber, Isabelle; Anheim, Mathieu; Castrioto, Anna; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Lory, Philippe; Stevanin, Giovanni

    2015-01-01

    Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. PMID:26456284

  4. Inherited protein S deficiency due to a novel nonsense mutation in the PROS1 gene in the patient with recurrent vascular access thrombosis: A case report

    Directory of Open Access Journals (Sweden)

    Eun Jin Cho

    2012-03-01

    Full Text Available Vascular access thrombosis is one of the major causes of morbidity in patients maintained on chronic hemodialysis. Thrombophilia has been recognized as a risk factor of vascular access thrombosis. The authors report a case of inherited protein S deficiency associated with vascular access thrombotic events. DNA sequence analysis of the PROS1 gene identified a novel heterozygous nonsense mutation in exon 10 by transition of AAG (lysine to TAG (stop codon at codon 473 (c.1417A>T, p.K473X. Results from the study suggest that the inherited protein S deficiency due to a PROS1 gene mutation may cause vascular access thrombosis in hemodialysis patients.

  5. [A novel homozygous mutation p.E25X in the HSD3B2 gene causing salt wasting 3β-hydroxysteroid dehydrogenases deficiency in a Chinese pubertal girl: a delayed diagnosis until recurrent ovary cysts].

    Science.gov (United States)

    Huang, Yonglan; Zheng, Jipeng; Xie, Ting; Xiao, Qing; Lu, Shaomei; Li, Xiuzhen; Cheng, Jing; Chen, Lihe; Liu, Li

    2014-12-01

    3β- hydroxysteroid dehydrogenase deficiency (3βHSD), a rare form of congenital adrenal hyperplasia (CAH) resulted from mutations in the HSD3B2 gene that impair steroidogenesis in both adrenals and gonads. We report clinical features and the results of HSD3B2 gene analysis of a Chinese pubertal girl with salt wasting 3βHSD deficiency. We retrospectively reviewed clinical presentations and steroid profiles of the patient diagnosed in Guangzhou Women and Children's Medical Center in 2013. PCR and direct sequencing were used to identify any mutation in the HSD3B2 gene. A 13-year-old girl was diagnosed as CAH after birth because of salt-wasting with mild clitorimegaly and then was treated with glucocorticoid replacement. Breast and pubic hair development were normal, and menarche occurred at 12 yr, followed by menstrual bleeding about every 45 days. In the last one year laparoscopic operation and ovariocentesis were performed one after another for recurrent ovary cysts. Under corticoid acetate therapy, ACTH 17.10 pmol/L (normal 0-10.12), testosterone 1.31 nmol/L (normal T (p.E25X) was identified in HSD3B2 gene. The girl was homozygous and her mother was heterozygous, while her father was not identified with this mutation. A classic 3βHSD deficiency is characterized by salt wasting and mild virilization in female. Ovary cysts may be the one of features of gonad phenotype indicating ovary 3βHSD deficiency. A novel homozygous mutation c.73G >T(p.E25X) was related to the classical phenotype.

  6. Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

    NARCIS (Netherlands)

    Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K.; Choudhri, Asim F.; Krüger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-01-01

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively,

  7. The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype.

    Science.gov (United States)

    Bertola, Débora; Yamamoto, Guilherme; Buscarilli, Michelle; Jorge, Alexander; Passos-Bueno, Maria Rita; Kim, Chong

    2017-03-01

    We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Recurrent Meningitis.

    Science.gov (United States)

    Rosenberg, Jon; Galen, Benjamin T

    2017-07-01

    Recurrent meningitis is a rare clinical scenario that can be self-limiting or life threatening depending on the underlying etiology. This review describes the causes, risk factors, treatment, and prognosis for recurrent meningitis. As a general overview of a broad topic, the aim of this review is to provide clinicians with a comprehensive differential diagnosis to aide in the evaluation and management of a patient with recurrent meningitis. New developments related to understanding the pathophysiology of recurrent meningitis are as scarce as studies evaluating the treatment and prevention of this rare disorder. A trial evaluating oral valacyclovir suppression after HSV-2 meningitis did not demonstrate a benefit in preventing recurrences. The data on prophylactic antibiotics after basilar skull fractures do not support their use. Intrathecal trastuzumab has shown promise in treating leptomeningeal carcinomatosis from HER-2 positive breast cancer. Monoclonal antibodies used to treat cancer and autoimmune diseases are new potential causes of drug-induced aseptic meningitis. Despite their potential for causing recurrent meningitis, the clinical entities reviewed herein are not frequently discussed together given that they are a heterogeneous collection of unrelated, rare diseases. Epidemiologic data on recurrent meningitis are lacking. The syndrome of recurrent benign lymphocytic meningitis described by Mollaret in 1944 was later found to be closely related to HSV-2 reactivation, but HSV-2 is by no means the only etiology of recurrent aseptic meningitis. While the mainstay of treatment for recurrent meningitis is supportive care, it is paramount to ensure that reversible and treatable causes have been addressed for further prevention.

  9. Association of recurrent pregnancy loss with chromosomal ...

    African Journals Online (AJOL)

    Objective: To evaluate the association of parental and fetal chromosomal abnormalities with recurrent pregnancy loss in our area and to analyze the frequency of three types of hereditary thrombophilia's; (MTHFR C677T polymorphisms, FV Leiden G1691A mutation and Prothrombin (factor II) G20210A mutation) in these ...

  10. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.

    2011-01-01

    selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...

  11. Recurrent vulvovaginitis.

    Science.gov (United States)

    Powell, Anna M; Nyirjesy, Paul

    2014-10-01

    Vulvovaginitis (VV) is one of the most commonly encountered problems by a gynecologist. Many women frequently self-treat with over-the-counter medications, and may present to their health-care provider after a treatment failure. Vulvovaginal candidiasis, bacterial vaginosis, and trichomoniasis may occur as discreet or recurrent episodes, and have been associated with significant treatment cost and morbidity. We present an update on diagnostic capabilities and treatment modalities that address recurrent and refractory episodes of VV. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Recurrent IVF failure and hereditary thrombophilia.

    Science.gov (United States)

    Safdarian, Leila; Najmi, Zahra; Aleyasin, Ashraf; Aghahosseini, Marzieh; Rashidi, Mandana; Asadollah, Sara

    2014-07-01

    The largest percentage of failed invitro fertilization (IVF (cycles, are due to lack of implantation. As hereditary thrombophilia can cause in placentation failure, it may have a role in recurrent IVF failure. Aim of this case-control study was to determine whether hereditary thrombophilia is more prevalent in women with recurrent IVF failures. Case group comprised 96 infertile women, with a history of recurrent IVF failure. Control group was comprised of 95 healthy women with proven fertility who had conceived spontaneously. All participants were assessed for the presence of inherited thrombophilias including: factor V Leiden, methilen tetrahydrofolate reductase (MTHFR) mutation, prothrombin mutation, homocystein level, protein S and C deficiency, antithrombin III (AT-III) deficiency and plasminogen activator inhibitor-1 (PAI-1) mutation. Presence of thrombophilia was compared between groups. Having at least one thrombophilia known as a risk factor for recurrent IVF failure (95% CI=1.74-5.70, OR=3.15, p=0.00). Mutation of factor V Leiden (95% CI=1.26-10.27, OR=3.06, P=0.01) and homozygote form of MTHFR mutation (95% CI=1.55-97.86, OR=12.33, p=0.05) were also risk factors for recurrent IVF failure. However, we could not find significant difference in other inherited thrombophilia's. Inherited thrombophilia is more prevalent in women with recurrent IVF failure compared with healthy women. Having at least one thrombophilia, mutation of factor V Leiden and homozygote form of MTHFR mutation were risk factors for recurrent IVF failure.

  13. Prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta associated with unaffected parents and paternal gonadal mosaicism

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2013-03-01

    Conclusion: Recurrent autosomal dominant OI may occur in the offspring of unaffected parents with parental gonadal mosaicism. Genetic counseling of recurrent autosomal dominant OI should include a thorough mutational analysis of the family members, and mutational analysis of the sperm may detect paternal gonadal mosaicism for the mutation.

  14. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi

    2014-10-01

    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  15. Screening for calreticulin mutations in a cohort of patients suspected ...

    African Journals Online (AJOL)

    Of the 36 types of insertions and deletions identified, type 1 (a. 52-base pair deletion) and type 2 (a 5-base pair insertion) mutations account for >80% of CALR mutations.[7] Phenotypic differences between type 1 and type 2 carriers have been implicated. [3] All recurrent mutations cause a frameshift in the region encoding.

  16. [Recurrent pulmonary infection and oral mucosal ulcer].

    Science.gov (United States)

    Kuang, Fei-Mei; Tang, Lan-Lan; Zhang, Hui; Xie, Min; Yang, Ming-Hua; Yang, Liang-Chun; Yu, Yan; Cao, Li-Zhi

    2017-04-01

    An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Routine blood tests and immune function tests performed in other hospitals had shown normal results. Multiple lung CT scans showed pulmonary infection. The patient had recurrent fever and cough and persistent presence of some lesions after anti-infective therapy. The antitubercular therapy was ineffective. Routine blood tests after admission showed agranulocytosis. Gene detection was performed and she was diagnosed with dyskeratosis congenita caused by homozygous mutation in RTEL1. Patients with dyskeratosis congenita with RTEL1 gene mutation tend to develop pulmonary complications. Since RTEL1 gene sequence is highly variable with many mutation sites and patterns and can be inherited via autosomal dominant or recessive inheritance, this disease often has various clinical manifestations, which may lead to missed diagnosis or misdiagnosis. For children with unexplained recurrent pulmonary infection, examinations of the oral cavity, skin, and nails and toes should be taken and routine blood tests should be performed to exclude dyskeratosis congenita. There are no specific therapies for dyskeratosis congenita at present, and when bone marrow failure and pulmonary failure occur, hematopoietic stem cell transplantation and lung transplantation are the only therapies. Androgen and its derivatives are effective in some patients. Drugs targeting the telomere may be promising for patients with dyskeratosis congenita.

  17. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders

    NARCIS (Netherlands)

    Campbell, I.M.; Yuan, B.; Robberecht, C.; Pfundt, R.P.; Szafranski, P.; McEntagart, M.E.; Nagamani, S.C.; Erez, A.; Bartnik, M.; Wisniowiecka-Kowalnik, B.; Plunkett, K.S.; Pursley, A.N.; Kang, S.H.; Bi, W.; Lalani, S.R.; Bacino, C.A.; Vast, M.; Marks, K.; Patton, M.; Olofsson, P.; Patel, A.; Veltman, J.A.; Cheung, S.W.; Shaw, C.A.; Vissers, L.E.L.M.; Vermeesch, J.R.; Lupski, J.R.; Stankiewicz, P.

    2014-01-01

    New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such

  18. Recurrent Intracerebral Hemorrhage

    DEFF Research Database (Denmark)

    Schmidt, Linnea Boegeskov; Goertz, Sanne; Wohlfahrt, Jan

    2016-01-01

    BACKGROUND: Intracerebral hemorrhage (ICH) is a disease with high mortality and a substantial risk of recurrence. However, the recurrence risk is poorly documented and the knowledge of potential predictors for recurrence among co-morbidities and medicine with antithrombotic effect is limited....... OBJECTIVES: 1) To estimate the short- and long-term cumulative risks of recurrent intracerebral hemorrhage (ICH). 2) To investigate associations between typical comorbid diseases, surgical treatment, use of medicine with antithrombotic effects, including antithrombotic treatment (ATT), selective serotonin...

  19. Recurrence in affective disorder

    DEFF Research Database (Denmark)

    Kessing, L V; Olsen, E W; Andersen, P K

    1999-01-01

    The risk of recurrence in affective disorder is influenced by the number of prior episodes and by a person's tendency toward recurrence. Newly developed frailty models were used to estimate the effect of the number of episodes on the rate of recurrence, taking into account individual frailty toward...... recurrence. The study base was the Danish psychiatric case register of all hospital admissions for primary affective disorder in Denmark during 1971-1993. A total of 20,350 first-admission patients were discharged with a diagnosis of major affective disorder. For women with unipolar disorder and for all...... kinds of patients with bipolar disorder, the rate of recurrence was affected by the number of prior episodes even when the effect was adjusted for individual frailty toward recurrence. No effect of episodes but a large effect of the frailty parameter was found for unipolar men. The authors concluded...

  20. Recurrent hamburger thyrotoxicosis

    Science.gov (United States)

    Parmar, Malvinder S.; Sturge, Cecil

    2003-01-01

    RECURRENT EPISODES OF SPONTANEOUSLY RESOLVING HYPERTHYROIDISM may be caused by release of preformed hormone from the thyroid gland after it has been damaged by inflammation (recurrent silent thyroiditis) or by exogenous administration of thyroid hormone, which might be intentional or surreptitious (thyrotoxicosis factitia). Community-wide outbreaks of “hamburger thyrotoxicosis” resulting from inadvertent consumption of beef contaminated with bovine thyroid gland have been previously reported. Here we describe a single patient who experienced recurrent episodes of this phenomenon over an 11-year period and present an approach to systematically evaluating patients with recurrent hyperthyroidism. PMID:12952802

  1. Recurrence of superficial vein thrombosis in patients with varicose veins.

    Science.gov (United States)

    Karathanos, Christos; Spanos, Konstantinos; Saleptsis, Vassileios; Tsezou, Aspasia; Kyriakou, Despina; Giannoukas, Athanasios D

    2016-08-01

    To investigate which factors other than history of superficial vein thrombosis (SVT) are associated with recurrent spontaneous SVT episodes in patients with varicose veins (VVs). Patients with a history of spontaneous SVT and VVs were followed up for a mean period of 55 months. Demographics, comorbidities, and thrombophilia screening test were analyzed. Patients were grouped according to the clinical-etiology-anatomy-pathophysiology classification. A multiple logistic regression analysis with the forward likelihood ratio method was undertaken. Thirteen patients out of 97 had a recurrence SVT episode during the follow-up period. All those patients were identified to have a thrombophilia defect. Protein C and S, antithrombin, and plasminogen deficiencies were more frequently present in patients without recurrence. Gene mutations were present in 38% in the nonrecurrence group and 77% in the recurrence group. After logistic regression analysis, patients with dislipidemia and mutation in prothrombin G20210A (FII) had an increased risk for recurrence by 5.4-fold and 4.6-fold, respectively. No deep vein thrombosis or pulmonary embolism occurred. Dislipidemia and gene mutations of F II are associated with SVT recurrence in patients with VVs. A selection of patients may benefit from anticoagulation in the short term and from VVs intervention in the long term. © The Author(s) 2015.

  2. Familial recurrences of FOXG1-related disorder: Evidence for mosaicism.

    Science.gov (United States)

    McMahon, Kelly Q; Papandreou, Apostolos; Ma, Mandy; Barry, Brenda J; Mirzaa, Ghayda M; Dobyns, William B; Scott, Richard H; Trump, Natalie; Kurian, Manju A; Paciorkowski, Alex R

    2015-12-01

    FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T > G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders. © 2015 Wiley Periodicals, Inc.

  3. Recurrent Takotsubo Cardiomyopathy Related to Recurrent Thyrotoxicosis.

    Science.gov (United States)

    Patel, Keval; Griffing, George T; Hauptman, Paul J; Stolker, Joshua M

    2016-04-01

    Takotsubo cardiomyopathy, or transient left ventricular apical ballooning syndrome, is characterized by acute left ventricular dysfunction caused by transient wall-motion abnormalities of the left ventricular apex and mid ventricle in the absence of obstructive coronary artery disease. Recurrent episodes are rare but have been reported, and several cases of takotsubo cardiomyopathy have been described in the presence of hyperthyroidism. We report the case of a 55-year-old woman who had recurrent takotsubo cardiomyopathy, documented by repeat coronary angiography and evaluations of left ventricular function, in the presence of recurrent hyperthyroidism related to Graves disease. After both episodes, the patient's left ventricular function returned to normal when her thyroid function normalized. These findings suggest a possible role of thyroid-hormone excess in the pathophysiology of some patients who have takotsubo cardiomyopathy.

  4. Persistent and recurrent hyperparathyroidism.

    Science.gov (United States)

    Guerin, Carole; Paladino, Nunzia Cinzia; Lowery, Aoife; Castinetti, Fréderic; Taieb, David; Sebag, Fréderic

    2017-06-01

    Despite remarkable progress in imaging modalities and surgical management, persistence or recurrence of primary hyperparathyroidism (PHPT) still occurs in 2.5-5% of cases of PHPT. The aim of this review is to expose the management of persistent and recurrent hyperparathyroidism. A literature search was performed on MEDLINE using the search terms "recurrent" or "persistent" and "hyperparathyroidism" within the past 10 years. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Before considering reoperation, the surgeon must confirm the diagnosis of PHPT. Then, the patient must be evaluated with new imaging modalities. A single adenoma is found in 68% of cases, multiglandular disease in 28%, and parathyroid carcinoma in 3%. Others causes (<1%) include parathyromatosis and graft recurrence. The surgeon must balance the benefits against the risks of a reoperation (permanent hypocalcemia and recurrent laryngeal nerve palsy). If surgery is necessary, a focused approach can be considered in cases of significant imaging foci, but in the case of multiglandular disease, a bilateral neck exploration could be necessary. Patients with multiple endocrine neoplasia syndromes are at high risk of recurrence and should be managed regarding their hereditary pathology. The cure rate of persistent-PHPT or recurrent-PHPT in expert centers is estimated from 93 to 97%. After confirming the diagnosis of PHPT, patients with persistent-PHPT and recurrent-PHPT should be managed in an expert center with all dedicated competencies.

  5. Calreticulin Mutations in Bulgarian MPN Patients.

    Science.gov (United States)

    Pavlov, Ivan; Hadjiev, Evgueniy; Alaikov, Tzvetan; Spassova, Sylva; Stoimenov, Angel; Naumova, Elissaveta; Shivarov, Velizar; Ivanova, Milena

    2018-01-01

    Somatic mutations in JAK2, MPL and CALR are recurrently identified in most of the cases with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). We applied four molecular genetic methods for identification of CALR exon 9 mutations, including high resolution melt (HRM) analysis, Sanger sequencing, semiconductor target genes sequencing and whole exome sequencing. A total of 78 patients with myeloid malignancies were included in the study. We identified 14 CALR exon 9 mutated cases out of 78 studied patients with myeloid malignancies. All mutated patients were diagnosed with MPN being either PMF (n = 7) or ET (n = 7). Nine cases had type 1 mutations and 5 cases had type 2 mutations. CALR exon 9, MPL exon 10 and JAK2 p. V617F were mutually exclusive. There were no statistically significant differences in the hematological parameters between the cases with CALR and JAK2 or MPL mutations. Notably, all four techniques were fully concordant in the detection of CALR mutations. This is one of the few reports on the CALR mutations frequency in South-eastern populations. Our study shows that the frequency and patterns of these mutations is identical to those in the patients' cohorts from Western countries. Besides we demonstrated the utility of four different methods for their detection.

  6. Telomerase reverse transcriptase promoter mutations in bladder cancer

    DEFF Research Database (Denmark)

    Allory, Yves; Beukers, Willemien; Sagrera, Ana

    2014-01-01

    for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription...... surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease...... frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC...

  7. Periodic cluster mutations and related integrable maps

    International Nuclear Information System (INIS)

    Fordy, Allan P

    2014-01-01

    One of the remarkable properties of cluster algebras is that any cluster, obtained from a sequence of mutations from an initial cluster, can be written as a Laurent polynomial in the initial cluster (known as the ‘Laurent phenomenon’). There are many nonlinear recurrences which exhibit the Laurent phenomenon and thus unexpectedly generate integer sequences. The mutation of a typical quiver will not generate a recurrence, but rather an erratic sequence of exchange relations. How do we ‘design’ a quiver which gives rise to a given recurrence? A key role is played by the concept of ‘periodic cluster mutation’, introduced in 2009. Each recurrence corresponds to a finite dimensional map. In the context of cluster mutations, these are called ‘cluster maps’. What properties do cluster maps have? Are they integrable in some standard sense?In this review I describe how integrable maps arise in the context of cluster mutations. I first explain the concept of ‘periodic cluster mutation’, giving some classification results. I then give a review of what is meant by an integrable map and apply this to cluster maps. Two classes of integrable maps are related to interesting monodromy problems, which generate interesting Poisson algebras of functions, used to prove complete integrability and a linearization. A connection to the Hirota–Miwa equation is explained. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘Cluster algebras in mathematical physics’. (review)

  8. Acromelic frontonasal dysostosis and ZSWIM6 mutation

    DEFF Research Database (Denmark)

    Twigg, Stephen R F; Ousager, Lilian Bomme; Miller, Kerry A

    2016-01-01

    Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this...... sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling....

  9. RECURRENT CROUP IN CHILDREN

    Directory of Open Access Journals (Sweden)

    S. L. Piskunova

    2014-01-01

    Full Text Available The article presents the results of examination of 1849 children, entering children's infectioushospitalofVladivostokwith the clinical picture of croup of viral etiology. The clinical features of primary and recurrent croup are described. Frequency of recurrent croup inVladivostokis 8%. Children with a recurrent croup had the burdened premorbid background, and also persistent herpetic infections (cytomegalic infection in 42,9% cases, cytomegalic infection in combination with the herpes simplex virus -1. Frequency of croups substantially rose in the period of epidemic of influenza.

  10. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6

    DEFF Research Database (Denmark)

    Zariwala, Maimoona A; Gee, Heon Yung; Kurkowiak, Małgorzata

    2013-01-01

    Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the ...

  11. Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation

    NARCIS (Netherlands)

    Hagebeuk, Eveline E. O.; Marcelis, Carlo L.; Alders, Mariëlle; Kaspers, Ageeth; de Weerd, Al W.

    2015-01-01

    This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who

  12. Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome.

    Science.gov (United States)

    Sunga, Annette Y; Ricker, Charité; Espenschied, Carin R; Castillo, Danielle; Melas, Marilena; Herzog, Josef; Bannon, Sarah; Cruz-Correa, Marcia; Lynch, Patrick; Solomon, Ilana; Gruber, Stephen B; Weitzel, Jeffrey N

    2017-04-01

    Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by mismatch repair (MMR) gene mutations. However, data about MMR mutations in Hispanics are limited. This study aims to describe the spectrum of MMR mutations in Hispanics with LS and explore ancestral origins. This case series involved an IRB-approved retrospective chart review of self-identified Hispanic patients (n = 397) seen for genetic cancer risk assessment at four collaborating academic institutions in California, Texas, and Puerto Rico who were evaluated by MMR genotyping and/or tumor analysis. A literature review was conducted for all mutations identified. Of those who underwent clinical genetic testing (n = 176), 71 had MMR gene mutations. Nine mutations were observed more than once. One third (3/9) of recurrent mutations and two additional mutations (seen only once) were previously reported in Spain, confirming the influence of Spanish ancestry on MMR mutations in Hispanic populations. The recurrent mutations identified (n = 9) included both previously reported mutations as well as unique mutations not in the literature. This is the largest report of Hispanic MMR mutations in North America; however, a larger sample and haplotype analyses are needed to better understand recurrent MMR mutations in Hispanic populations. Copyright © 2017. Published by Elsevier Inc.

  13. Hyperhomocysteinemia in Recurrent Miscarriage

    International Nuclear Information System (INIS)

    Gaber, Kh.R.; Farag, M.K.; Soliman, S.Et.; Abd Al-Kaderm, M.A.

    2008-01-01

    Objective: An elevated total plasma homocysteine level has been suggested as a possible risk factor in women suffering from recurrent pregnancy loss. The current study was undertaken to assess the association between homocysteine, folate, cobalamin (vitamin B12) and the risk of recurrent pregnancy loss. Design: Case . control study Materials and Methods: The study included 57 non-pregnant Egyptian women. They were classified according to their obstetric history into 2 groups: 32 cases with at least two consecutive miscarriages (Study group), and 25 cases with normal obstetric history (Control group). All cases were tested for plasma total homocysteine, serum folate and cobalamin (vitamin B12). Results: The fasting total homocysteine was significantly higher in the study group as compared to the control group. While the median concentrations for the vitamins studied were significantly lower in women of the study group as compared to the controls. Elevated homocysteine and reduced vitamin B12 can be considered risk factors for recurrent miscarriage with odds ratio (OR) and 95% confidence intervals (95% CI) of 1.839 (1.286, 2.63) and 1.993 (1.346, 2.951) respectively in the group of recurrent miscarriages. The OR (95% CI) in the study population for low serum folate concentrations was 1.23 (0.776, 2.256). Conclusion: Elevated homocysteine and reduced serum vitamin B12 are risk factors for recurrent miscarriage. Low serum folate did not seem a risk factor for recurrent miscarriage. Testing for homocysteine levels in women suffering from unexplained recurrent miscarriage and pre-conceptional supplementation with vitamin B12 might be beneficial to improve pregnancy outcome

  14. Hyperhomocysteinemia in Recurrent Miscarriage

    Energy Technology Data Exchange (ETDEWEB)

    Gaber, Kh R; Farag, M K [Prenatal Diagnosis and Fetal Medicine Department, National Research Centre, Dokki, Giza (Egypt); Soliman, S Et [Radioisotope Department, Nuclear Research Centre, Atomic Energy Authority, Cairo (Egypt); Abd Al-Kaderm, M A [Obstetrics and Gynecology Department, Faculty of Medicine, Cairo University, Cairo (Egypt)

    2008-07-01

    Objective: An elevated total plasma homocysteine level has been suggested as a possible risk factor in women suffering from recurrent pregnancy loss. The current study was undertaken to assess the association between homocysteine, folate, cobalamin (vitamin B12) and the risk of recurrent pregnancy loss. Design: Case . control study Materials and Methods: The study included 57 non-pregnant Egyptian women. They were classified according to their obstetric history into 2 groups: 32 cases with at least two consecutive miscarriages (Study group), and 25 cases with normal obstetric history (Control group). All cases were tested for plasma total homocysteine, serum folate and cobalamin (vitamin B12). Results: The fasting total homocysteine was significantly higher in the study group as compared to the control group. While the median concentrations for the vitamins studied were significantly lower in women of the study group as compared to the controls. Elevated homocysteine and reduced vitamin B12 can be considered risk factors for recurrent miscarriage with odds ratio (OR) and 95% confidence intervals (95% CI) of 1.839 (1.286, 2.63) and 1.993 (1.346, 2.951) respectively in the group of recurrent miscarriages. The OR (95% CI) in the study population for low serum folate concentrations was 1.23 (0.776, 2.256). Conclusion: Elevated homocysteine and reduced serum vitamin B12 are risk factors for recurrent miscarriage. Low serum folate did not seem a risk factor for recurrent miscarriage. Testing for homocysteine levels in women suffering from unexplained recurrent miscarriage and pre-conceptional supplementation with vitamin B12 might be beneficial to improve pregnancy outcome.

  15. Recurrences of Bell's palsy.

    Science.gov (United States)

    Cirpaciu, D; Goanta, C M; Cirpaciu, M D

    2014-01-01

    Bell's palsy in known as the most common cause of facial paralysis, determined by the acute onset of lower motor neuron weakness of the facial nerve with no detectable cause. With a lifetime risk of 1 in 60 and an annual incidence of 11-40/100,000 population, the condition resolves completely in around 71% of the untreated cases. Clinical trials performed for Bell's palsy have reported some recurrences, ipsilateral or contralateral to the side affected in the primary episode of facial palsy. Only few data are found in the literature. Melkersson-Rosenthal is a rare neuromucocutaneous syndrome characterized by recurrent facial paralysis, fissured tongue (lingua plicata), orofacial edema. We attempted to analyze some clinical and epidemiologic aspects of recurrent idiopathic palsy, and to develop relevant correlations between the existing data in literature and those obtained in this study. This is a retrospective study carried out on a 10-years period for adults and a five-year period for children. A number of 185 patients aged between 4 and 70 years old were analyzed. 136 of them were adults and 49 were children. 22 of 185 patients with Bell's palsy (12%) had a recurrent partial or complete facial paralysis with one to six episodes of palsy. From this group of 22 cases, 5 patients were diagnosed with Melkersson-Rosenthal syndrome. The patients' age was between 4 and 70 years old, with a medium age of 27,6 years. In the group studied, fifteen patients, meaning 68%, were women and seven were men. The majority of patients in our group with more than two facial palsy episodes had at least one episode on the contralateral side. Our study found a significant incidence of recurrences of idiopathic facial palsy. Recurrent idiopathic facial palsy and Melkersson-Rosenthal syndrome is diagnosed more often in young females. Recurrence is more likely to occur in the first two years from the onset, which leads to the conclusion that we should have a follow up of patients

  16. Hotspots of missense mutation identify novel neurodevelopmental disorder genes and functional domains

    Science.gov (United States)

    Geisheker, Madeleine R.; Heymann, Gabriel; Wang, Tianyun; Coe, Bradley P.; Turner, Tychele N.; Stessman, Holly A.F.; Hoekzema, Kendra; Kvarnung, Malin; Shaw, Marie; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Thompson, Elizabeth M.; Haan, Eric; Guo, Hui; Anderlid, Britt-Marie; Nordgren, Ann; Lindstrand, Anna; Vandeweyer, Geert; Alberti, Antonino; Avola, Emanuela; Vinci, Mirella; Giusto, Stefania; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Michaelson, Jacob J.; Sedlacek, Zdenek; Santen, Gijs W.E.; Peeters, Hilde; Hakonarson, Hakon; Courchesne, Eric; Romano, Corrado; Kooy, R. Frank; Bernier, Raphael A.; Nordenskjöld, Magnus; Gecz, Jozef; Xia, Kun; Zweifel, Larry S.; Eichler, Evan E.

    2017-01-01

    Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,689 NDD patients identified 21 new patients with identical missense mutations. One recurrent site (p.Ala636Thr) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology. PMID:28628100

  17. Recurrent parotitis in children

    Directory of Open Access Journals (Sweden)

    Bhattarai M

    2006-01-01

    Full Text Available Recurrent parotitis is an uncommon condition in children. Its etiological factors have not been proved till date although causes due to genetic inheritance, local autoimmune manifestation, allergy, viral infection and immunodeficiency have been suggested. The exact management of this disorder is not yet standardized, but a conservative approach is preferred and all affected children should be screened for Sjogren′s syndrome and immune deficiency including human immunodeficiency virus. We report a 12 years female child who presented with 12 episodes of non-painful recurrent swellings of the bilateral parotid gland in the past 3 years.

  18. Recurrent atrial myxoma.

    Science.gov (United States)

    Macarie, C; Stoica, E; Chioncel, O; Carp, A; Gherghiceanu, D; Stiru, O; Zarma, L; Herlea, V

    2004-01-01

    We have chosen this case of sporadic atrial myxoma for our presentation because it had a particular evolution, with recurrence at 8 years after surgical excision (echocardiography was performed every year) and a particular diagnostic means - at echocardiographic follow-up, the patient being asymptomatic. This presentation, together with a review of literature included in the article, emphasizes the importance of a careful postoperative follow-up of the patients and the existence of some particular aspects of the evolution and symptomatology of recurrent atrial myxoma.

  19. Lung Cancer Indicators Recurrence

    Science.gov (United States)

    This study describes prognostic factors for lung cancer spread and recurrence, as well as subsequent risk of death from the disease. The investigators observed that regardless of cancer stage, grade, or type of lung cancer, patients in the study were more

  20. Recurrent diabetic ketoacidosis

    DEFF Research Database (Denmark)

    Skinner, T. Chas

    2002-01-01

    Longitudinal studies indicate that 20% of paediatric patients account for 80% of all admissions for diabetic ketoacidosis (DKA). The frequency of DKA peaks during adolescence and, although individuals generally go into remission, they may continue to have bouts of recurrent DKA in adulthood. The ...

  1. Recurrent infantile digital fibromatosis

    African Journals Online (AJOL)

    We present a case of an 8-year-old-boy with recurrent infantile digital fibromatosis (IDF) who presented with new ... Keywords: fibrous tumors, inclusion body fibromatosis, infantile digital fibromatosis, spindle cells, Reye tumor .... watch-and-wait strategy for patients with histologically confirmed IDF nodules that do not cause ...

  2. On Solving Linear Recurrences

    Science.gov (United States)

    Dobbs, David E.

    2013-01-01

    A direct method is given for solving first-order linear recurrences with constant coefficients. The limiting value of that solution is studied as "n to infinity." This classroom note could serve as enrichment material for the typical introductory course on discrete mathematics that follows a calculus course.

  3. Identifying pathways affected by cancer mutations.

    Science.gov (United States)

    Iengar, Prathima

    2017-12-16

    Mutations in 15 cancers, sourced from the COSMIC Whole Genomes database, and 297 human pathways, arranged into pathway groups based on the processes they orchestrate, and sourced from the KEGG pathway database, have together been used to identify pathways affected by cancer mutations. Genes studied in ≥15, and mutated in ≥10 samples of a cancer have been considered recurrently mutated, and pathways with recurrently mutated genes have been considered affected in the cancer. Novel doughnut plots have been presented which enable visualization of the extent to which pathways and genes, in each pathway group, are targeted, in each cancer. The 'organismal systems' pathway group (including organism-level pathways; e.g., nervous system) is the most targeted, more than even the well-recognized signal transduction, cell-cycle and apoptosis, and DNA repair pathway groups. The important, yet poorly-recognized, role played by the group merits attention. Pathways affected in ≥7 cancers yielded insights into processes affected. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas.

    Science.gov (United States)

    Muñoz, Jorge; Inda, María Del Mar; Lázcoz, Paula; Zazpe, Idoya; Fan, Xing; Alfaro, Jorge; Tuñón, Teresa; Rey, Juan A; Castresana, Javier S

    2012-01-01

    While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14(ARF), and p16(INK4A)), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14(ARF) and p16(INK4A) did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14(ARF) and p16(INK4A), in which other alterations (mutations, homozygous deletions) are prevalent.

  5. Coping with Fear of Recurrence

    Science.gov (United States)

    ... What Comes Next After Finishing Treatment Coping With Fear of Recurrence Having a Baby After Cancer: Pregnancy ... treatment and preparing for the future. Coping With Fear of Recurrence Learn ways to manage the fear ...

  6. Chaotic diagonal recurrent neural network

    International Nuclear Information System (INIS)

    Wang Xing-Yuan; Zhang Yi

    2012-01-01

    We propose a novel neural network based on a diagonal recurrent neural network and chaos, and its structure and learning algorithm are designed. The multilayer feedforward neural network, diagonal recurrent neural network, and chaotic diagonal recurrent neural network are used to approach the cubic symmetry map. The simulation results show that the approximation capability of the chaotic diagonal recurrent neural network is better than the other two neural networks. (interdisciplinary physics and related areas of science and technology)

  7. Immunomodulators to treat recurrent miscarriage

    NARCIS (Netherlands)

    Prins, Jelmer R.; Kieffer, Tom E.C.; Scherjon, Sicco A.

    2014-01-01

    Recurrent miscarriage is a reproductive disorder affecting many couples. Although several factors are associated with recurrent miscarriage, in more than 50% of the cases the cause is unknown. Maladaptation of the maternal immune system is associated with recurrent miscarriage and could explain part

  8. Data on the recurrence of breast tumors fit a model in which dormant cells are subject to slow attrition but can randomly awaken to become malignant

    DEFF Research Database (Denmark)

    Stein, Wilfred D; Litman, Thomas

    2006-01-01

    appears to be a random event. Inasmuch as the kinetics of cancer recurrence in published data sets closely follows the model found for the appearance of sporadic retinoblastoma, tumor recurrence could be triggered by mutations in awakening- suppressor mechanisms. The retinoblastoma tumor suppressor gene...... was identified by tracing its occurrence in familial retinoblastoma pedigrees. Will it be possible to track the postulated cancer recurrence, awakening suppressor gene(s) in early recurrence breast cancer patients?...

  9. Clinical and Molecular Characteristics in 100 Chinese Pediatric Patients with m.3243A>G Mutation in Mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Chang-Yu Xia

    2016-01-01

    Conclusions: Our study showed that half of Chinese pediatric patients with m.3243A>G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A>G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.

  10. Recurrent giant juvenile fibroadenoma

    Directory of Open Access Journals (Sweden)

    Kathryn S. King

    2017-11-01

    Full Text Available Breast masses in children, though rare, present a difficult clinical challenge as they can represent a wide variety of entities from benign fibroadenomas to phyllodes tumors. Rapidly growing or recurrent masses can be particularly concerning to patients, families and physicians alike. Clinical examination and conventional imaging modalities are not efficacious in distinguishing between different tumor types and surgical excision is often recommended for both final diagnosis and for treatment of large or rapidly growing masses. While surgical excision can result in significant long-term deformity of the breast there are some surgical techniques that can be used to limit deformity and/or aid in future reconstruction. Here we present a case of recurrent giant juvenile fibroadenoma with a review of the clinical presentation, diagnostic tools and treatment options.

  11. Recurrent Partial Words

    Directory of Open Access Journals (Sweden)

    Francine Blanchet-Sadri

    2011-08-01

    Full Text Available Partial words are sequences over a finite alphabet that may contain wildcard symbols, called holes, which match or are compatible with all letters; partial words without holes are said to be full words (or simply words. Given an infinite partial word w, the number of distinct full words over the alphabet that are compatible with factors of w of length n, called subwords of w, refers to a measure of complexity of infinite partial words so-called subword complexity. This measure is of particular interest because we can construct partial words with subword complexities not achievable by full words. In this paper, we consider the notion of recurrence over infinite partial words, that is, we study whether all of the finite subwords of a given infinite partial word appear infinitely often, and we establish connections between subword complexity and recurrence in this more general framework.

  12. Recurrent epileptic Wernicke aphasia.

    Science.gov (United States)

    Sahaya, Kinshuk; Dhand, Upinder K; Goyal, Munish K; Soni, Chetan R; Sahota, Pradeep K

    2010-04-15

    We report a patient with recurrent epileptic Wernicke aphasia who prior to this presentation, had been misdiagnosed as transient ischemic attacks for several years. This case report emphasizes the consideration of epileptic nature of aphasia when a clear alternate etiology is unavailable, even when EEG fails to show a clear ictal pattern. We also present a brief discussion of previously reported ictal aphasias. Copyright 2010 Elsevier B.V. All rights reserved.

  13. Training Recurrent Networks

    DEFF Research Database (Denmark)

    Pedersen, Morten With

    1997-01-01

    Training recurrent networks is generally believed to be a difficult task. Excessive training times and lack of convergence to an acceptable solution are frequently reported. In this paper we seek to explain the reason for this from a numerical point of view and show how to avoid problems when...... training. In particular we investigate ill-conditioning, the need for and effect of regularization and illustrate the superiority of second-order methods for training...

  14. Recurrent Tricuspid Insufficiency

    Science.gov (United States)

    Kara, Ibrahim; Koksal, Cengiz; Cakalagaoglu, Canturk; Sahin, Muslum; Yanartas, Mehmet; Ay, Yasin; Demir, Serdar

    2013-01-01

    This study compares the medium-term results of De Vega, modified De Vega, and ring annuloplasty techniques for the correction of tricuspid insufficiency and investigates the risk factors for recurrent grades 3 and 4 tricuspid insufficiency after repair. In our clinic, 93 patients with functional tricuspid insufficiency underwent surgical tricuspid repair from May 2007 through October 2010. The study was retrospective, and all the data pertaining to the patients were retrieved from hospital records. Functional capacity, recurrent tricuspid insufficiency, and risk factors aggravating the insufficiency were analyzed for each patient. In the medium term (25.4 ± 10.3 mo), the rates of grades 3 and 4 tricuspid insufficiency in the De Vega, modified De Vega, and ring annuloplasty groups were 31%, 23.1%, and 6.1%, respectively. Logistic regression analysis revealed that chronic obstructive pulmonary disease, left ventricular dysfunction (ejection fraction, tricuspid insufficiency. Medium-term survival was 90.6% for the De Vega group, 96.3% for the modified De Vega group, and 97.1% for the ring annuloplasty group. Ring annuloplasty provided the best relief from recurrent tricuspid insufficiency when compared with DeVega annuloplasty. Modified De Vega annuloplasty might be a suitable alternative to ring annuloplasty when rings are not available. PMID:23466680

  15. Multiplex Recurrence Networks

    Science.gov (United States)

    Eroglu, Deniz; Marwan, Norbert

    2017-04-01

    The complex nature of a variety of phenomena in physical, biological, or earth sciences is driven by a large number of degrees of freedom which are strongly interconnected. Although the evolution of such systems is described by multivariate time series (MTS), so far research mostly focuses on analyzing these components one by one. Recurrence based analyses are powerful methods to understand the underlying dynamics of a dynamical system and have been used for many successful applications including examples from earth science, economics, or chemical reactions. The backbone of these techniques is creating the phase space of the system. However, increasing the dimension of a system requires increasing the length of the time series in order get significant and reliable results. This requirement is one of the challenges in many disciplines, in particular in palaeoclimate, thus, it is not easy to create a phase space from measured MTS due to the limited number of available obervations (samples). To overcome this problem, we suggest to create recurrence networks from each component of the system and combine them into a multiplex network structure, the multiplex recurrence network (MRN). We test the MRN by using prototypical mathematical models and demonstrate its use by studying high-dimensional palaeoclimate dynamics derived from pollen data from the Bear Lake (Utah, US). By using the MRN, we can distinguish typical climate transition events, e.g., such between Marine Isotope Stages.

  16. Predictors of recurrence in pheochromocytoma.

    Science.gov (United States)

    Press, Danielle; Akyuz, Muhammet; Dural, Cem; Aliyev, Shamil; Monteiro, Rosebel; Mino, Jeff; Mitchell, Jamie; Hamrahian, Amir; Siperstein, Allan; Berber, Eren

    2014-12-01

    The recurrence rate of pheochromocytoma after adrenalectomy is 6.5-16.5%. This study aims to identify predictors of recurrence and optimal biochemical testing and imaging for detecting the recurrence of pheochromocytoma. In this retrospective study we reviewed all patients who underwent adrenalectomy for pheochromocytoma during a 14-year period at a single institution. One hundred thirty-five patients had adrenalectomy for pheochromocytoma. Eight patients (6%) developed recurrent disease. The median time from initial operation to diagnosis of recurrence was 35 months. On multivariate analysis, tumor size >5 cm was an independent predictor of recurrence. One patient with recurrence died, 4 had stable disease, 2 had progression of disease, and 1 was cured. Recurrence was diagnosed by increases in plasma and/or urinary metanephrines and positive imaging in 6 patients (75%), and by positive imaging and normal biochemical levels in 2 patients (25%). Patients with large tumors (>5 cm) should be followed vigilantly for recurrence. Because 25% of patients with recurrence had normal biochemical levels, we recommend routine imaging and testing of plasma or urinary metanephrines for prompt diagnosis of recurrence. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, S.J.; Gladwin, A.J.; Dixon, M.J. [Univ. of Manchester (United Kingdom)

    1997-03-01

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5-bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploin-sufficiency. 49 refs., 4 figs., 3 tabs.

  18. SPOP Mutations in Prostate Cancer across Demographically Diverse Patient Cohorts

    Directory of Open Access Journals (Sweden)

    Mirjam Blattner

    2014-01-01

    Full Text Available BACKGROUND: Recurrent mutations in the Speckle-Type POZ Protein (SPOP gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown. OBJECTIVE: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material. DESIGN, SETTING, AND PARTICIPANTS: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion as well as clinical and pathologic features. RESULTS AND LIMITATIONS: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%, SPOP mutation was inversely associated with ERG rearrangement (P < .01, and SPOP mutant (SPOPmut cancers had higher rates of CHD1 deletions (P < .01. There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes. CONCLUSION: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.

  19. Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India.

    Science.gov (United States)

    Bashyam, Murali D; Chaudhary, Ajay K; Kiran, Manjari; Nagarajaram, Hampapathalu A; Devi, Radha Rama; Ranganath, Prajnya; Dalal, Ashwin; Bashyam, Leena; Gupta, Neerja; Kabra, Madhulika; Muranjan, Mamta; Puri, Ratna D; Verma, Ishwar C; Nampoothiri, Sheela; Kadandale, Jayarama S

    2014-03-01

    Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutational inactivation of the phenylalanine hydroxylase (PAH) gene. Missense mutations are the most common PAH mutation type detected in PKU patients worldwide. We performed PAH mutation analysis in 27 suspected Indian PKU families (including 7 from our previous study) followed by structure and function analysis of specific missense and splice/insertion-deletion/nonsense mutations, respectively. Of the 27 families, disease-causing mutations were detected in 25. A total of 20 different mutations were identified of which 7 "unique" mutations accounted for 13 of 25 mutation positive families. The unique mutations detected exclusively in Indian PKU patients included three recurrent mutations detected in three families each. The 20 mutations included only 5 missense mutations in addition to 5 splice, 4 each nonsense and insertion-deletion mutations, a silent variant in coding region and a 3'UTR mutation. One deletion and two nonsense mutations were characterized to confirm significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay. All missense mutations affected conserved amino acid residues and sequence and structure analysis suggested significant perturbations in the enzyme activity of respective mutant proteins. This is probably the first report of identification of a significantly low proportion of missense PAH mutations from PKU families and together with the presence of a high proportion of splice, insertion-deletion, and nonsense mutations, points to a unique PAH mutation profile in Indian PKU patients. © 2013 Wiley Periodicals, Inc.

  20. Genomic characterization of recurrent high-grade astroblastoma.

    Science.gov (United States)

    Bale, Tejus A; Abedalthagafi, Malak; Bi, Wenya Linda; Kang, Yun Jee; Merrill, Parker; Dunn, Ian F; Dubuc, Adrian; Charbonneau, Sarah K; Brown, Loreal; Ligon, Azra H; Ramkissoon, Shakti H; Ligon, Keith L

    2016-01-01

    Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors (IDH1/2, TP53, ATRX, and PTEN) or ependymoma were not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM (NF1(N1054H/K63)*, PIK3CA(R38H) and ERG(A403T)). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas (BCOR, BCORL1, ERBB3, MYB, ATM) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Recurrent cerebral thrombosis

    International Nuclear Information System (INIS)

    Iwamoto, Toshihiko; Abe, Shin-e; Kubo, Hideki; Hanyu, Haruo; Takasaki, Masaru

    1992-01-01

    Neuroradiological techniques were used to elucidate pathophysiology of recurrent cerebral thrombosis. Twenty-two patients with cerebral thrombosis who suffered a second attack under stable conditions more than 22 days after the initial stroke were studied. Hypertension, diabetes mellitus, and hypercholesterolemia were also seen in 20, 8, and 12 patients, respectively. The patients were divided into three groups according to their symptoms: (I) symptoms differed between the first and second strokes (n=12); (II) initial symptoms were suddenly deteriorated (n=6); and (III) symptoms occurring in groups I and II were seen (n=4). In group I, contralateral hemiparesis or suprabulbar palsy was often associated with the initial hemiparesis. The time of recurrent stroke varied from 4 months to 9 years. CT and MRI showed not only lacunae in both hemispheres, but also deep white-matter ischemia of the centrum semi-ovale. In group II, hemiparesis or visual field defect was deteriorated early after the initial stroke. In addition, neuroimaging revealed that infarction in the posterior cerebral artery was progressed on the contralateral side, or that white matter lesion in the middle artery was enlarged in spite of small lesion in the left cerebral hemisphere. All patients in group III had deterioration of right hemiparesis associated with aphasia. CT, MRI, SPECT, and angiography indicated deep white-matter ischemia caused by main trunk lesions in the left hemisphere. Group III seemed to be equivalent to group II, except for laterality of the lesion. Neuroradiological assessment of the initial stroke may help to predict the mode of recurrence, although pathophysiology of cerebral thrombosis is complicated and varies from patient to patient. (N.K.)

  2. Stress and recurrent miscarriage.

    Science.gov (United States)

    Craig, M

    2001-09-01

    Our current understanding into the role of stress in unexplained recurrent miscarriages comes from two different research strategies. The majority of research has examined the role of psychological support within this patient population. This support has been provided in a number of ways ranging from weekly interviews with a psychiatrist or gynaecologist and or visual re-assurance in the form of ultrasound scans. A comparison of psychological support with an absence of such intervention has found differences in successful pregnancy outcome varying from as great as 84 versus 26%, respectively. It has been assumed that psychological support reduces the miscarriage rate by reducing “stress”within this patient population. In addition it provides indirect support for a role of stress in the aetiology of unexplained recurrent miscarriage. Other studies have attempted to directly assess the effect of personality characteristics on miscarriage rate; these studies have yielded conflicting results.The mechanism by which stress may be causal in the aetiology of unexplained recurrent miscarriage has not been examined in humans. Animal studies, however, have found that psychological distress can alter immune parameters that may be intricately involved with implantation. These parameters include an elevation of the “abortive” cytokine TNF-a and a reduction in the “anti-abortive” cytokine TGF-P2. Cells that are involved in the release of TNF-a at the feto-maternal interface include T cells, macrophages and mast cells.Mechanisms through which stress may act on these cells are explored and an integrated model is postulated.

  3. Recurrent Bilateral Focal Myositis.

    Science.gov (United States)

    Nagafuchi, Hiroko; Nakano, Hiromasa; Ooka, Seido; Takakuwa, Yukiko; Yamada, Hidehiro; Tadokoro, Mamoru; Shimojo, Sadatomo; Ozaki, Shoichi

    This report describes a rare case of recurrent bilateral focal myositis and its successful treatment via methotrexate. A 38-year-old man presented myalgia of the right gastrocnemius in May 2005. Magnetic resonance imaging showed very high signal intensity in the right gastrocnemius on short-tau inversion recovery images. A muscle biopsy revealed inflammatory CD4+ cell-dominant myogenic change. Focal myositis was diagnosed. The first steroid treatment was effective. Tapering of prednisolone, however, repeatedly induced myositis relapse, which progressed to multiple muscle lesions of both lower limbs. Initiation of methotrexate finally allowed successful tapering of prednisolone, with no relapse in the past 4 years.

  4. Recurrent Pregnancy Loss

    Directory of Open Access Journals (Sweden)

    Véronique Piroux

    1997-01-01

    Full Text Available Antiphospholipid antibodies (APA are associated with thrombosis, thrombocytopenia and fetal loss but they occur in a variety of diseases. Despite many efforts, a correlation between the specificity of particular subgroups of APA and particular clinical situations remains to be established. The antigens at the origin of APA remain to be identified. We discuss here the possible links between cell apoptosis or necrosis, leading to plasma membrane alterations, and the occurrence of APA in response to sustained stimulation. The pathogenic potential of APA is also considered with respect to recurrent pregnancy loss.

  5. Equine recurrent airway obstruction

    Directory of Open Access Journals (Sweden)

    Artur Niedźwiedź

    2014-10-01

    Full Text Available Equine Recurrent Airway Obstruction (RAO, also known as heaves or broken wind, is one of the most common disease in middle-aged horses. Inflammation of the airway is inducted by organic dust exposure. This disease is characterized by neutrophilic inflammation, bronchospasm, excessive mucus production and pathologic changes in the bronchiolar walls. Clinical signs are resolved in 3-4 weeks after environmental changes. Horses suffering from RAO are susceptible to allergens throughout their lives, therefore they should be properly managed. In therapy the most importanthing is to eliminate dustexposure, administration of corticosteroids and use bronchodilators to improve pulmonary function.

  6. Recurrent oral angioleiomyoma

    Directory of Open Access Journals (Sweden)

    V G Mahima

    2011-01-01

    Full Text Available Angioleiomyomas are vascular variant of leiomyomas which are benign tumors of smooth muscle. They are exceedingly rare in the oral cavity. Malignant transformation of these tumors has also been reported occasionally which warrants knowledge of this soft tissue tumor. A 57 year old male patient reported with a 15 day history of an asymptomatic growth that had started insidiously in his lower left back tooth region. Clinical examination revealed a solitary, oval, sessile growth in the mandibular left retro molar region. Excisional biopsy was suggestive of Angioleiomyoma. A recurrence of the same was noted two months later which was also histopathologically reported as Angioleiomyoma. The same was confirmed using special stains. This case reports an unusual presentation of Angioleiomyoma with regards to both recurrence as well as rapid growth. It is important to be well aware of this uncommon entity as these tumors often can mimic or transform into malignancy. Precise clinicopathological examinations are therefore invaluable in establishing an accurate diagnosis and delivering suitable treatment.

  7. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

    Science.gov (United States)

    Campbell, Ian M; Stewart, Jonathan R; James, Regis A; Lupski, James R; Stankiewicz, Paweł; Olofsson, Peter; Shaw, Chad A

    2014-10-02

    Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. A resolution of the mutation load paradox in humans.

    Science.gov (United States)

    Lesecque, Yann; Keightley, Peter D; Eyre-Walker, Adam

    2012-08-01

    Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation () for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation.

  9. Systematic Analysis of Splice-Site-Creating Mutations in Cancer

    Directory of Open Access Journals (Sweden)

    Reyka G. Jayasinghe

    2018-04-01

    Full Text Available Summary: For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. : Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease. Keywords: splicing, RNA, mutations of clinical relevance

  10. RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients.

    Science.gov (United States)

    Fan, Cong; Zhang, Juan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2018-05-04

    RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In this study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n=6 cases; K994fs, n=5 cases; and H1269fs, n=5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5000 healthy controls was 0.18% (9/5000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; P = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; P=0.018] and disease-specific survival (DSS) (adjusted HR 4.36; 95% CI, 1.58-12.03; P=0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared with patients without these mutations. This article is protected by copyright. All rights reserved. © 2018 UICC.

  11. A novel mutation in MED12 causes FG syndrome (Opitz-Kaveggia syndrome)

    NARCIS (Netherlands)

    Rump, P.; Niessen, R. C.; Verbruggen, K. T.; Brouwer, O. F.; de Raad, M.; Hordijk, R.

    Opitz-Kaveggia syndrome is a rare X-linked multiple congenital anomalies and intellectual disability disorder caused by the recurrent p.R961W mutation in the MED12 gene. Twenty-three affected males from 10 families with this mutation in the MED12 gene have been described so far. Here we report on a

  12. Mutations found in the Danish population causing Hereditary Hemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Tørring, Pernille M; Brusgaard, Klaus

    2011-01-01

    University Hospital, Denmark HHT is an autosomal vascular disorder caused by mutations of either of three loci ENG, ACVLR1 or MADH4. HHT is characterised by recurrent nosebleeds, mucocutaneous telangiectases, and more severe visceral malformations. During the last decade the Danish HHT centre has...

  13. Age-related cancer mutations associated with clonal hematopoietic expansion

    Science.gov (United States)

    Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.; Wendl, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Chen, Feng; Wilson, Richard K.; Ley, Timothy J.; Ding, Li

    2015-01-01

    Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion. PMID:25326804

  14. Acute recurrent pancreatitis: Etiopathogenesis, diagnosis and treatment

    Science.gov (United States)

    Testoni, Pier Alberto

    2014-01-01

    Acute recurrent pancreatitis (ARP) refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion. Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland, however, an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up. The aetiology of ARP can be identified in the majority of patients. Most common causes include common bile duct stones or sludge and bile crystals; sphincter of oddi dysfunction; anatomical ductal variants interfering with pancreatic juice outflow; obstruction of the main pancreatic duct or pancreatico-biliary junction; genetic mutations; alcohol consumption. However, despite diagnostic technologies, the aetiology of ARP still remains unknown in up to 30% of cases: in these cases the term “idiopathic” is used. Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases, cholecystectomy, and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases. Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80% of patients. Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge. In uncertain cases toxin botulin injection may help in identifying some sphincter of oddi dysfunction, but this treatment is not widely used. In the last twenty years, pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction, independently from the cause of obstruction, and has been widely used instead of more aggressive approaches. PMID:25493002

  15. Recurrent pregnancy loss

    DEFF Research Database (Denmark)

    Egerup, P; Kolte, A M; Larsen, E C

    2016-01-01

    STUDY QUESTION: Is there a different prognostic impact for consecutive and non-consecutive early pregnancy losses in women with secondary recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Only consecutive early pregnancy losses after the last birth have a statistically significant negative prognostic...... impact in women with secondary RPL. WHAT IS KNOWN ALREADY: The risk of a new pregnancy loss increases with the number of previous pregnancy losses in patients with RPL. Second trimester losses seem to exhibit a stronger negative impact than early losses. It is unknown whether the sequence of pregnancy...... losses plays a role for the prognosis in patients with a prior birth. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study of pregnancy outcome in patients with unexplained secondary RPL included in three previously published, Danish double-blinded placebo-controlled trials of intravenous...

  16. Recurrent Spatial Transformer Networks

    DEFF Research Database (Denmark)

    Sønderby, Søren Kaae; Sønderby, Casper Kaae; Maaløe, Lars

    2015-01-01

    We integrate the recently proposed spatial transformer network (SPN) [Jaderberg et. al 2015] into a recurrent neural network (RNN) to form an RNN-SPN model. We use the RNN-SPN to classify digits in cluttered MNIST sequences. The proposed model achieves a single digit error of 1.5% compared to 2.......9% for a convolutional networks and 2.0% for convolutional networks with SPN layers. The SPN outputs a zoomed, rotated and skewed version of the input image. We investigate different down-sampling factors (ratio of pixel in input and output) for the SPN and show that the RNN-SPN model is able to down-sample the input...

  17. Recurrent Aggressive Angiomyxoma*

    Directory of Open Access Journals (Sweden)

    Suelene Suassuna Silvestre de Alencar

    2013-10-01

    Full Text Available Introduction: aggressive angiomyxoma is a highly aggressive, rare neoplasm of the mesen- chymal tissue with a high recurrence rate. It represents an important differential diagnosis of pelvic tumors in women of reproductive age. This study aims to describe a case of ag- gressive angiomyxoma.Case report: woman, 37 years old, complained about a bulge on the right perianal region, and anal itching and burning, bleeding, tenesmus and incontinence. The proctologic examina- tion confirmed the perianal bulge and extrinsic compression of the posterior wall of the rectum. Computed tomography (CT of the pelvis showed a well-defined pelvic mass ex- tending to the right rectal area. Exploratory laparotomy showed a mass of fibro elastic con- sistency adjacent to the pelvic organs and closely attached to the distal rectum, and per- formed a resection of the pelvic tumor afterward. Anatomopathological analysis revealed an aggressive angiomyxoma. Magnetic resonance imaging (MRI of the pelvis showed signs of recurrence in the pelvic cavity on the right side of the rectum. A surgical procedure was performed to resect the lesion. After an asymptomatic period, the MRI showed solid growths located in the right ischiorectal fossa. A new surgical procedure identified only retention cysts in the pelvis and right ischiorectal fossa, only lysis of adhesions was per- formed. The patient is currently undergoing follow-up without disease recurrence. Resumo: Introdução: o angiomixoma agressivo é uma rara neoplasia do tecido mesenquimal de gran- de agressividade e alta taxa de recorrência. Representa um importante diagnóstico diferen- cial de tumorações pélvicas de mulheres em idade reprodutiva. Este estudo objetiva relatar um caso de angiomixoma agressivo.Relato de caso: mulher, 37 anos, com queixa de abaulamento em região perianal direita, além de prurido e ardor anal, sangramento, tenesmo e incontinência anal. Exame procto- lógico confirmou o abaulamento

  18. Analysis of Brain Recurrence

    Science.gov (United States)

    Frilot, Clifton; Kim, Paul Y.; Carrubba, Simona; McCarty, David E.; Chesson, Andrew L.; Marino, Andrew A.

    Analysis of Brain Recurrence (ABR) is a method for extracting physiologically significant information from the electroencephalogram (EEG), a non-stationary electrical output of the brain, the ultimate complex dynamical system. ABR permits quantification of temporal patterns in the EEG produced by the non-autonomous differential laws that govern brain metabolism. In the context of appropriate experimental and statistical designs, ABR is ideally suited to the task of interpreting the EEG. Present applications of ABR include discovery of a human magnetic sense, increased mechanistic understanding of neuronal membrane processes, diagnosis of degenerative neurological disease, detection of changes in brain metabolism caused by weak environmental electromagnetic fields, objective characterization of the quality of human sleep, and evaluation of sleep disorders. ABR has important beneficial implications for the development of clinical and experimental neuroscience.

  19. Hot spot mutations in Finnish non-small cell lung cancers.

    Science.gov (United States)

    Mäki-Nevala, Satu; Sarhadi, Virinder Kaur; Rönty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari

    2016-09-01

    Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy

    DEFF Research Database (Denmark)

    Svenstrup, K; Møller, R S; Christensen, J

    2011-01-01

    or signs are found. Mutations in the NIPA1 gene have been reported to cause spastic paraplegia type 6 (SPG6) in 10 families. SPG6 is a rare form of autosomal dominantly inherited HSP associated with a pure phenotype; however, in one complex SPG6 family, idiopathic generalized epilepsy (IGE) has been...... described and in addition, recurrent microdeletions at 15q11.2 including NIPA1 have been identified in patients with IGE. The purpose was to identify NIPA1 mutations in patients with pure and complex HSP. Methods: Fifty-two patients with HSP were screened for mutations in NIPA1. Results: One previously...... reported missense mutation c.316G>A, p.Gly106Arg, was identified in a complex HSP patient with spastic dysarthria, facial dystonia, atrophy of the small hand muscles, upper limb spasticity, and presumably IGE. The epilepsy co-segregated with HSP in the family. Conclusion: NIPA1 mutations were rare in our...

  1. Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia.

    Science.gov (United States)

    Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W; Papadopoulos, Nickolas; Malek, Sami N

    2011-11-24

    To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ∼ 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML.

  2. Mutation spectrum of Chinese patients with Bartter syndrome.

    Science.gov (United States)

    Han, Yue; Lin, Yi; Sun, Qing; Wang, Shujuan; Gao, Yanxia; Shao, Leping

    2017-11-24

    Bartter syndrome (BS) has been rarely reported in Chinese population except for a few case reports. This investigation was aimed to analyze the mutations of the causal genes in sixteen Chinese patients with BS, and review their followup and treatment. Identify mutations by the next generation sequencing and the multiplex ligation-dependent probe amplification (MLPA). Clinical characteristics and biochemical findings at the first presentation as well as follow-up were reviewed. 15 different CLCNKB gene mutations were identified in fourteen patients with BS, including 11 novel ones. A novel missense mutation and a novel small deletion were found from SLC12A1 gene. A novel gross deletion was found in CLCNKA gene. A recurrent missense mutation was identified from BSND gene. We found that the whole gene deletion mutation of CLCNKB gene was the most frequent mutation (32%), and the rate of gross deletion was up to 50 percent in this group of Chinese patients. The present study has found 19 mutations, including 14 novel ones, which would enrich the human gene mutation database (HGMD) and provide valuable references to the genetic counseling and diagnosis of the Chinese population.

  3. BRCA2 Mutations in 154 Finnish Male Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Kirsi Syrjäkoski

    2004-09-01

    Full Text Available The etiology and pathogenesis of male breast cancer (MBC are poorly known. This is due to the fact that the disease is rare, and large-scale genetic epidemiologic studies have been difficult to carry out. Here, we studied the frequency of eight recurrent Finnish BRCA2 founder mutations in a large cohort of 154 MBC patients (65% diagnosed in Finland from 1967 to 1996. Founder mutations were detected in 10 patients (6.5%, eight of whom carried the 9346(-2 A>G mutation. Two novel mutations (4075 delGT and 5808 del5 were discovered in a screening of the entire BRCA2 coding region in 34 samples. However, these mutations were not found in the rest of the 120 patients studied. Patients with positive family history of breast and/or ovarian cancer were often BRCA2 mutation carriers (44%, whereas those with no family history showed a low frequency of involvement (3.6%; P < .0001. Finally, we found only one Finnish MBC patient with 999 dell, the most common founder mutation in Finnish female breast cancer (FBC patients, and one that explains most of the hereditary FBC and MBC cases in Iceland. The variation in BRCA2 mutation spectrum between Finnish MBC patients and FBC patients in Finland and breast cancer patients in Iceland suggests that modifying genetic and environmental factors may significantly influence the penetrance of MBC and FBC in individuals carrying germline BRCA2 mutations in some populations.

  4. Recurrent vulvovaginal candidiasis.

    Science.gov (United States)

    Blostein, Freida; Levin-Sparenberg, Elizabeth; Wagner, Julian; Foxman, Betsy

    2017-09-01

    Recurrent vulvovaginal candidiasis (RVVC), multiple episodes of vulvovaginal candidiasis (VVC; vaginal yeast infection) within a 12-month period, adversely affects quality of life, mental health, and sexual activity. Diagnosis is not straightforward, as VVC is defined by the combination of often nonspecific vaginal symptoms and the presence of yeast-which is a common vaginal commensal. Estimating the incidence and prevalence is challenging: most VVC is diagnosed and treated empirically, the availability for purchase of effective therapies over the counter enables self-diagnosis and treatment, and the duration of the relatively benign VVC symptoms is short, introducing errors into any estimates relying on medical records or patient recall. We evaluate current estimates of VVC and RVVC and provide new prevalence estimates using data from a 2011 seven-country (n = 7345) internet panel survey on VVC conducted by Ipsos Health (https://www.ipsos.com/en). We also evaluate information on VVC-associated visits using the National Ambulatory Medical Care Survey. The estimated probability of VVC by age 50 varied widely by country (from 23% to 49%, mean 39%), as did the estimated probability of RVVC after VVC (from 14% to 28%, mean 23%). However estimated, the probability of RVVC was high suggesting RVVC is a common condition. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis

    Science.gov (United States)

    ... Home » Health Info » Voice, Speech, and Language Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis On this page: What ... find additional information about RRP? What is recurrent respiratory papillomatosis? Recurrent respiratory papillomatosis (RRP) is a disease ...

  6. Mondini dysplasia with recurrent meningitis.

    Science.gov (United States)

    Lu, M Y; Lee, P I; Lee, C Y; Hsu, C J

    1996-01-01

    Mondini dysplasia is a congenital malformation of the inner ear, commonly associated with hearing impairment, cerebrospinal fluid otorrhea/rhinorrhea and recurrent meningitis. Two such cases are described, with hearing impairment, cerebrospinal fluid rhinorrhea, and several episodes of meningitis. Diagnosis was confirmed by high-resolution computed tomography. After surgical correction of the malformation, there was no recurrent episode of meningitis at subsequent follow-up. To avoid the suffering and the sequelae of recurrent meningitis, an early diagnosis and prompt surgical intervention are crucial for such patients.

  7. Deletion mutations of bacteriophage

    International Nuclear Information System (INIS)

    Ryo, Yeikou

    1975-01-01

    Resolution of mutation mechanism with structural changes of DNA was discussed through the studies using bacteriophage lambda. One of deletion mutations inductions of phage lambda is the irradiation of ultraviolet ray. It is not clear if the inductions are caused by errors in reparation of ultraviolet-induced damage or by the activation of int gene. Because the effective site of int gene lies within the regions unnecessary for existing, it is considered that int gene is connected to deletion mutations induction. A certain system using prophage complementarity enables to detect deletion mutations at essential hereditary sites and to solve the relations of deletion mutations with other recombination system, DNA reproduction and repairment system. Duplication and multiplication of hereditary elements were discussed. If lambda deletion mutations of the system, which can control recombination, reproduction and repairment of added DNA, are constructed, mutations mechanism with great changes of DNA structure can be solved by phage lambda. (Ichikawa, K.)

  8. Hereditary thrombophilia and recurrent pregnancy loss: a retrospective cohort study of pregnancy outcome and obstetric complications

    DEFF Research Database (Denmark)

    Lund, Marie; Nielsen, H S; Hviid, T V

    2010-01-01

    The association among hereditary thrombophilia, recurrent pregnancy loss (RPL) and obstetric complications is yet uncertain. The objective of the study was to assess the prognostic value of the factor V Leiden (FVL) and prothrombin (PT) mutations for the subsequent chance of live birth for women...

  9. Studies on the DNA-excision repair in lymphocytes of patients with recurrent Herpes simplex

    International Nuclear Information System (INIS)

    Fanta, D.; Topaloglou, A.; Altmann, H.

    1978-01-01

    Investigations of the semiconservatrive DNA replication and the excision repair in lymphocytes of patients with recurrent herpes simplex showed defects that could lead to mutations in the DNA with following lower immuncompetence and possibility for activation of already present oncogenic virus formations within the cellular DNA

  10. Recurrent networks for wave forecasting

    Digital Repository Service at National Institute of Oceanography (India)

    Mandal, S.; Prabaharan, N.

    , merchant vessel routing, nearshore construction, etc. more efficiently and safely. This paper presents an application of the Artificial Neural Network, namely Backpropagation Recurrent Neural Network (BRNN) with rprop update algorithm for wave forecasting...

  11. Opioids and breast cancer recurrence

    DEFF Research Database (Denmark)

    Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P

    2015-01-01

    BACKGROUND: Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence. METHODS: Patients with incident, early stage breast cancer who were diagnosed during 1996 through...... 2008 in Denmark were identified from the Danish Breast Cancer Cooperative Group Registry. Opioid prescriptions were ascertained from the Danish National Prescription Registry. Follow-up began on the date of primary surgery for breast cancer and continued until breast cancer recurrence, death......, emigration, 10 years, or July 31, 2013, whichever occurred first. Cox regression models were used to compute hazard ratios and 95% confidence intervals associating breast cancer recurrence with opioid prescription use overall and by opioid type and strength, immunosuppressive effect, chronic use (≥6 months...

  12. Characterization of six mutations in Exon 37 of neurofibromatosis type 1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Upadhyaya, M.; Osborn, M.; Maynard, J.; Harper, P. [Institute of Medical Genetics, Cardiff, Wales (United Kingdom)

    1996-07-26

    Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences. 17 refs., 2 figs., 1 tab.

  13. Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency

    DEFF Research Database (Denmark)

    Bay, Jakob Thaning; Katzenstein, Terese Lea; Kofoed, Kristian

    2015-01-01

    presentation of Factor I deficiency varies and includes severe recurrent bacterial infections, glomerulonephritis and autoimmune diseases. The patient, a 28-years old woman with consanguineous parents, presented with recurrent leukocytoclastic vasculitis in the lower extremities with no associated systemic...... mutations vary among patients sole association with leukocytoclastic vasculitis redefines the clinical spectrum of complete Factor I deficiency....

  14. Asymptomatic parental mosaicism for osteogenesis imperfect associated with a new splice site mutation in COL1A2

    DEFF Research Database (Denmark)

    Frederiksen, Anja Lisbeth; Dunø, Morten; Johnsen, Iben Birgit Gade

    2016-01-01

    Recurrent lethal perinatal osteogenesis imperfecta may result from asymptomatic parental mosaicism. A previously unreported mutation in COL1A2 leads to recurrent cases of fetal osteogenesis imperfecta Sillence type IIA, which emphasizes the importance of clinical and genetic evaluation of mosaicism...

  15. Recurrent atypical hemolytic uremic syndrome after renal transplantation: treatment with eculizumab

    Directory of Open Access Journals (Sweden)

    Ana B. Latzke

    2018-04-01

    Full Text Available Atypical hemolytic uremic syndrome (aHUS is a rare entity. It is characterized by a thrombotic microangiopathy (nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure, with a typical histopathology of thickening of capillary and arteriolar walls and an obstructive thrombosis of the vascular lumen. The syndrome is produced by a genetic or acquired deregulation of the alternative pathway of the complement system, with high rates of end stage renal disease, post-transplant recurrence, and high mortality. Mutations associated with factor H, factor B and complement C3 show the worst prognosis. Even though plasma therapy is occasionally useful, eculizumab is effective both for treatment and prevention of post-transplant recurrence. We describe here an adult case of congenital aHUS (C3 mutation under preventive treatment with eculizumab after renal transplantation, with neither disease recurrence nor drug-related adverse events after a 36-months follow-up.

  16. Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Xiang Chen

    2014-04-01

    Full Text Available Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs and copy number alterations (CNAs. To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%–53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.

  17. Recurrent rhabdomyolysis and glutaric aciduria type I: a case report and literature review.

    Science.gov (United States)

    Qian, Gu-Ling; Hong, Fang; Tong, Fan; Fu, Hai-Dong; Liu, Ai-Min

    2016-08-01

    Glutaric acidemia type I (GA-I) is a rare metabolic disorder caused by mutation of the glutaryl- CoA dehydrogenase (GCDH) gene. The occurrence of rhabdomyolysis with GA-I is extremely rare. We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I (GA-I). And a literature review was performed. A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years. At the third admission, she was diagnosed with GA-I by biochemical testing and mutation analysis. The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764. Other three patients with rhabdomyolysis and GA-I were discovered by literature searching. This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.

  18. Biochemical Characterization of P4-ATPase Mutations Associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine

    The cholestatic disorders progressive familial intrahepatic cholestasis type 1 (PFIC1, also referred to as Byler’s disease) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1. The substrate of ATP8B1 is very likely to be phosphatidylserine...... families have been investigated, and more than 50 distinct disease mutations have been identified, with roughly half being missense mutations. In this project we try to answer the question whether PFIC1 mutations are generally more disturbing than BRIC1 mutations with respect to expression, structural...... stability and function. We investigate the mutations in our well functioning system of ATP8A2, being expressed in mammalian HEK293T cells, affinity-purified, and reconstituted in lipid vesicles. Well-known mutations from both groups of patients have been selected for study. I91P in ATP8A2 (L127P in ATP8B1...

  19. Recurrence of anxiety disorders and its predictors

    NARCIS (Netherlands)

    Scholten, Willemijn D.; Batelaan, Neeltje M.; van Balkom, Anton J. L. M.; Penninx, Brenda; Smit, Johannes H.; van Oppen, Patricia

    Background: The chronic course of anxiety disorders and its high burden of disease are partly due to the recurrence of anxiety disorders after remission. However, knowledge about recurrence rates and predictors of recurrence is scarce. This article reports on recurrence rates of anxiety disorders

  20. Recurrence of anxiety disorders and its predictors

    NARCIS (Netherlands)

    Scholten, W.D.; Batelaan, N.M.; van Balkom, A.J.L.M.; Penninx, B.W.J.H.; Smit, J.H.; van Oppen, P.

    2013-01-01

    Background: The chronic course of anxiety disorders and its high burden of disease are partly due to the recurrence of anxiety disorders after remission. However, knowledge about recurrence rates and predictors of recurrence is scarce. This article reports on recurrence rates of anxiety disorders

  1. Norrie-Warburg syndrome: two novel mutations in patients with classical clinical phenotype.

    Science.gov (United States)

    Gal, A; Veske, A; Jojart, G; Grammatico, B; Huber, B; Gu, S; del Porto, G; Senyi, K

    1996-01-01

    Norrie-Warburg syndrome (NWS) is a rare X-linked disorder characterized by blindness, which is invariable, deafness and mental disturbances, which are present occasionally. We describe here two novel mutations, a missense mutation (C126S) and a 1-base pair insertion (insT466/T467), together with a recurrent mutation (M1V), found in patients presenting with the classical clinical phenotype of NWS. All three mutations are likely to result in prominent structural changes of the norrin protein.

  2. Recurrent pregnancy loss: current perspectives

    Directory of Open Access Journals (Sweden)

    El Hachem H

    2017-05-01

    Full Text Available Hady El Hachem,1,2 Vincent Crepaux,3 Pascale May-Panloup,4 Philippe Descamps,3 Guillaume Legendre,3 Pierre-Emmanuel Bouet3 1Department of Reproductive Medicine, Ovo Clinic, Montréal, QC, Canada; 2Department of Obstetrics and Gynecology, University of Montreal, Montréal, QC, Canada; 3Department of Obstetrics and Gynecology, Angers University Hopsital, Angers, France; 4Department of Reproductive Biology, Angers University Hospital, Angers, France Abstract: Recurrent pregnancy loss is an important reproductive health issue, affecting 2%–5% of couples. Common established causes include uterine anomalies, antiphospholipid syndrome, hormonal and metabolic disorders, and cytogenetic abnormalities. Other etiologies have been proposed but are still considered controversial, such as chronic endometritis, inherited thrombophilias, luteal phase deficiency, and high sperm DNA fragmentation levels. Over the years, evidence-based treatments such as surgical correction of uterine anomalies or aspirin and heparin for antiphospholipid syndrome have improved the outcomes for couples with recurrent pregnancy loss. However, almost half of the cases remain unexplained and are empirically treated using progesterone supplementation, anticoagulation, and/or immunomodulatory treatments. Regardless of the cause, the long-term prognosis of couples with recurrent pregnancy loss is good, and most eventually achieve a healthy live birth. However, multiple pregnancy losses can have a significant psychological toll on affected couples, and many efforts are being made to improve treatments and decrease the time needed to achieve a successful pregnancy. This article reviews the established and controversial etiologies, and the recommended therapeutic strategies, with a special focus on unexplained recurrent pregnancy losses and the empiric treatments used nowadays. It also discusses the current role of preimplantation genetic testing in the management of recurrent pregnancy

  3. Better plants through mutations

    International Nuclear Information System (INIS)

    1988-01-01

    This is a public relations film describing problems associated with the genetic improvement of crop plants through induced mutations. Mutations are the ultimate source of genetic variation in plants. Mutation induction is now established as a practical tool in plant breeding. The Joint FAO/IAEA Division and the IAEA's laboratory at Seibersdorf have supported research and practical implementation of mutation breeding of both seed propagated and vegetatively propagated plants. Plant biotechnology based on in vitro culture and recombinant DNA technology will make a further significant contribution to plant breeding

  4. RECURRENT NOVAE IN M31

    Energy Technology Data Exchange (ETDEWEB)

    Shafter, A. W. [Department of Astronomy, San Diego State University, San Diego, CA 92182 (United States); Henze, M. [European Space Astronomy Centre, P.O. Box 78, E-28692 Villanueva de la Cañada, Madrid (Spain); Rector, T. A. [Department of Physics and Astronomy, University of Alaska Anchorage, 3211 Providence Dr., Anchorage, AK 99508 (United States); Schweizer, F. [Carnegie Observatories, 813 Santa Barbara St., Pasadena, CA 91101 (United States); Hornoch, K. [Astronomical Institute, Academy of Sciences, CZ-251 65 Ondřejov (Czech Republic); Orio, M. [Astronomical Observatory of Padova (INAF), I-35122 Padova (Italy); Pietsch, W. [Max Planck Institute for Extraterrestrial Physics, P.O. Box 1312, Giessenbachstr., D-85741, Garching (Germany); Darnley, M. J.; Williams, S. C.; Bode, M. F. [Astrophysics Research Institute, Liverpool John Moores University, Liverpool L3 5RF (United Kingdom); Bryan, J., E-mail: aws@nova.sdsu.edu [McDonald Observatory, Austin, TX 78712 (United States)

    2015-02-01

    The reported positions of 964 suspected nova eruptions in M31 recorded through the end of calendar year 2013 have been compared in order to identify recurrent nova (RN) candidates. To pass the initial screen and qualify as a RN candidate, two or more eruptions were required to be coincident within 0.′1, although this criterion was relaxed to 0.′15 for novae discovered on early photographic patrols. A total of 118 eruptions from 51 potential RN systems satisfied the screening criterion. To determine what fraction of these novae are indeed recurrent, the original plates and published images of the relevant eruptions have been carefully compared. This procedure has resulted in the elimination of 27 of the 51 progenitor candidates (61 eruptions) from further consideration as RNe, with another 8 systems (17 eruptions) deemed unlikely to be recurrent. Of the remaining 16 systems, 12 candidates (32 eruptions) were judged to be RNe, with an additional 4 systems (8 eruptions) being possibly recurrent. It is estimated that ∼4% of the nova eruptions seen in M31 over the past century are associated with RNe. A Monte Carlo analysis shows that the discovery efficiency for RNe may be as low as 10% that for novae in general, suggesting that as many as one in three nova eruptions observed in M31 arise from progenitor systems having recurrence times ≲100 yr. For plausible system parameters, it appears unlikely that RNe can provide a significant channel for the production of Type Ia supernovae.

  5. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency

    DEFF Research Database (Denmark)

    Munthe-Fog, Lea; Hummelshøj, Tina; Honoré, Christian

    2009-01-01

    Ficolin-3, encoded by the FCN3 gene and expressed in the lung and liver, is a recognition molecule in the lectin pathway of the complement system. Heterozygosity for an FCN3 frameshift mutation (rs28357092), leading to a distortion of the C-terminal end of the molecule, occurs in people without...... disease (allele frequency among whites, 0.01). We describe a patient with recurrent infections who was homozygous for this mutation, who had undetectable serum levels of ficolin-3, and who had a deficiency in ficolin-3-dependent complement activation....

  6. Recurrent Novae — A Review

    Directory of Open Access Journals (Sweden)

    K. Mukai

    2015-02-01

    Full Text Available In recent years, recurrent nova eruptions are often observed very intensely in wide range of wavelengths from radio to optical to X-rays. Here I present selected highlights from recent multi-wavelength observations. The enigma of T Pyx is at the heart of this paper. While our current understanding of CV and symbiotic star evolution can explain why certain subset of recurrent novae have high accretion rate, that of T Pyx must be greatly elevated compared to the evolutionary mean. At the same time, we have extensive data to be able to estimate how the nova envelope was ejected in T Pyx, and it turns to be a rather complex tale. One suspects that envelope ejection in recurrent and classical novae in general is more complicated than the textbook descriptions. At the end of the review, I will speculate that these two may be connected.

  7. MED12 exon 2 mutations in phyllodes tumors of the breast

    International Nuclear Information System (INIS)

    Nagasawa, Satoi; Maeda, Ichiro; Fukuda, Takayo; Wu, Wenwen; Hayami, Ryosuke; Kojima, Yasuyuki; Tsugawa, Ko-ichiro; Ohta, Tomohiko

    2015-01-01

    Exon 2 of MED12, a subunit of the transcriptional mediator complex, has been frequently mutated in uterine leiomyomas and breast fibroadenomas; however, it has been rarely mutated in other tumors. Although the mutations were also found in uterine leiomyosarcomas, the frequency was significantly lower than in uterine leiomyomas. Here, we examined the MED12 mutation in phyllodes tumors, another biphasic tumor with epithelial and stromal components related to breast fibroadenomas. Mutations in MED12 exon 2 were analyzed in nine fibroadenomas and eleven phyllodes tumors via Sanger sequencing. A panel of cancer- and sarcoma-related genes was also analyzed using Ion Torrent next-generation sequencing. Six mutations in fibroadenomas, including those previously reported (6/9, 67%), and five mutations in phyllodes tumors (5/11, 45%) were observed. Three mutations in the phyllodes tumors were missense mutations at Gly44, which is common in uterine leiomyomas and breast fibroadenomas. In addition, two deletion mutations (in-frame c.133-144del12 and loss of splice acceptor c.100-68-137del106) were observed in the phyllodes tumors. No other recurrent mutation was observed with next-generation sequencing. Frequent mutations in MED12 exon 2 in the phyllodes tumors suggest that it may share genetic etiology with uterine leiomyoma, a subgroup of uterine leiomyosarcomas and breast fibroadenoma

  8. Mutation and premating isolation

    Science.gov (United States)

    Woodruff, R. C.; Thompson, J. N. Jr

    2002-01-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  9. Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma.

    Directory of Open Access Journals (Sweden)

    Francesco Abate

    2015-10-01

    Full Text Available Endemic Burkitt lymphoma (eBL is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%, in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL, we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF. We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

  10. Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma.

    Science.gov (United States)

    Abate, Francesco; Ambrosio, Maria Raffaella; Mundo, Lucia; Laginestra, Maria Antonella; Fuligni, Fabio; Rossi, Maura; Zairis, Sakellarios; Gazaneo, Sara; De Falco, Giulia; Lazzi, Stefano; Bellan, Cristiana; Rocca, Bruno Jim; Amato, Teresa; Marasco, Elena; Etebari, Maryam; Ogwang, Martin; Calbi, Valeria; Ndede, Isaac; Patel, Kirtika; Chumba, David; Piccaluga, Pier Paolo; Pileri, Stefano; Leoncini, Lorenzo; Rabadan, Raul

    2015-10-01

    Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

  11. Lineage dynamics and mutation-selection balance in non-adapting asexual populations

    Science.gov (United States)

    Pénisson, Sophie; Sniegowski, Paul D.; Colato, Alexandre; Gerrish, Philip J.

    2013-02-01

    In classical population genetics, mutation-selection balance refers to the equilibrium frequency of a deleterious allele established and maintained under two opposing forces: recurrent mutation, which tends to increase the frequency of the allele; and selection, which tends to decrease its frequency. In a haploid population, if μ denotes the per capita rate of production of the deleterious allele by mutation and s denotes the selective disadvantage of carrying the allele, then the classical mutation-selection balance frequency of the allele is approximated by μ/s. This calculation assumes that lineages carrying the mutant allele in question—the ‘focal allele’—do not accumulate deleterious mutations linked to the focal allele. In principle, indirect selection against the focal allele caused by such additional mutations can decrease the frequency of the focal allele below the classical mutation-selection balance. This effect of indirect selection will be strongest in an asexual population, in which the entire genome is in linkage. Here, we use an approach based on a multitype branching process to investigate this effect, analyzing lineage dynamics under mutation, direct selection, and indirect selection in a non-adapting asexual population. We find that the equilibrium balance between recurrent mutation to the focal allele and the forces of direct and indirect selection against the focal allele is closely approximated by γμ/(s + U) (s = 0 if the focal allele is neutral), where γ ≈ eθθ-(ω+θ)(ω + θ)(Γ(ω + θ) - Γ(ω + θ,θ)), \\theta =U/\\tilde {s}, and \\omega =s/\\tilde {s}; U denotes the genomic deleterious mutation rate and \\tilde {s} denotes the geometric mean selective disadvantage of deleterious mutations elsewhere on the genome. This mutation-selection balance for asexual populations can remain surprisingly invariant over wide ranges of the mutation rate.

  12. Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations.

    Science.gov (United States)

    Gu, Shun; Tian, Yuanyuan; Chen, Xue; Zhao, Chen

    2016-01-01

    We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease-relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant's colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all Chinese patients carrying mutations in the EYS

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

    Science.gov (United States)

    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.

  14. Recurrence quantification analysis of chimera states

    International Nuclear Information System (INIS)

    Santos, M.S.; Szezech, J.D.; Batista, A.M.; Caldas, I.L.; Viana, R.L.; Lopes, S.R.

    2015-01-01

    Chimera states, characterised by coexistence of coherence and incoherence in coupled dynamical systems, have been found in various physical systems, such as mechanical oscillator networks and Josephson-junction arrays. We used recurrence plots to provide graphical representations of recurrent patterns and identify chimera states. Moreover, we show that recurrence plots can be used as a diagnostic of chimera states and also to identify the chimera collapse. - Highlights: • Chimera states have been found in various physical systems. • Recurrence plots is a graphical method useful to locate recurring patterns. • We used recurrence plots to identify the chimera states. • We show also the recurrence plots can identify the chimera collapse

  15. Recurrence quantification analysis of chimera states

    Energy Technology Data Exchange (ETDEWEB)

    Santos, M.S. [Pós-Graduação em Ciências/Física, Universidade Estadual de Ponta Grossa, 84030-900, Ponta Grossa, PR (Brazil); Szezech, J.D., E-mail: jdanilo@gmail.com [Departamento de Matemática e Estatística, Universidade Estadual de Ponta Grossa, 84030-900, Ponta Grossa, PR (Brazil); Batista, A.M., E-mail: antoniomarcosbatista@gmail.com [Departamento de Matemática e Estatística, Universidade Estadual de Ponta Grossa, 84030-900, Ponta Grossa, PR (Brazil); Caldas, I.L. [Instituto de Física, Universidade de São Paulo, 05315-970, São Paulo, SP (Brazil); Viana, R.L.; Lopes, S.R. [Departamento de Física, Universidade Federal do Paraná, 81531-990, Curitiba, PR (Brazil)

    2015-10-02

    Chimera states, characterised by coexistence of coherence and incoherence in coupled dynamical systems, have been found in various physical systems, such as mechanical oscillator networks and Josephson-junction arrays. We used recurrence plots to provide graphical representations of recurrent patterns and identify chimera states. Moreover, we show that recurrence plots can be used as a diagnostic of chimera states and also to identify the chimera collapse. - Highlights: • Chimera states have been found in various physical systems. • Recurrence plots is a graphical method useful to locate recurring patterns. • We used recurrence plots to identify the chimera states. • We show also the recurrence plots can identify the chimera collapse.

  16. Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma.

    Science.gov (United States)

    Dinani, N; Ali, M; Liu, L; McGrath, J; Mellerio, J

    2017-04-01

    Punctate palmoplantar keratoderma type 1 (PPPK1) is a rare autosomal dominant inherited skin disease, characterized by multiple hyperkeratotic lesions on the palms and soles. The causative gene for PPPK1 has been identified as AAGAB, which encodes α- and γ-adaptin-binding protein p34. We describe the clinical features in three unrelated families with PPPK1, and report three recurrent causative mutations in AAGAB. © 2017 British Association of Dermatologists.

  17. Peer Influence and Addiction Recurrence

    OpenAIRE

    Paul Markdissi

    2009-01-01

    In this paper we highlight the role of peers in the recurrence of addictive behavior. To do so, we use a simple “forward looking” model with procrastination and peers influence. Our results show that while procrastination can explain the decision to postpone rehabilitation, peers influence is essential to explain the cyclical patterns of addiction-rehabilitation-addiction.

  18. Interpretation of Recurrent Neural Networks

    DEFF Research Database (Denmark)

    Pedersen, Morten With; Larsen, Jan

    1997-01-01

    This paper addresses techniques for interpretation and characterization of trained recurrent nets for time series problems. In particular, we focus on assessment of effective memory and suggest an operational definition of memory. Further we discuss the evaluation of learning curves. Various nume...

  19. Relativistic phase space: dimensional recurrences

    International Nuclear Information System (INIS)

    Delbourgo, R; Roberts, M L

    2003-01-01

    We derive recurrence relations between phase space expressions in different dimensions by confining some of the coordinates to tori or spheres of radius R and taking the limit as R→∞. These relations take the form of mass integrals, associated with extraneous momenta (relative to the lower dimension), and produce the result in the higher dimension

  20. Generalized Moshinsky bracket recurrence relations

    International Nuclear Information System (INIS)

    Bevelacqua, J.J.

    1979-01-01

    Recurrence relations for generalized Talmi-Moshinsky brackets are derived. These relations permit the generation of transformation brackets once appropriate starting brackets are determined. The savings in computer time, when compared with generating brackets individually, is at least a factor of 10 for brackets with radial quantum numbers as large as 9 and angular quantum numbers as large as 2. (author)

  1. Recurrent processing during object recognition

    Directory of Open Access Journals (Sweden)

    Randall C. O'Reilly

    2013-04-01

    Full Text Available How does the brain learn to recognize objects visually, and perform this difficult feat robustly in the face of many sources of ambiguity and variability? We present a computational model based on the biology of the relevant visual pathways that learns to reliably recognize 100 different object categories in the face of of naturally-occurring variability in location, rotation, size, and lighting. The model exhibits robustness to highly ambiguous, partially occluded inputs. Both the unified, biologically plausible learning mechanism and the robustness to occlusion derive from the role that recurrent connectivity and recurrent processing mechanisms play in the model. Furthermore, this interaction of recurrent connectivity and learning predicts that high-level visual representations should be shaped by error signals from nearby, associated brain areas over the course of visual learning. Consistent with this prediction, we show how semantic knowledge about object categories changes the nature of their learned visual representations, as well as how this representational shift supports the mapping between perceptual and conceptual knowledge. Altogether, these findings support the potential importance of ongoing recurrent processing throughout the brain's visual system and suggest ways in which object recognition can be understood in terms of interactions within and between processes over time.

  2. Ovarian irradiation in recurrent endometriosis

    International Nuclear Information System (INIS)

    Kochbati, L.; Chaari, N.; Besbes, M.; Maalej, M.; Neji, K.; Ben Amara, F.; Ben Romdhane, N.K.

    2005-01-01

    We describe a case of a young woman with a history of an aplastic anaemia in which pelvic radiotherapy was used successfully in the management of a recurrent and inoperable endometriosis. The use of therapeutic pelvic or ovarian irradiation in endometriosis may be considered, when surgical and medical treatments have been exhausted and have failed. (authors)

  3. Report of a newly indentified patient with mutations in BMP1 and underlying pathogenetic aspects

    DEFF Research Database (Denmark)

    Valencia, María; Caparrós-Martin, Jose A; Sirerol-Piquer, María Salomé

    2014-01-01

    Osteogenesis imperfecta is a genetic condition characterized by bone fragility and recurrent fractures, which in the large majority of patients are caused by defects in the production of type I collagen. Mutations in the gene encoding bone morphogenetic protein 1 (BMP1, also known as procollagen C......-endopeptidase) have been associated with osteogenesis imperfecta in two sib pairs. In this report, we describe an additional patient with osteogenesis imperfecta with normal bone density and a recurrent, homozygous c.34G>C mutation in BMP1. Western blot analysis of dermal fibroblasts from this patient showed...

  4. Clinical Outcomes of Lung Transplantation in Patients with Telomerase Mutations

    Science.gov (United States)

    Tokman, Sofya; Singer, Jonathan P.; Devine, Megan S.; Westall, Glen P.; Aubert, John-David; Tamm, Michael; Snell, Gregory I.; Lee, Joyce S.; Goldberg, Hilary J.; Kukreja, Jasleen; Golden, Jeffrey A.; Leard, Lorriana E.; Garcia, Christine K.; Hays, Steven R.

    2017-01-01

    Background Successful lung transplantation (LT) for patients with pulmonary fibrosis from telomerase mutations is limited by systemic complications of telomerase dysfunction including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes among 14 LT recipients with telomerase mutations. Methods Subjects underwent LT between February 2005 and April 2014 at 5 LT centers. We abstracted data from medical records, focusing on outcomes reflecting post-LT treatment effects likely to be complicated by telomerase mutations. Results The median age of subjects was 60.5 years (IQR 52.0–62.0), 64.3% were male, and the mean post-LT observation time was 3.2 years (SD ±2.9). Eleven subjects had a mutation in telomerase reverse transcriptase, 2 in telomerase RNA component, and 1 had an uncharacterized mutation. Ten subjects were leukopenic post-LT; leukopenia prompted cessation of mycophenolate mofetil in 5 and treatment with filgrastim in 4. Six subjects had recurrent lower respiratory tract infections (LRTI), 7 had acute cellular rejection (ACR) (A1), and 4 developed chronic lung allograft dysfunction (CLAD). Ten LT recipients developed chronic renal insufficiency and 8 experienced acute, reversible renal failure. Three developed cancer, none had cirrhosis. Thirteen subjects were alive at data censorship. Conclusions The clinical course for LT recipients with telomerase mutations is complicated by renal disease, leukopenia prompting a change in the immunosuppressive regimen, and recurrent LTRI. In contrast, cirrhosis was absent, ACR was mild, and development of CLAD was comparable to other LT populations. While posing challenges, lung transplantation may be feasible for patients with pulmonary fibrosis due to telomerase mutations. PMID:26169663

  5. Impact of KRAS, BRAF and PI3KCA mutations in rectal carcinomas treated with neoadjuvant radiochemotherapy and surgery

    International Nuclear Information System (INIS)

    Derbel, Olfa; La Fouchardière, Christelle de; Wang, Qing; Desseigne, Françoise; Rivoire, Michel; Meeus, Pierre; Peyrat, Patrice; Stella, Mattia; Martel-Lafay, Isabelle; Lemaistre, Anne-Isabelle

    2013-01-01

    Conventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients. We retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available. In the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4–74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences. The frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship

  6. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries

    Science.gov (United States)

    Kwong, Ava; Shin, Vivian Y; Ho, John C W; Kang, Eunyoung; Nakamura, Seigo; Teo, Soo-Hwang; Lee, Ann S G; Sng, Jen-Hwei; Ginsburg, Ophira M; Kurian, Allison W; Weitzel, Jeffrey N; Siu, Man-Ting; Law, Fian B F; Chan, Tsun-Leung; Narod, Steven A; Ford, James M; Ma, Edmond S K; Kim, Sung-Won

    2015-01-01

    Approximately 5%–10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer. PMID:26187060

  7. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis.

    Science.gov (United States)

    Xiao, Yuan; Yuan, Wentao; Yu, Bo; Guo, Yan; Xu, Xu; Wang, Xinqiong; Yu, Yi; Yu, Yi; Gong, Biao; Xu, Chundi

    2017-12-01

    To identify causal mutations in certain genes in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). After patients were enrolled (CP, 55; ARP, 14) and their clinical characteristics were investigated, we performed next-generation sequencing to detect nucleotide variations among the following 10 genes: cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor, Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), calcium-sensing receptor (CASR), cathepsin B (CTSB), keratin 8 (KRT8), CLAUDIN 2 (CLDN2), carboxypeptidase A1 (CPA1), and ATPase type 8B member 1 (ATP8B1). Mutations were searched against online databases to obtain information on the cause of the diseases. Certain novel mutations were analyzed using the SIFT2 and Polyphen-2 to predict the effect on protein function. There were 45 patients with CP and 10 patients with ARP who harbored 1 or more mutations in these genes; 45 patients had at least 1 mutation related to pancreatitis. Mutations were observed in the PRSS1, SPINK1, and CFTR genes in 17 patients, the CASR gene in 5 patients, and the CTSB, CTRC, and KRT8 genes in 1 patient. Mutations were not found in the CLDN, CPA1, or ATP8B1 genes. We found that mutations in SPINK1 may increase the risk of pancreatic duct stones (OR, 11.07; P = .003). The patients with CFTR mutations had a higher level of serum amylase (316.0 U/L vs 92.5 U/L; P = .026). Mutations, especially those in PRSS1, SPINK1, and CFTR, accounted for the major etiologies in Chinese children with CP or ARP. Children presenting mutations in the SPINK1 gene may have a higher risk of developing pancreatic duct stones. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Studies on the DNA excision repair in lymphocytes of patients with recurrent herpes simplex

    International Nuclear Information System (INIS)

    Fanta, D.; Topaloglou, A.; Altmann, H.

    1979-01-01

    DNA repair was investigated in lymphocytes from patients with recurrent herpes simplex and from healthy controls. From the results - depressed UV type repair, depressed gamma type repair, reduced RF - it may be concluded that mutations can be expected due to the faults remaining in the DNA. This may not only lower cellular immunocompetence, but also activate already present oncogenic virus informations within the cellular DNA. Thus, irrespective of the possible oncogenic potential of HSV, there seems to be an increased risk of late effects in patients with recurrent herpetic manifestations. (Auth.)

  9. Radiation induced chimeric rearrangement flower structure of Rhododendron simsii Planch. (Azaleaindica L. ) Use of recurrent irradiation

    Energy Technology Data Exchange (ETDEWEB)

    de Loose, R [IWONL (IRSIA) Irradiation Laboratory, Institute of Ornamental Plant Growing, Melle (Belgium)

    1979-02-01

    A radiation-induced chimeric flower colour sport of vegetatively propagated Rhododendron simsii Planch was recurrently irradiated (up to three times in three consecutive years) with soft X-rays (50kV-30mA), as compared to a single treatment. Because of the low true flower colour mutation frequency the efficiency of the different radiation treatments was compared on the basis of the number of chimeric rearrangements in flower structure i.e. the flower colour change from red with broad white edge towards either homogeneous carminered or white. It is quite clear that recurrent irradiation with appropiate doses is most efficient.

  10. Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study.

    Science.gov (United States)

    Wang, Chunping; Lu, Yinying; Chen, Yan; Feng, Yongyi; An, Linjing; Wang, Xinzhen; Su, Shuhui; Bai, Wenlin; Zhou, Lin; Yang, Yongping; Xu, Dongping

    2009-01-01

    To determine the long-term prognosis of hepatocellular carcinoma (HCC) after argon-helium cryoablation and identify the risk factors that predict metastasis and recurrence. A total of 156 patients with hepatitis B-related HCC less than 5 cm in diameter who underwent curative cryoablation were followed up prospectively for tumor metastasis and recurrence. Immunohistochemistry was used to analyze the expression of vascular endothelial growth factor (VEGF). HBV basal core promoter (BCP) and precore mutations were detected by DNA sequence analysis. Post-treatment prognostic factors influencing survival, tumor metastasis and recurrence were assessed by univariate and multivariate analyses. The variables included the expression of VEGF in HCC tissues, clinical and pathologic characteristics of patients, and HBV features (HBV DNA level, HBV genotype, BCP mutation). The median follow-up period of the 156 patients was 37 months (range 8-48 months). The 1-, 2-, and 3-year overall survival rates were 92, 82 and 64%, respectively. The 1-, 2-, and 3-year recurrence-free survival rates were 72, 56 and 43%, respectively. Eighty-five patients (54.5%) had tumor recurrence or metastasis. The multivariate analysis showed that Child-Pugh class and the expression of VEGF in HCC tissues could be used as independent prognostic factors for overall survival. Meanwhile, the expression of VEGF in HCC tissues and HBV BCP mutations were found to be independent prognostic factors for recurrence-free survival. Strong expression of VEGF in HCC tissues and HBV BCP mutations are important risk predictors for recurrence or metastasis of HCC smaller than 5 cm in diameter.

  11. The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation.

    Science.gov (United States)

    Lu, Di; Zhuo, Jianyong; Yang, Modan; Wang, Chao; Linhui, Pan; Xie, Haiyang; Xu, Xiao; Zheng, Shusen

    2018-04-05

    Hepatitis B recurrence adversely affects patients' survival after liver transplantation. This study aims to find association between donor gene variations of one carbon metabolism and post-transplant hepatitis B recurrence. This study enrolled 196 patients undergoing liver transplantation for HBV related end-stage liver diseases. We detected 11 single nucleotide polymorphisms (SNP) of 7 one-carbon metabolism pathway genes (including MTHFR, MTR, MTRR, ALDH1L1, GART, SHMT1 and CBS) in donor livers and analyzed their association with HBV reinfection after liver transplantation. Hepatitis B recurrence was observed in 19 of the 196 patients (9.7%) undergoing liver transplantation. Hepatitis B recurrence significantly affected post-transplant survival in the 196 patients (p = 0.018), and correlate with tumor recurrence in the subgroup of HCC patients (n = 99, p = 0.006). Among the 11 SNPs, donor liver mutation in rs1979277 (G > A) was adversely associated with post-transplant hepatitis B recurrence (p = 0.042). In the subgroup of HCC patients, survival analysis showed donor liver mutations in rs1801133 (G > A) and rs1979277 (G > A) were risk factors for hepatitis B recurrence (p B recurrence in non-HCC patients (n = 97, p > 0.05). Hepatitis B recurrence impaired post-transplant survival. Donor liver genetic variations in one-carbon metabolism pathway genes were significantly associated with post-transplant hepatitis B recurrence. Copyright © 2017. Published by Elsevier B.V.

  12. Fifth International Symposium on Recurrence Plot

    CERN Document Server

    Riley, Michael; Giuliani, Alessandro; Webber, Charles; Jr, Jr; Translational Recurrences : From Mathematical Theory to Real-World Applications

    2014-01-01

    This book features 13 papers presented at the Fifth International Symposium on Recurrence Plots, held August 2013 in Chicago, IL. It examines recent applications and developments in recurrence plots and recurrence quantifi cation analysis (RQA) with special emphasis on biological and cognitive systems and the analysis of coupled systems using cross-recurrence methods. Readers will discover new applications and insights into a range of systems provided by recurrence plot analysis and new theoretical and mathematical developments in recurrence plots. Recurrence plot based analysis is a powerful tool that operates on real-world complex systems that are nonlinear, non-stationary, noisy, of any statistical distribution, free of any particular model type, and not particularly long. Quantitative analyses promote the detection of system state changes, synchronized dynamical regimes, or classifi cation of system states. Th e book will be of interest to an interdisciplinary audience of recurrence plot users and researc...

  13. Temperature, age, and recurrence of febrile seizure

    NARCIS (Netherlands)

    M. van Stuijvenberg (Margriet); E.W. Steyerberg (Ewout); G. Derksen-Lubsen (Gerarda); H.A. Moll (Henriëtte)

    1998-01-01

    textabstractOBJECTIVE: Prediction of a recurrent febrile seizure during subsequent episodes of fever. DESIGN: Study of the data of the temperatures, seizure recurrences, and baseline patient characteristics that were collected at a randomized placebo controlled trial of ibuprofen

  14. Recurrence of hypertensive disorders of pregnancy

    DEFF Research Database (Denmark)

    van Oostwaard, Miriam F; Langenveld, Josje; Schuit, Ewoud

    2015-01-01

    OBJECTIVE: We performed an individual participant data (IPD) metaanalysis to calculate the recurrence risk of hypertensive disorders of pregnancy (HDP) and recurrence of individual hypertensive syndromes. STUDY DESIGN: We performed an electronic literature search for cohort studies that reported ...

  15. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

    Science.gov (United States)

    Mortera-Blanco, Teresa; Dimitriou, Marios; Woll, Petter S; Karimi, Mohsen; Elvarsdottir, Edda; Conte, Simona; Tobiasson, Magnus; Jansson, Monika; Douagi, Iyadh; Moarii, Matahi; Saft, Leonie; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

    2017-08-17

    Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal ( SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. © 2017 by The American Society of Hematology.

  16. Study of hTERT and Histone 3 Mutations in Medulloblastoma.

    Science.gov (United States)

    Viana-Pereira, Marta; Almeida, Gisele Caravina; Stavale, João Norberto; Malheiro, Susana; Clara, Carlos; Lobo, Patrícia; Pimentel, José; Reis, Rui Manuel

    2017-01-01

    Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in medulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in medulloblastoma. © 2016 S. Karger AG, Basel.

  17. Genetic Mutations in Cancer

    Science.gov (United States)

    Many different types of genetic mutations are found in cancer cells. This infographic outlines certain types of alterations that are present in cancer, such as missense, nonsense, frameshift, and chromosome rearrangements.

  18. AIP mutations and gigantism.

    Science.gov (United States)

    Rostomyan, Liliya; Potorac, Iulia; Beckers, Pablo; Daly, Adrian F; Beckers, Albert

    2017-06-01

    AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Age-related mutations associated with clonal hematopoietic expansion and malignancies.

    Science.gov (United States)

    Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D; Johnson, Kimberly J; Wendl, Michael C; McMichael, Joshua F; Schmidt, Heather K; Yellapantula, Venkata; Miller, Christopher A; Ozenberger, Bradley A; Welch, John S; Link, Daniel C; Walter, Matthew J; Mardis, Elaine R; Dipersio, John F; Chen, Feng; Wilson, Richard K; Ley, Timothy J; Ding, Li

    2014-12-01

    Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

  20. Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

    Science.gov (United States)

    Mantere, T; Haanpää, M; Hanenberg, H; Schleutker, J; Kallioniemi, A; Kähkönen, M; Parto, K; Avela, K; Aittomäki, K; von Koskull, H; Hartikainen, J M; Kosma, V-M; Laasanen, S-L; Mannermaa, A; Pylkäs, K; Winqvist, R

    2015-07-01

    Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Mutation breeding in peas

    Energy Technology Data Exchange (ETDEWEB)

    Jaranowski, J [Institute of Genetics and Plant Breeding, Academy of Agriculture, Poznan (Poland); Micke, A [Joint FAO/IAEA Division of Isotope and Radiation Applications of Atomic Energy for Food and Agricultural Development, International Atomic Energy Agency, Vienna (Austria)

    1985-02-01

    The pea as an ancient crop plant still today has wide uses and is an import source of food protein. It is also an important object for genetic studies and as such has been widely used in mutation induction experiments. However, in comparison with cereals this ancient crop plant (like several other grain legumes) has gained relatively little from advances in breeding. The review focuses on the prospects of genetic improvement of pea by induced mutations, discusses principles and gives methodological information. (author)

  2. Mutation breeding in peas

    International Nuclear Information System (INIS)

    Jaranowski, J.; Micke, A.

    1985-01-01

    The pea as an ancient crop plant still today has wide uses and is an import source of food protein. It is also an important object for genetic studies and as such has been widely used in mutation induction experiments. However, in comparison with cereals this ancient crop plant (like several other grain legumes) has gained relatively little from advances in breeding. The review focuses on the prospects of genetic improvement of pea by induced mutations, discusses principles and gives methodological information. (author)

  3. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.

    Directory of Open Access Journals (Sweden)

    Swati Tomar

    Full Text Available Retinoblastoma (RB is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59 while only 42.4% (25/59 of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9% of tumors screened. There were 3 cases (5.1% in which no mutations could be detected and germline mutations were detected in 19.5% (8/41 of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59 of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and

  4. Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.

    Science.gov (United States)

    Chen, Kaitian; Zhan, Yuan; Wu, Xuan; Zong, Ling; Jiang, Hongyan

    2018-01-01

    Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. 14 CFR 121.427 - Recurrent training.

    Science.gov (United States)

    2010-01-01

    ... procedures set forth in the certificate holder's approved low-altitude windshear flight training program and... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Recurrent training. 121.427 Section 121.427..., FLAG, AND SUPPLEMENTAL OPERATIONS Training Program § 121.427 Recurrent training. (a) Recurrent training...

  6. Decidability of uniform recurrence of morphic sequences

    OpenAIRE

    Durand , Fabien

    2012-01-01

    We prove that the uniform recurrence of morphic sequences is decidable. For this we show that the number of derived sequences of uniformly recurrent morphic sequences is bounded. As a corollary we obtain that uniformly recurrent morphic sequences are primitive substitutive sequences.

  7. Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer

    Science.gov (United States)

    2018-04-18

    BRAF Gene Mutation; Poorly Differentiated Thyroid Gland Carcinoma; RAS Family Gene Mutation; Recurrent Thyroid Gland Carcinoma; Stage IV Thyroid Gland Follicular Carcinoma AJCC v7; Stage IV Thyroid Gland Papillary Carcinoma AJCC v7; Stage IVA Thyroid Gland Follicular Carcinoma AJCC v7; Stage IVA Thyroid Gland Papillary Carcinoma AJCC v7; Stage IVB Thyroid Gland Follicular Carcinoma AJCC v7; Stage IVB Thyroid Gland Papillary Carcinoma AJCC v7; Stage IVC Thyroid Gland Follicular Carcinoma AJCC v7; Stage IVC Thyroid Gland Papillary Carcinoma AJCC v7

  8. Pheochromocytomatosis associated with a novel TMEM127 mutation

    Directory of Open Access Journals (Sweden)

    Run Yu

    2017-05-01

    Full Text Available Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case.

  9. Recurrent impetigo herpetiformis: case report.

    Science.gov (United States)

    Wamalwa, Emmanuel Wekesa

    2017-01-01

    Impetigo herpetiformis (pustular psoriasis of pregnancy) is a rare dermatosis of pregnancy that typically starts in the 2 nd half of pregnancy and resolves postpartum. It may recur in subsequent pregnancies. I present a case of 23 year old female gravida 4 para 3 with recurrent impetigo herpetiformis at 26 weeks gestation. She presented with a one month history of pustular lesions which responded to treatment with prednisone. She delivered at term with a favourable outcome. The disease resolved one month postpartum. This was the second recurrence of the disease. She had her first episode of impetigo herpetiformis during the second pregnancy. The disease recurred in the 3 rd pregnancy and resulted in a still birth.

  10. Management of Recurrent Subdural Hematomas.

    Science.gov (United States)

    Desai, Virendra R; Scranton, Robert A; Britz, Gavin W

    2017-04-01

    Subdural hematomas commonly recur after surgical evacuation, at a rate of 2% to 37%. Risk factors for recurrence can be patient related, radiologic, or surgical. Patient-related risk factors include alcoholism, seizure disorders, coagulopathy, and history of ventriculoperitoneal shunt. Radiologic factors include poor brain reexpansion postoperatively, significant subdural air, greater midline shift, heterogeneous hematomas (layered or multi-loculated), and higher-density hematomas. Surgical factors include lack of or poor postoperative drainage. Most recurrent hematomas are managed successfully with burr hole craniostomies with postoperative closed-system drainage. Refractory hematomas may be managed with a variety of techniques, including craniotomy or subdural-peritoneal shunt placement. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Recurrent gossypiboma in the thigh

    International Nuclear Information System (INIS)

    Puri, Ajay; Anchan, Chetan; Agarwal, Manish G.; Jambhekar, Nirmala A.; Badwe, Rajendra A.

    2007-01-01

    Gossypiboma, an iatrogenic mass lesion caused by a retained surgical sponge is an extremely rare event following musculoskeletal procedures. This entity is therefore a very unusual experience and can create considerable confusion. Unsuspecting surgeons may thus be caught out by this unlikely presentation. We present our experience with a recurrent gossypiboma in the thigh occurring several years after surgical evacuation of a similar gossypiboma from the same anatomic location with interval resolution of symptoms. The purpose of this case report is to highlight the possibility of a ''recurrent'' soft tissue mass occurring for reasons other than a neoplasm. In the absence of a definitive biopsy diagnosis of tumor in patients who have undergone prior surgical procedures in that area, it may be more prudent to adopt a conservative surgical resection rather than a conventional radical resection as warranted by the dramatic clinical presentation mimicking a soft tissue sarcoma. (orig.)

  12. Systematic Analysis of Splice-Site-Creating Mutations in Cancer.

    Science.gov (United States)

    Jayasinghe, Reyka G; Cao, Song; Gao, Qingsong; Wendl, Michael C; Vo, Nam Sy; Reynolds, Sheila M; Zhao, Yanyan; Climente-González, Héctor; Chai, Shengjie; Wang, Fang; Varghese, Rajees; Huang, Mo; Liang, Wen-Wei; Wyczalkowski, Matthew A; Sengupta, Sohini; Li, Zhi; Payne, Samuel H; Fenyö, David; Miner, Jeffrey H; Walter, Matthew J; Vincent, Benjamin; Eyras, Eduardo; Chen, Ken; Shmulevich, Ilya; Chen, Feng; Ding, Li

    2018-04-03

    For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Recurrent Respiratory Infections in Children

    Directory of Open Access Journals (Sweden)

    F. Yurochko

    2012-02-01

    Full Text Available The paper covers a problem of recurrent respiratory infections (RRI in children. Their description, risk factors, diagnostic algorithm have been dwelt. A special attention is paid to the treatment. An optimal antibiotic in RRI of bacterial genesis is a high-dose amoxicillin/clavulanate (registered as Augmentin™ ES in Ukraine, the efficacy of which is 94.6–96.3 % according to different data.

  14. Recurrent spontaneous attacks of dizziness.

    Science.gov (United States)

    Lempert, Thomas

    2012-10-01

    This article describes the common causes of recurrent vertigo and dizziness that can be diagnosed largely on the basis of history. Ninety percent of spontaneous recurrent vertigo and dizziness can be explained by six disorders: (1) Ménière disease is characterized by vertigo attacks, lasting 20 minutes to several hours, with concomitant hearing loss, tinnitus, and aural fullness. Aural symptoms become permanent during the course of the disease. (2) Attacks of vestibular migraine may last anywhere from minutes to days. Most patients have a previous history of migraine headaches, and many experience migraine symptoms during the attack. (3) Vertebrobasilar TIAs affect older adults with vascular risk factors. Most attacks last less than 1 hour and are accompanied by other symptoms from the posterior circulation territory. (4) Vestibular paroxysmia is caused by vascular compression of the eighth cranial nerve. It manifests itself with brief attacks of vertigo that recur many times per day, sometimes with concomitant cochlear symptoms. (5) Orthostatic hypotension causes brief episodes of dizziness lasting seconds to a few minutes after standing up and is relieved by sitting or lying down. In older adults, it may be accompanied by supine hypertension. (6) Panic attacks usually last minutes, occur in specific situations, and are accompanied by choking, palpitations, tremor, heat, and anxiety. Less common causes of spontaneous recurrent vertigo and dizziness include perilymph fistula, superior canal dehiscence, autoimmune inner ear disease, otosclerosis, cardiac arrhythmia, and medication side effects. Neurologists need to venture into otolaryngology, internal medicine, and psychiatry to master the differential diagnosis of recurrent dizziness.

  15. Deep Gate Recurrent Neural Network

    Science.gov (United States)

    2016-11-22

    and Fred Cummins. Learning to forget: Continual prediction with lstm . Neural computation, 12(10):2451–2471, 2000. Alex Graves. Generating sequences...DSGU) and Simple Gated Unit (SGU), which are structures for learning long-term dependencies. Compared to traditional Long Short-Term Memory ( LSTM ) and...Gated Recurrent Unit (GRU), both structures require fewer parameters and less computation time in sequence classification tasks. Unlike GRU and LSTM

  16. MR investigation of recurrent cholesteatomas

    Energy Technology Data Exchange (ETDEWEB)

    Doyon, D.; Chan, K.Y.; Attia, M.; Halimi, P.; Sigal, R.; Bobin, S.; Sterkers, J.M.

    1989-03-01

    Nine cases of recurrent petrous cholesteatomas have been studied by a 1.5 T MR unit. Gadolinium was injected in 1 case. In all cases, comparison between MR, CT and clinical findings were made. MR allows for accurate topographic study and assessment of cholesteatomas extension, in particular in the posterior fossa and skull base. Relationships with the internal carotid artery and the jugular vein are clearly depicted.

  17. MR investigation of recurrent cholesteatomas

    International Nuclear Information System (INIS)

    Doyon, D.; Chan, K.Y.; Attia, M.; Halimi, P.; Sigal, R.; Bobin, S.; Sterkers, J.M.

    1989-01-01

    Nine cases of recurrent petrous cholesteatomas have been studied by a 1.5 T MR unit. Gadolinium was injected in 1 case. In all cases, comparison between MR, CT and clinical findings were made. MR allows for accurate topographic study and assessment of cholesteatomas extension, in particular in the posterior fossa and skull base. Relationships with the internal carotid artery and the jugular vein are clearly depicted [fr

  18. Recurrent Bleeding After Perimesencephalic Hemorrhage.

    Science.gov (United States)

    Kauw, Frans; Velthuis, Birgitta K; Kizilates, Ufuk; van der Schaaf, Irene C; Rinkel, Gabriel J E; Vergouwen, Mervyn D I

    2017-12-01

    Perimesencephalic hemorrhage (PMH) is a type of subarachnoid hemorrhage with excellent long-term outcomes. Only 1 well-documented case of in-hospital rebleeding after PMH is described in the literature, which occurred after initiating antithrombotic treatment because of myocardial ischemia. We describe a patient with PMH without antithrombotic treatment who had 2 episodes of recurrent bleeding on the day of ictus. To validate the radiologic findings, we conducted a case-control study. Six neuroradiologists and 2 neuroradiology fellows performed a blinded assessment of serial unenhanced head computed tomography (CT) scans of 8 patients with a perimesencephalic bleeding pattern (1 index patient, 6 patients with PMH, 1 patient with perimesencephalic bleeding pattern and basilar artery aneurysm) to investigate a potential increase in amount of subarachnoid blood. A 56-year-old woman with a perimesencephalic bleeding pattern and negative CT angiography had 2 episodes after the onset headache with a sudden increase of the headache. Blinded assessment of serial head CT scans of 8 patients with a perimesencephalic bleeding pattern identified the patient who was clinically suspected to have 2 episodes of recurrent bleeding to have an increased amount of subarachnoid blood on 2 subsequent CT scans. Recurrent bleeding after PMH may also occur in patients not treated with antithrombotics. Even after early rebleeding, the prognosis of PMH is excellent. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. [Recurrent benign cystic peritoneal mesothelioma].

    Science.gov (United States)

    Stroescu, C; Negulescu, Raluca; Herlea, V; David, L; Ivanov, B; Nitipir, Cornelia; Popescu, I

    2008-01-01

    The benign cystic peritoneal mesothelioma (BCPM) is a rare neoplasm affecting mainly females at reproductive age. The natural history and physiopathology of the BCPM are not entirely known. It is mainly characterized by the lack of malignant elements, no tendency to metastasis and by a pervasive tendency to generate local recurrences after surgical removal. The clinical manifestations are insidious, uncharacteristic; the benign cystic peritoneal mesothelioma is often discovered during a surgical procedure addressing another condition. Imaging tests can raise the suspicion of BCPM but the diagnostic can only be confirmed by histopathological examination corroborated with an immunohistochemical analysis. There are no long term studies dictating a single therapeutic attitude but a high risk of local recurrences and the possibility of transformation into malignant mesothelioma have lead to the current tendency towards an aggressive treatment of the tumor. We present the case of a recurrent benign cystic peritoneal mesothelioma in a 40 years old female patient, emphasizing the therapeutic approach and the role of radical surgery in the treatment of BPCM.

  20. MRI in recurrent nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Ng, S.H.; Ko, S.F.; Wan, Y.L.; Chang, J.T.C.; Chen, W.C.; Tang, L.M.

    1999-01-01

    In this study, we retrospectively reviewed the MRI features of recurrent nasopharyngeal carcinoma (NPC) in 72 patients who underwent MRI before and after gadolinium injection. Recurrent NPC exhibited a high degree of regional spread and a variety of signal intensities and contours. MRI showed a nasopharyngeal mass in 50 patients (69.4 %); other sites of involvement included the parapharyngeal space (44.4 %), nasal cavity (12.5 %), paranasal sinuses (27.8 %), oropharynx (4.2 %), orbit (8.3 %), infratemporal fossa (18.1 %), skull base (59.8 %), intracranial area (51.4 %) and regional lymph nodes (15.3 %). On T2-weighted images, the nasopharyngeal mass gave high signal in 9 of 50 cases (18 %), intermediate in 27 (54 %), mixed in 8 (16 %) and low signal in 6 (12 %). Contrast enhancement was strong in 12 cases (24 %), moderate in 29 (58 %) and heterogeneous in 9 (18 %). The lesion was convex in 31 cases (62 %) and concave or straight in 19 (38 %). Recognition of the distribution and the appearance of recurrent NPC on MRI is essential for timely diagnosis and appropriate treatment. (orig.)

  1. Ring enhancement in recurrent gliomas

    International Nuclear Information System (INIS)

    Ogashiwa, Motohide; Takeuchi, Kazuo; Akai, Keiichiro

    1981-01-01

    The clinical courses,CT scans, and postmortem reports for 6 glioma patients treated by surgery, radiation, and chemotherapy were reviewed. They underwent reoperation and/or retreatment with radiation or chemotherapy for recurrent tumors. CT scans taken at the time of recurrence or about one month prior to death showed ring enhancement of varied size and form after intensive treatment. The cases were examined histologically in correlation with the CT features and divided into two groups based on the pathological findings in the centers surrounded by areas of ring enhancement. The 1st group demonstrated a large necrotic area in the center, and the 2nd group, a cystic tumor. Tumor cells were found to have spread throughout the high-density areas around the necrotic area or cyst. However, gross differentiation between tumor and necrosis was difficult. In addition to an increase in cellularity, all cases demonstrated vascular proliferation, and dilatation of vessels in the sulci or sulci adjacent to gyri invaded by the tumor. The contrast enhancement corresponded well with the vascular proliferation in these areas. It is concluded that vascular proliferation or dilatation of vessels in and around the tumor is an important factor in demonstrating high-density areas in ring enhancement, while a cyst or necrosis in the tumor center is revealed as a low-density area in the CT scan of recurrent gliomas. (author)

  2. Ring enhancement in recurrent gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ogashiwa, M; Takeuchi, K; Akai, K [Kyorin Univ., Mitaka, Tokyo (Japan). School of Medicine

    1981-08-01

    The clinical courses,CT scans, and postmortem reports for 6 glioma patients treated by surgery, radiation, and chemotherapy were reviewed. They underwent reoperation and/or retreatment with radiation or chemotherapy for recurrent tumors. CT scans taken at the time of recurrence or about one month prior to death showed ring enhancement of varied size and form after intensive treatment. The cases were examined histologically in correlation with the CT features and divided into two groups based on the pathological findings in the centers surrounded by areas of ring enhancement. The 1st group demonstrated a large necrotic area in the center, and the 2nd group, a cystic tumor. Tumor cells were found to have spread throughout the high-density areas around the necrotic area or cyst. However, gross differentiation between tumor and necrosis was difficult. In addition to an increase in cellularity, all cases demonstrated vascular proliferation, and dilatation of vessels in the sulci or sulci adjacent to gyri invaded by the tumor. The contrast enhancement corresponded well with the vascular proliferation in these areas. It is concluded that vascular proliferation or dilatation of vessels in and around the tumor is an important factor in demonstrating high-density areas in ring enhancement, while a cyst or necrosis in the tumor center is revealed as a low-density area in the CT scan of recurrent gliomas.

  3. Rhabdoid tumor predisposition syndrome caused by SMARCB1 constitutional deletion: prenatal detection of new case of recurrence in siblings due to gonadal mosaicism.

    Science.gov (United States)

    Gigante, Laura; Paganini, Irene; Frontali, Marina; Ciabattoni, Serena; Sangiuolo, Federica Carla; Papi, Laura

    2016-01-01

    Rhabdoid tumors are aggressive malignancies that show loss-of-function mutations of SMARCB1 gene, a member of the SWI/SNF chromatin-remodeling complex controlling gene transcription. One-third of patients affected by rhabdoid tumor harbor a germ-line mutation of SMARCB1 defining a rhabdoid tumor predisposition syndrome. The occurrence of a second somatic mutation determines the development of neoplasia in a two-hit model. Most germ-line mutations occur de novo, and few cases of recurrence in a sibship have been described. Here we report on a new Italian family with recurrence of SMARCB1 germ-line deletion in two siblings due to gonadal mosaicism. The deletion was identified in the 9-month-old proband with malignant rhabdoid tumor of the right kidney and disseminated metastases. Testing of both parents confirmed the de novo origin of the mutation, but recurrence was then detected prenatally in a new pregnancy. This is the sixth family with malignant rhabdoid tumor predisposition syndrome with the recurrence of the same germ-line SMARCB1 mutation in the sibship but not in healthy parents, suggesting that gonadal mosaicism is a less rare event than supposed. The clinical outcome in our patient confirms previous data of poorer outcome in patients with rhabdoid tumor predisposition syndrome.

  4. Mutator activity in Schizophyllum commune

    Energy Technology Data Exchange (ETDEWEB)

    Shneyour, Y.; Koltin, Y. (Tel Aviv Univ. (Israel). Dept. of Microbiology)

    1983-01-01

    A strain with an elevated level of spontaneous mutations and an especially high rate of reversion at a specific locus (pab/sup -/) was identified. The mutator trait is recessive. UV sensitivity and the absence of a UV-specific endonucleolytic activity were associated with the enhancement of the mutation rate in mutator strains. The endonuclease associated with the regulation of the mutation rate also acted on single-stranded DNA. The molecular weight of this enzyme is about 38,000 daltons.

  5. NRF2 Mutation Confers Malignant Potential and Resistance to Chemoradiation Therapy in Advanced Esophageal Squamous Cancer

    Directory of Open Access Journals (Sweden)

    Tatsuhiro Shibata

    2011-09-01

    Full Text Available Esophageal squamous cancer (ESC is one of the most aggressive tumors of the gastrointestinal tract. A combination of chemotherapy and radiation therapy (CRT has improved the clinical outcome, but the molecular background determining the effectiveness of therapy remains unknown. NRF2 is a master transcriptional regulator of stress adaptation, and gain of-function mutation of NRF2 in cancer confers resistance to stressors including anticancer therapy. Direct resequencing analysis revealed that Nrf2 gain-of-function mutation occurred recurrently (18/82, 22% in advanced ESC tumors and ESC cell lines (3/10. The presence of Nrf2 mutation was associated with tumor recurrence and poor prognosis. Short hairpin RNA-mediated down-regulation of NRF2 in ESC cells that harbor only mutated Nrf2 allele revealed that themutant NRF2 conferred increased cell proliferation, attachment-independent survival, and resistance to 5-fluorouracil and γ-irradiation. Based on the Nrf2 mutation status, gene expression signatures associated with NRF2 mutation were extracted from ESC cell lines, and their potential utility for monitoring and prognosis was examined in a cohort of 33 pre-CRT cases of ESC. The molecular signatures of NRF2 mutation were significantly predictive and prognostic for CRT response. In conclusion, recurrent NRF2 mutation confers malignant potential and resistance to therapy in advanced ESC, resulting in a poorer outcome. Molecular signatures of NRF2 mutation can be applied as predictive markers of response to CRT, and efficient inhibition of aberrant NRF2 activation could be a promising approach in combination with CRT.

  6. Recurrent Kawasaki disease: USA and Japan.

    Science.gov (United States)

    Maddox, Ryan A; Holman, Robert C; Uehara, Ritei; Callinan, Laura S; Guest, Jodie L; Schonberger, Lawrence B; Nakamura, Yosikazu; Yashiro, Mayumi; Belay, Ermias D

    2015-12-01

    Descriptive epidemiologic studies of recurrent and non-recurrent Kawasaki disease (KD) may identify other potentially important differences between these illnesses. Data from the USA and Japan, the Centers for Disease Control and Prevention (CDC) national KD surveillance(1984-2008) and the 17th Japanese nationwide survey (2001-2002), respectively, were analyzed to examine recurrent KD patients <18 years of age meeting the CDC KD case or atypical KD case definition. These patients were compared with non-recurrent KD patients. Of the 5557 US KD patients <18 years of age during 1984-2008, 97 (1.7%) were identified as having had recurrent KD. Among the US Asian/Pacific Islander KD patients, 3.5% had recurrent KD, which was similar to the percentage identified among KD patients (3.5%) in the Japanese survey. Compared with non-recurrent KD patients, KD patients [with recurrent KD] were more likely to be older, fulfill the atypical KD case definition, and have coronary artery abnormalities (CAA) despite i.v. immunoglobulin (IVIG) treatment. Differences in the age, race, and frequency of CAA exist between recurrent and non-recurrent KD patients. The increased association of CAA with recurrent KD suggests that more aggressive treatment strategies in conjunction with IVIG may be indicated for the second episode of KD. © 2015 Japan Pediatric Society.

  7. Recurrent Kawasaki disease, United States and Japan

    Science.gov (United States)

    Maddox, Ryan A.; Holman, Robert C.; Uehara, Ritei; Callinan, Laura S.; Guest, Jodie L.; Schonberger, Lawrence B.; Nakamura, Yosikazu; Yashiro, Mayumi; Belay, Ermias D.

    2015-01-01

    Background Descriptive epidemiologic studies of recurrent and non-recurrent Kawasaki disease (KD) may identify other potentially important differences between these illnesses. Methods Data from the United States and Japan, the Centers for Disease Control and Prevention (CDC) national KD surveillance (1984–2008) and the 17th Japanese nationwide survey (2001–2002), respectively, were analyzed to examine recurrent KD patients <18 years of age meeting the CDC KD case or atypical KD case definition. These patients were compared to non-recurrent KD patients. Results Of the 5557 US KD patients <18 years of age during 1984–2008, 97 (1.7%) were identified as having had recurrent KD. Among the US Asian/Pacific Islander KD patients, 3.5% had recurrent KD, which was similar to the percentage identified among KD patients (3.5%) in the Japanese survey. Compared to non-recurrent KD patients, KD patients experiencing a recurrent KD episode were more likely to be older, fulfill the atypical KD case definition, and have coronary artery abnormalities (CAA) despite IVIG treatment. Conclusions Differences in the age, race, and frequency of CAA exist between recurrent and non-recurrent KD patients. The increased association of CAA with recurrent KD suggests that more aggressive treatment strategies in conjunction with IVIG may be indicated for the second episode of KD. PMID:26096590

  8. Risk factors of recurrent anal sphincter ruptures

    DEFF Research Database (Denmark)

    Jangö, Hanna; Langhoff-Roos, J; Rosthøj, Steen

    2012-01-01

    Please cite this paper as: Jangö H, Langhoff-Roos J, Rosthøj S, Sakse A. Risk factors of recurrent anal sphincter ruptures: a population-based cohort study. BJOG 2012;00:000-000 DOI: 10.1111/j.1471-0528.2012.03486.x. Objective  To determine the incidence and risk factors of recurrent anal sphincter...... were used to determine risk factors of recurrent ASR. Main outcome measures  The incidence of recurrent ASR and odds ratios for possible risk factors of recurrent ASR: age, body mass index, grade of ASR, birthweight, head circumference, gestational age, presentation, induction of labour, oxytocin...... augmentation, epidural, episiotomy, vacuum extraction, forceps, shoulder dystocia, delivery interval and year of second delivery. Results  Out of 159 446 women, 7336 (4.6%) experienced an ASR at first delivery, and 521 (7.1%) had a recurrent ASR (OR 5.91). The risk factors of recurrent ASR in the multivariate...

  9. Stress Reduction in Improving Quality of Life in Patients With Recurrent Gynecologic or Breast Cancer

    Science.gov (United States)

    2015-10-08

    Anxiety Disorder; Depression; Fatigue; Leydig Cell Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Pain; Peritoneal Carcinomatosis; Pseudomyxoma Peritonei; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Endometrial Carcinoma; Recurrent Fallopian Tube Cancer; Recurrent Gestational Trophoblastic Tumor; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Cavity Cancer; Recurrent Uterine Sarcoma; Recurrent Vaginal Cancer; Recurrent Vulvar Cancer

  10. Identification of coding and non-coding mutational hotspots in cancer genomes.

    Science.gov (United States)

    Piraino, Scott W; Furney, Simon J

    2017-01-05

    The identification of mutations that play a causal role in tumour development, so called "driver" mutations, is of critical importance for understanding how cancers form and how they might be treated. Several large cancer sequencing projects have identified genes that are recurrently mutated in cancer patients, suggesting a role in tumourigenesis. While the landscape of coding drivers has been extensively studied and many of the most prominent driver genes are well characterised, comparatively less is known about the role of mutations in the non-coding regions of the genome in cancer development. The continuing fall in genome sequencing costs has resulted in a concomitant increase in the number of cancer whole genome sequences being produced, facilitating systematic interrogation of both the coding and non-coding regions of cancer genomes. To examine the mutational landscapes of tumour genomes we have developed a novel method to identify mutational hotspots in tumour genomes using both mutational data and information on evolutionary conservation. We have applied our methodology to over 1300 whole cancer genomes and show that it identifies prominent coding and non-coding regions that are known or highly suspected to play a role in cancer. Importantly, we applied our method to the entire genome, rather than relying on predefined annotations (e.g. promoter regions) and we highlight recurrently mutated regions that may have resulted from increased exposure to mutational processes rather than selection, some of which have been identified previously as targets of selection. Finally, we implicate several pan-cancer and cancer-specific candidate non-coding regions, which could be involved in tumourigenesis. We have developed a framework to identify mutational hotspots in cancer genomes, which is applicable to the entire genome. This framework identifies known and novel coding and non-coding mutional hotspots and can be used to differentiate candidate driver regions from

  11. Genetic Alterations and Their Clinical Implications in High-Recurrence Risk Papillary Thyroid Cancer.

    Science.gov (United States)

    Lee, Min-Young; Ku, Bo Mi; Kim, Hae Su; Lee, Ji Yun; Lim, Sung Hee; Sun, Jong-Mu; Lee, Se-Hoon; Park, Keunchil; Oh, Young Lyun; Hong, Mineui; Jeong, Han-Sin; Son, Young-Ik; Baek, Chung-Hwan; Ahn, Myung-Ju

    2017-10-01

    Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString's nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CA mutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence-free survival or overall survival among patients lacking genetic alterations. In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.

  12. Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

    Directory of Open Access Journals (Sweden)

    Michael Seiler

    2018-04-01

    Full Text Available Summary: Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA, and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like, or hotspot mutation profile (oncogene-like. Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis. : Seiler et al. report that 119 splicing factor genes carry putative driver mutations over 33 tumor types in TCGA. The most common mutations appear to be mutually exclusive and are associated with lineage-independent altered splicing. Samples with these mutations show deregulation of cell-autonomous pathways and immune infiltration. Keywords: splicing, SF3B1, U2AF1, SRSF2, RBM10, FUBP1, cancer, mutation

  13. Clinical relevance of sensitive and quantitative STAT3 mutation analysis using next-generation sequencing in T-cell large granular lymphocytic leukemia

    DEFF Research Database (Denmark)

    Kielsgaard Kristensen, Thomas; Larsen, Martin; Rewes, Annika

    2014-01-01

    Diagnosis of T-cell large granular lymphocytic leukemia (T-LGL) is often challenging because clinical and laboratory characteristics are overlapping with nonneoplastic conditions. Recently, mutation in the STAT3 gene has been identified as a recurrent genetic abnormality in T-LGL. STAT3 mutation...

  14. Identification of Constrained Cancer Driver Genes Based on Mutation Timing

    Science.gov (United States)

    Sakoparnig, Thomas; Fried, Patrick; Beerenwinkel, Niko

    2015-01-01

    Cancer drivers are genomic alterations that provide cells containing them with a selective advantage over their local competitors, whereas neutral passengers do not change the somatic fitness of cells. Cancer-driving mutations are usually discriminated from passenger mutations by their higher degree of recurrence in tumor samples. However, there is increasing evidence that many additional driver mutations may exist that occur at very low frequencies among tumors. This observation has prompted alternative methods for driver detection, including finding groups of mutually exclusive mutations and incorporating prior biological knowledge about gene function or network structure. Dependencies among drivers due to epistatic interactions can also result in low mutation frequencies, but this effect has been ignored in driver detection so far. Here, we present a new computational approach for identifying genomic alterations that occur at low frequencies because they depend on other events. Unlike passengers, these constrained mutations display punctuated patterns of occurrence in time. We test this driver–passenger discrimination approach based on mutation timing in extensive simulation studies, and we apply it to cross-sectional copy number alteration (CNA) data from ovarian cancer, CNA and single-nucleotide variant (SNV) data from breast tumors and SNV data from colorectal cancer. Among the top ranked predicted drivers, we find low-frequency genes that have already been shown to be involved in carcinogenesis, as well as many new candidate drivers. The mutation timing approach is orthogonal and complementary to existing driver prediction methods. It will help identifying from cancer genome data the alterations that drive tumor progression. PMID:25569148

  15. A novel CYBB mutation with the first genetically confirmed case of ...

    African Journals Online (AJOL)

    A case of a child with chronic granulomatous disease (CGD) presenting with recurrent mycobacterial infections and invasive Aspergillus fumigatus disease is described. Genetic analysis confirmed X-linked CGD with a novel mutation in exon 10 of the CYBB gene – the first South African report of genetically confirmed CGD.

  16. A novel MEFV gene mutation (A511V) in a Chilean FMF patient ...

    African Journals Online (AJOL)

    Familial Mediterranean fever (FMF) is an autosomal recessive disease which is characterized by recurrent fever and inflammation of serous membranes. A Chilean FMF patient was investigated for MEFV mutations. After DNA extraction, exons 3, 5, 10 and 30UTR region of MEFV gene were analyzed by DNA sequencing ...

  17. Identification of a novel STAT3 mutation in a patient with hyper-IgE syndrome

    DEFF Research Database (Denmark)

    Mogensen, Trine H; Jakobsen, Marianne; Larsen, Carsten S

    2013-01-01

    Here we describe a patient with hyper-IgE syndrome presenting with recurrent staphylococcal abscesses, pneumonia, and chronic mucocutaneous candidiasis, and report the identification of a novel STAT3 mutation at amino acid position 621, which has not previously been described. In addition, we...

  18. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Strefford, J C; Sutton, L-A; Baliakas, P

    2013-01-01

    Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B...

  19. NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina

    NARCIS (Netherlands)

    Segarra, Nuria Garcia; Ballhausen, Diana; Crawford, Heather; Perreau, Matthieu; Campos-Xavier, Belinda; van Spaendonck-Zwarts, Karin; Vermeer, Cees; Russo, Michel; Zambelli, Pierre-Yves; Stevenson, Brian; Royer-Bertrand, Beryl; Rivolta, Carlo; Candotti, Fabio; Unger, Sheila; Munier, Francis L.; Superti-Furga, Andrea; Bonafé, Luisa

    2015-01-01

    We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting,

  20. Sperm DNA fragmentation, recurrent implantation failure and recurrent miscarriage

    Directory of Open Access Journals (Sweden)

    Carol Coughlan

    2015-01-01

    Full Text Available Evidence is increasing that the integrity of sperm DNA may also be related to implantation failure and recurrent miscarriage (RM. To investigate this, the sperm DNA fragmentation in partners of 35 women with recurrent implantation failure (RIF following in vitro fertilization, 16 women diagnosed with RM and seven recent fathers (control were examined. Sperm were examined pre- and post-density centrifugation by the sperm chromatin dispersion (SCD test and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay. There were no significant differences in the age of either partner or sperm concentration, motility or morphology between three groups. Moreover, there were no obvious differences in sperm DNA fragmentation measured by either test. However, whilst on average sperm DNA fragmentation in all groups was statistically lower in prepared sperm when measured by the SCD test, this was not seen with the results from the TUNEL assay. These results do not support the hypothesis that sperm DNA fragmentation is an important cause of RIF or RM, or that sperm DNA integrity testing has value in such patients. It also highlights significant differences between test methodologies and sperm preparation methods in interpreting the data from sperm DNA fragmentation tests.

  1. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

    Science.gov (United States)

    McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

    2016-10-18

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

  2. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

    Science.gov (United States)

    McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

    2016-01-01

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

  3. Prediction of recurrent venous thromboembolism by clot lysis time: a prospective cohort study.

    Science.gov (United States)

    Traby, Ludwig; Kollars, Marietta; Eischer, Lisbeth; Eichinger, Sabine; Kyrle, Paul A

    2012-01-01

    Venous thromboembolism (VTE) is a chronic disease, which tends to recur. Whether an abnormal fibrinolytic system is associated with an increased risk of VTE is unclear. We assessed the relationship between fibrinolytic capacity (reflected by clot lysis time [CLT]) and risk of recurrent VTE. We followed 704 patients (378 women; mean age 48 yrs) with a first unprovoked VTE for an average of 46 months after anticoagulation withdrawal. Patients with natural coagulation inhibitor deficiency, lupus anticoagulant, cancer, homozygosity for factor V Leiden or prothrombin mutation, or requirement for indefinite anticoagulation were excluded. Study endpoint was symptomatic recurrent VTE. For measurement of CLT, a tissue factor-induced clot was lysed by adding tissue-type plasminogen activator. Time between clot formation and lysis was determined by measuring the turbidity. 135 (19%) patients had recurrent VTE. For each increase in CLT of 10 minutes, the crude relative risk (RR) of recurrence was 1.13 (95% CI 1.02-1.25; p = 0.02) and was 1.08 (95% CI 0.98-1.20; p = 0.13) after adjustment for age and sex. For women only, the adjusted RR was 1.14 (95% CI, 0.91-1.42, p = 0.22) for each increase in CLT of 10 minutes. CLT values in the 4(th) quartile of the female patient population, as compared to values in the 1(st) quartile, conferred a risk of recurrence of 3.28 (95% CI, 1.07-10.05; p = 0.04). No association between CLT and recurrence risk was found in men. Hypofibrinolysis as assessed by CLT confers a moderate increase in the risk of recurrent VTE. A weak association between CLT and risk of recurrence was found in women only.

  4. Prediction of recurrent venous thromboembolism by clot lysis time: a prospective cohort study.

    Directory of Open Access Journals (Sweden)

    Ludwig Traby

    Full Text Available Venous thromboembolism (VTE is a chronic disease, which tends to recur. Whether an abnormal fibrinolytic system is associated with an increased risk of VTE is unclear. We assessed the relationship between fibrinolytic capacity (reflected by clot lysis time [CLT] and risk of recurrent VTE. We followed 704 patients (378 women; mean age 48 yrs with a first unprovoked VTE for an average of 46 months after anticoagulation withdrawal. Patients with natural coagulation inhibitor deficiency, lupus anticoagulant, cancer, homozygosity for factor V Leiden or prothrombin mutation, or requirement for indefinite anticoagulation were excluded. Study endpoint was symptomatic recurrent VTE. For measurement of CLT, a tissue factor-induced clot was lysed by adding tissue-type plasminogen activator. Time between clot formation and lysis was determined by measuring the turbidity. 135 (19% patients had recurrent VTE. For each increase in CLT of 10 minutes, the crude relative risk (RR of recurrence was 1.13 (95% CI 1.02-1.25; p = 0.02 and was 1.08 (95% CI 0.98-1.20; p = 0.13 after adjustment for age and sex. For women only, the adjusted RR was 1.14 (95% CI, 0.91-1.42, p = 0.22 for each increase in CLT of 10 minutes. CLT values in the 4(th quartile of the female patient population, as compared to values in the 1(st quartile, conferred a risk of recurrence of 3.28 (95% CI, 1.07-10.05; p = 0.04. No association between CLT and recurrence risk was found in men. Hypofibrinolysis as assessed by CLT confers a moderate increase in the risk of recurrent VTE. A weak association between CLT and risk of recurrence was found in women only.

  5. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  6. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  7. [Recurrent herpes zoster with neuralgia].

    Science.gov (United States)

    Schwickert, Myriam; Saha, Joyonto

    2006-06-01

    We present the case of a 40-year-old female patient suffering from recurrent herpes zoster and postherpetic neuralgia. Herpes zoster has recurred several times per year for more than 15 years. At admission, rash localised on the right sacral region and accompanied by neuralgia had lasted for 3 months. Standard out-patient treatment remained unsuccessful. A multimodal integrative therapy regimen including fasting, hydrotherapy, leech application and treatment with autologous blood led to rapid healing of herpetic lesions and persistent pain relief. The case is discussed.

  8. Recurrent intussusception in children and infants

    Directory of Open Access Journals (Sweden)

    Amine Ksia

    2013-01-01

    Full Text Available Background: Recurrent intussusceptions in child and infants are problematic and there are controversies about its management. The aim of this study is to determine the details of the clinical diagnosis of recurrent intussusception and to determine the aetiology of recurrent intussusceptions. Patients and Methods: It′s a retrospective study of 28 cases of recurrent intussusception treated in the paediatric surgery department of Monastir (Tunisia between January 1998 and December 2011. Results: During the study period, 505 patients were treated for 544 episodes of intussusception; there were 39 episodes of recurrent intussusceptions in 28 patients; the rate of patients with recurrence was 5.5%. With comparison to the initial episode, clinical features were similar to the recurrent episode, except bloody stool that was absent in the recurrent group (P = 0,016. Only one patient had a pathologic local point. Conclusion: In recurrent intussusception, patients are less symptomatic and consult quickly. Systematic surgical exploration is not needed as recurrent intussusceptions are easily reduced by air or hydrostatic enema and are not associated with a high rate of pathologic leading points.

  9. PEDIATRIC ACUTE RECURRENT AND CHRONIC PANCREATITIS: LESSONS FROM INSPPIRE

    Science.gov (United States)

    Kumar, Soma; Ooi, Chee Y.; Werlin, Steven; Abu-El-Haija, Maisam; Barth, Bradley; Bellin, Melena D.; Durie, Peter R.; Fishman, Douglas S.; Freedman, Steven D.; Gariepy, Cheryl; Giefer, Matthew J.; Gonska, Tanja; Heyman, Melvin B.; Himes, Ryan; Husain, Sohail Z.; Lin, Tom K.; Lowe, Mark E.; Morinville, Veronique; Palermo, Joseph J.; Pohl, John F.; Schwarzenberg, Sarah Jane; Troendle, David; Wilschanski, Michael; Zimmerman, M. Bridget; Uc, Aliye

    2017-01-01

    Importance Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood. Objective To characterize and identify risk factors associated with ARP and CP in childhood. Design A multinational cross-sectional study of children with ARP or CP at the time of enrollment to INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a CuRE) study. Setting Participant institutions of the INSPPIRE Consortium. Participants From September 2012 to February 2015, 155 children with ARP and 146 with CP (≤ 19 years of age) were enrolled. Their demographic and clinical information were entered into the REDCap database at fifteen centers. Interventions None. Main Outcomes and Measures A cross-sectional study of the cohort was performed to assess demographics, risk factors, abdominal pain and disease burden. Differences were analyzed using two-sample t-test or Wilcoxon-rank sum test for the continuous variables, and Pearson Chi-square or Fisher’s exact test for categorical variables. Disease burden variables (pain variables, hospital/ER visits, missed school days) were compared using Wilcoxon rank-sum test. Results The majority of children with CP reported prior recurrent episodes of acute pancreatitis. Gender distribution was similar between the groups. ARP was more common in Hispanics, CP in non-Hispanics. Forty-eight percent of patients with ARP versus 73% of patients with CP had at least one gene mutation in pancreatitis-related genes (p=0.0002). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (ptoxic/metabolic risk factors (~20% of patients) did not differ between children with ARP or CP. Pancreatitis-related abdominal pain was a major complaint in 81% of children with ARP or CP within the last year. The disease burden was higher in CP compared with ARP (more ER visits, hospitalizations, missed school days, medical, endoscopic and surgical interventions). Conclusions and

  10. Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

    DEFF Research Database (Denmark)

    Rafiq, Jabin; Duno, Morten; Østergaard, Elsebet

    2016-01-01

    The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated...... myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR...... myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA....

  11. [CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases].

    Science.gov (United States)

    Mamedova, E O; Mokrysheva, N G; Pigarova, E A; Przhiyalkovskaya, E G; Voronkova, I A; Vasilyev, E V; Petrov, V M; Gorbunova, V A; Rozhinskaya, L Ya; Belaya, Zh E; Tyulpakov, A N

    The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

  12. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia.

    Science.gov (United States)

    Shiba, Norio; Yoshida, Kenichi; Shiraishi, Yuichi; Okuno, Yusuke; Yamato, Genki; Hara, Yusuke; Nagata, Yasunobu; Chiba, Kenichi; Tanaka, Hiroko; Terui, Kiminori; Kato, Motohiro; Park, Myoung-Ja; Ohki, Kentaro; Shimada, Akira; Takita, Junko; Tomizawa, Daisuke; Kudo, Kazuko; Arakawa, Hirokazu; Adachi, Souichi; Taga, Takashi; Tawa, Akio; Ito, Etsuro; Horibe, Keizo; Sanada, Masashi; Miyano, Satoru; Ogawa, Seishi; Hayashi, Yasuhide

    2016-11-01

    Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence. © 2016 John Wiley & Sons Ltd.

  13. Genetic Analysis of Japanese Children With Acute Recurrent and Chronic Pancreatitis.

    Science.gov (United States)

    Saito, Nobutomo; Suzuki, Mitsuyoshi; Sakurai, Yumiko; Nakano, Satoshi; Naritaka, Nakayuki; Minowa, Kei; Sai, Jin K; Shimizu, Toshiaki

    2016-10-01

    Causes of acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) are sometimes difficult to determine in children. In such patients, genetic analysis may prove helpful. The present study analyzed mutations of cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsin C (CTRC), and carboxypeptidase A1 (CPA1) and investigated the clinical features of children with these mutations. Genetic analyses of mutations in these 4 genes were conducted in 128 patients with ARP or CP. Characteristics of the patients showing mutations were investigated using medical records. Fifty of the 128 (39.1%) subjects had at least 1 mutation (median age at onset, 7.6 years). Abdominal pain was the presenting symptom of pancreatitis in 48 of the 50 patients (96%). Fifteen of those 50 patients (30.0%) had a family history of pancreatitis. Gene mutations were present in PRSS1 in 26 patients, SPINK1 in 23, CTRC in 3, and CPA1 in 5. In the 31 patients with mutations in SPINK1, CTRC, or CPA1, 16 (51.6%) had homozygous or heterozygous mutations with other mutations. Three patients underwent surgery and another 4 patients underwent endoscopy to manage ARP or CP. Although 3 of the 7 patients complained of mild abdominal pain, none of those 7 patients experienced any obvious episode of ARP after treatment. In pediatric patients with idiopathic ARP and CP, genetic analysis is useful for identifying the cause of pancreatitis. Early endoscopic or surgical treatment prevents ARP by extending the interval between episodes of pancreatitis in this population.

  14. Mutation, somatic mutation and diseases of man

    International Nuclear Information System (INIS)

    Burnet, F.M.

    1976-01-01

    The relevance of the intrinsic mutagenesis for the evolution process, genetic diseases and the process of aging is exemplified. The fundamental reaction is the function of the DNA and the DNA-enzymes like the DNA-polymerases in replication, repair, and transcription. These defects are responsible for the mutation frequency and the genetic drift in the evolution process. They cause genetic diseases like Xeroderma pigmentosum which is described here in detail. The accumulation of structural and functional mistakes leads to diseases of old age, for example to autoimmune diseases and immune suppression. There is a proportionality between the duration of life and the frequency of mistakes in the enzymatic repair system. No possibility of prophylaxis or therapy is seen. Methods for prognosis could be developed. (AJ) [de

  15. Recurrent vaginal discharge in children.

    Science.gov (United States)

    McGreal, Sharon; Wood, Paul

    2013-08-01

    Childhood vaginal discharge remains a frequent reason for referral from primary to secondary care. The Pediatric and Adolescent Gynecology (PAG) service at Kettering General Hospital was established in 1993 and provides a specialized service that meets the needs of children with gynaecological conditions. To investigate recurrent vaginal discharge noting symptomatology, defining pathogens, common and rarer causes, exploring management regimes, and any changes in practice over time. Retrospective review spanning 15 years identifying prepubertal children attending the outpatient PAG clinic with recurrent vaginal discharge. We reviewed the medical notes individually. 110 patients were identified; 85% were referred from primary care. The age distribution was bimodal at four and eight years. Thirty-five percent of our patients were discharged after the initial consultation. The commonest cause of discharge was vulvovaginitis (82%). Other important causes included suspected sexual abuse (5%), foreign body (3%), labial adhesions (3%), vaginal agenesis (2%). 35% of patients were admitted for vaginoscopy. Vaginal discharge is the most common gynecological symptom in prepubertal girls and can cause repeated clinical episodes. Vulvovaginitis is the most common cause and often responds to simple hygiene measures. Awareness of the less common causes of vaginal discharge is essential. Copyright © 2013 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  16. Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor

    Science.gov (United States)

    2018-03-07

    EGFR Exon 19 Deletion Mutation; EGFR Exon 20 Insertion Mutation; EGFR NP_005219.2:p.G719X; EGFR NP_005219.2:p.L858R; EGFR NP_005219.2:p.L861Q; EGFR NP_005219.2:p.T790M; EGFR T790M Mutation Negative; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7

  17. Mutations and chromosomal aberrations

    International Nuclear Information System (INIS)

    Kihlman, B.A.

    1977-01-01

    The genetic changes of mutations and chromosomal aberrations are discussed. The consequences of both depend not only on the type of genetic change produced but also on the type of cell that is affected and on the development stage of the organism. (C.F.)

  18. Mutations in GABRB3

    DEFF Research Database (Denmark)

    Møller, Rikke S; Wuttke, Thomas V; Helbig, Ingo

    2017-01-01

    OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing ...

  19. BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma

    International Nuclear Information System (INIS)

    Henke, Lauren E; Pfeifer, John D; Ma, Changquing; Perkins, Stephanie M; DeWees, Todd; El-Mofty, Samir; Moley, Jeffrey F; Nussenbaum, Brian; Haughey, Bruce H; Baranski, Thomas J; Schwarz, Julie K; Grigsby, Perry W

    2015-01-01

    The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1–2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1–2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1–2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan–Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy

  20. Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease.

    Science.gov (United States)

    Faucz, Fabio R; Tirosh, Amit; Tatsi, Christina; Berthon, Annabel; Hernández-Ramírez, Laura C; Settas, Nikolaos; Angelousi, Anna; Correa, Ricardo; Papadakis, Georgios Z; Chittiboina, Prashant; Quezado, Martha; Pankratz, Nathan; Lane, John; Dimopoulos, Aggeliki; Mills, James L; Lodish, Maya; Stratakis, Constantine A

    2017-08-01

    Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options. Copyright © 2017 Endocrine Society

  1. Recurrence plots of exchange rates of currencies

    OpenAIRE

    Sparavigna, Amelia Carolina

    2014-01-01

    Used to investigate the presence of distinctive recurrent behaviours in natural processes, the recurrence plots can be applied to the analysis of economic data, and, in particular, to the characterization of exchange rates of currencies too. In this paper, we will show that these plots are able to characterize the periods of oscillation and random walk of currencies and enhance their reply to news and events, by means of texture transitions. The examples of recurrence plots given here are obt...

  2. Recurrence of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Watanabe, Toshikazu; Kiyono, Kunihiro; Niibe, Hideo; Horiuchi, Junichi; Kaneta, Koichi; Morita, Kozo; Masaki, Norie; Hayabuchi, Naofumi.

    1988-01-01

    563 patients with Stage I and II non-Hodgkin's lymphoma were treated by radiotherapy. 34 recurrences that occured after 3 years from initial treatment were seen in those patients. 15 (44 %) of 34 recurrences occured after 5 years. 20 patients (59 %) had remission by re-treatment, and 13 (38 %) survived more than 2 years. 20 (59 %) of recurrences were seen on head and neck lesions and superficial lymph nodes. (author)

  3. Equivalence of Equilibrium Propagation and Recurrent Backpropagation

    OpenAIRE

    Scellier, Benjamin; Bengio, Yoshua

    2017-01-01

    Recurrent Backpropagation and Equilibrium Propagation are algorithms for fixed point recurrent neural networks which differ in their second phase. In the first phase, both algorithms converge to a fixed point which corresponds to the configuration where the prediction is made. In the second phase, Recurrent Backpropagation computes error derivatives whereas Equilibrium Propagation relaxes to another nearby fixed point. In this work we establish a close connection between these two algorithms....

  4. Recurrent, giant subcutaneous leiomyosarcoma of the thigh

    Directory of Open Access Journals (Sweden)

    Gao Chuanping, MD

    2015-10-01

    Full Text Available We present a case of recurrent, massive subcutaneous leiomyosarcoma involving the left thigh in a 29-year-old male from Madagascar. The patient had earlier undergone local resection of subcutaneous leiomyosarcoma a half year before. After surgical intervention, local recurrence developed at this site and was rapidly growing. The patient was surgically treated with a 2-cm-wide margin local excision in our hospital. The patient has remained recurrence free at 1-year follow-up.

  5. Radiotherapy in Locoregional Recurrent Breast Carcinoma

    International Nuclear Information System (INIS)

    Ha, Sung Whan; Yang, Mi Gyoung; Chung, Woong Ki; Park, Charn Il; Bang, Yung Jue; Kim, Noe Kyung; Choe, Kuk Jin

    1988-01-01

    Thirty eight women with recurrent breast carcinoma involving chest wall and/or regional lymph nodes after surgery with or without systemic therapy were treated with radiation between 1979 and 1986. Among them, 5 patients were excluded from analysis because of incomplete treatment. The median follow up of survivors was 30 months (ranged 1-79 months). Fifteen (45%) patients had their disease confined to the chest wall and eighteen patients had lymph node involvement as some of their locoregional recurrent disease. Within 36 months after the initial treatment, 87% of recurrences manifested themselves. All patients had radiotherapy to at least the site of involvement. In 8 patients, recurrent tumors were treated with complete excision followed by radiation. Of the remaining 25 patients, 18(72%) had complete response (CR) following radiotherapy. The actuarial 3-year survival of all patients following locoregional recurrence was 50%. Three year survival was 24% in those 25 patients who had recurrences within 24 months of the initial treatment. For those 8 patients whose recurrences occurred after more than 24 month disease free interval, the 3-year survival was 100%. For those patients with recurrences confined to chest wall alone, 3-year survival was 57%. The patients who had lymph node involvement as part of their locoregional recurrences had a 43% 3-year survival. The majority of them developed distant metastases. Those patients who had a CR showed 63% 3-year survival. On the other hand, 1 year survival was only 33% for those patients who had a less than CR. Three patients developed carcinoma of the contralateral breast following radiotherapy. Three year survival following locoregional recurrence was 40% for patients whose initial treatment for their primary breast carcinoma was surgery and adjuvant systemic therapy. For those patients whose primary breast carcinoma was treated by surgery alone, the 3-year survival following locoregional recurrence was 71%. In

  6. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)

    1995-10-01

    This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

  7. Mutation breeding newsletter. No. 45

    International Nuclear Information System (INIS)

    2001-07-01

    This issue of the Mutation Breeding newsletter contains 39 articles dealing with radiation induced mutations and chemical mutagenesis techniques in plant breeding programs with the aims of improving crop productivity and disease resistance as well as exploring genetic variabilities

  8. Mutation breeding newsletter. No. 33

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-01-01

    This issue of the newsletter reports a number of research news and research abstracts on application of radiation induced mutation techniques to increase mutagenesis and mutation frequency in plant breeding projects.

  9. Mutation breeding newsletter. No. 33

    International Nuclear Information System (INIS)

    1989-01-01

    This issue of the newsletter reports a number of research news and research abstracts on application of radiation induced mutation techniques to increase mutagenesis and mutation frequency in plant breeding projects

  10. Genomic instability--an evolving hallmark of cancer.

    Science.gov (United States)

    Negrini, Simona; Gorgoulis, Vassilis G; Halazonetis, Thanos D

    2010-03-01

    Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

  11. Recurrent and multiple bladder tumors show conserved expression profiles

    International Nuclear Information System (INIS)

    Lindgren, David; Fioretos, Thoas; Månsson, Wiking; Höglund, Mattias; Gudjonsson, Sigurdur; Jee, Kowan Ja; Liedberg, Fredrik; Aits, Sonja; Andersson, Anna; Chebil, Gunilla; Borg, Åke; Knuutila, Sakari

    2008-01-01

    Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin. However, the genetic relationship among consecutive tumors has been shown to be complex in as much as the genetic evolution does not adhere to the chronological appearance of the metachronous tumors. Consequently, genetically less evolved tumors may appear chronologically later than genetically related but more evolved tumors. Forty-nine meta- or synchronous urothelial tumors from 22 patients were analyzed using expression profiling, conventional CGH, LOH, and mutation analyses. We show by CGH that partial chromosomal losses in the initial tumors may not be present in the recurring tumors, by LOH that different haplotypes may be lost and that detected regions of LOH may be smaller in recurring tumors, and that mutations present in the initial tumor may not be present in the recurring ones. In contrast we show that despite apparent genomic differences, the recurrent and multiple bladder tumors from the same patients display remarkably similar expression profiles. Our findings show that even though the vast majority of the analyzed meta- and synchronous tumors from the same patients are not likely to have originated directly from the preceding tumor they still show remarkably similar expressions profiles. The presented data suggests that an expression profile is established early in tumor development and that this profile is stable and maintained in recurring tumors

  12. Recurrent odontogenic keratocyst within the masticatory space

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Su Yeon; Huh, Kyung Hoe; Yi, Won Jin; Choi, Hyun Bae; Choi, Soon Chul [School of Dentistry, Seoul National University, Seoul (Korea, Republic of)

    2008-06-15

    The odontogenic keratocyst (OKC) is a developmental odontogenic cyst typically occurring in the jaws. Since the first description of OKC was published in 1956, the lesion has been of particular interest because of its specific histopathologic features, high recurrence rate, and aggressive behavior. Recurrences most commonly arise within bone at the site of the original cyst. However, as lining cells may find their way into surrounding tissues either from implantation during surgery or from cortical perforation recurrences may arise at a distance from the original cyst. Here, we report a rare case of recurrent OKC which was first developed in mandible and recurred within the masticatory space.

  13. Recurrent odontogenic keratocyst within the masticatory space

    International Nuclear Information System (INIS)

    Lim, Su Yeon; Huh, Kyung Hoe; Yi, Won Jin; Choi, Hyun Bae; Choi, Soon Chul

    2008-01-01

    The odontogenic keratocyst (OKC) is a developmental odontogenic cyst typically occurring in the jaws. Since the first description of OKC was published in 1956, the lesion has been of particular interest because of its specific histopathologic features, high recurrence rate, and aggressive behavior. Recurrences most commonly arise within bone at the site of the original cyst. However, as lining cells may find their way into surrounding tissues either from implantation during surgery or from cortical perforation recurrences may arise at a distance from the original cyst. Here, we report a rare case of recurrent OKC which was first developed in mandible and recurred within the masticatory space.

  14. Recurrence and Relapse in Bipolar Mood Disorder

    Directory of Open Access Journals (Sweden)

    S Gh Mousavi

    2004-06-01

    Full Text Available Background: Despite the effectiveness of pharmacotherapy in acute phase of bipolar mood disorder, patients often experience relapses or recurrent episodes. Hospitalization of patients need a great deal of financial and humanistic resources which can be saved through understanding more about the rate of relapse and factors affecting this rate. Methods: In a descriptive analytical study, 380 patients with bipolar disorder who were hospitalized in psychiatric emergency ward of Noor hospital, Isfahan, Iran, were followed. Each patient was considered for; the frequency of relapse and recurrence, kind of pharmachotherapy, presence of psychotherapeutic treatments, frequency of visits by psychiatrist and the rank of present episode. Results: The overall prevalence of recurrence was 42.2%. Recurrence was lower in patients using lithium carbonate or sodium valproate or combined therapy (about 40%, compared to those using carbamazepine (80%. Recurrence was higher in patients treated with only pharmacotherapy (44.5% compared to those treated with both pharmacotherapy and psychotherapy (22.2%. Patients who were visited monthy by psychiatrist had lower rate of recurrence compared to those who had irregular visits. Conclusion: The higher rate of recurrence observed in carbamazepine therapy may be due to its adverse reactions and consequently poor compliance to this drug. Lower rates of recurrence with psychotherapy and regular visits may be related to the preventive effects of these procedures and especially to the effective management of stress. Keywords: Bipolar Mood Disorder, Recurrence, Relapse.

  15. Generalised recurrence plot analysis for spatial data

    International Nuclear Information System (INIS)

    Marwan, Norbert; Kurths, Juergen; Saparin, Peter

    2007-01-01

    Recurrence plot based methods are highly efficient and widely accepted tools for the investigation of time series or one-dimensional data. We present an extension of the recurrence plots and their quantifications in order to study recurrent structures in higher-dimensional spatial data. The capability of this extension is illustrated on prototypical 2D models. Next, the tested and proved approach is applied to assess the bone structure from CT images of human proximal tibia. We find that the spatial structures in trabecular bone become more recurrent during the bone loss in osteoporosis

  16. Radiotherapy of Recurrent Uterine Cervical Cancer

    International Nuclear Information System (INIS)

    Ha, Sung Whan; Park, Charn Il; Chai, Kyu Young; Kang, Soon Beom; Lee, Hyo Pyo; Shin, Myon Woo

    1987-01-01

    Forty seven patients with locally recurrent uterine cerival cancer after surgery were treated with radiation during the 6 year period from 1979 through 1984 at the Department of Therapeutic Radiology of Seoul National University Hospital. In 30 out of the 47 patients, recurrence was diagnosed within 2 years after surgery. Site of recurrence was vagina in 19 patients, vagina and parametrium in 21 patients and parametrium only in 7 patients. Complete tumor control was achieved in 35 patients (74.5%) ; the complete response rates were 94.7% (18/19( in vaginal recurrences, 57.1% (12/21) in combined vaginal and parametrial recurrences and 71.4% (5/7) in parametrial recurrences. Overall and disease free survival rates at 4 years were 55.2 and 50.1 percent, respectively, for entire group. Overall 4 year survival rates were 77.0% for vaginal recurrences, 44.1% for vaginal and parametrial recurrences and 42.9% for parametrial recurrences. When the disease extent was classified in the same way as the staging system of FIGO, the 4 year survival was 80.4, 73.0, 25.0 and 0 percent for stage IIa, IIb and IVa, respectively

  17. Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

    Science.gov (United States)

    2017-09-27

    Childhood Choroid Plexus Tumor; Childhood Ependymoblastoma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

  18. The allele-frequency spectrum in a decoupled Moran model with mutation, drift, and directional selection, assuming small mutation rates.

    Science.gov (United States)

    Vogl, Claus; Clemente, Florian

    2012-05-01

    We analyze a decoupled Moran model with haploid population size N, a biallelic locus under mutation and drift with scaled forward and backward mutation rates θ(1)=μ(1)N and θ(0)=μ(0)N, and directional selection with scaled strength γ=sN. With small scaled mutation rates θ(0) and θ(1), which is appropriate for single nucleotide polymorphism data in highly recombining regions, we derive a simple approximate equilibrium distribution for polymorphic alleles with a constant of proportionality. We also put forth an even simpler model, where all mutations originate from monomorphic states. Using this model we derive the sojourn times, conditional on the ancestral and fixed allele, and under equilibrium the distributions of fixed and polymorphic alleles and fixation rates. Furthermore, we also derive the distribution of small samples in the diffusion limit and provide convenient recurrence relations for calculating this distribution. This enables us to give formulas analogous to the Ewens-Watterson estimator of θ for biased mutation rates and selection. We apply this theory to a polymorphism dataset of fourfold degenerate sites in Drosophila melanogaster. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. BRCA1 and BRCA2 Germline Mutations in Asian and European Populations

    Directory of Open Access Journals (Sweden)

    Ute Hamann

    2017-02-01

    Full Text Available Women who carry a pathogenic mutation in the breast cancer susceptibility genes BRCA1 or BRCA2 (BRCA have markedly increased risks of developing breast and ovarian cancers during their lifetime. It has been estimated that their breast and ovarian cancer risks are in the range of 46-87% and 15-68%, respectively. Therefore it is of utmost clinical importance to identify BRCA mutation carriers in order to target unaffected women for prevention and/or close surveillance and to help affected women choose the best chemotherapy regimen. Genetic testing for BRCA germline mutations is expanding in clinical oncology centers worldwide. Given the high costs of complete BRCA gene screens, a lot of effort has been expended on deciding upon whom to test. Relevant issues involved in decision making include the prior probability of a woman having a BRCA mutation, which is a function of her age and her disease status, her ethnic group, and her family history of breast or ovarian cancer. The frequency and spectrum of mutations in these genes show considerable variation by ethnic groups and by geographic regions. Most studies have been conducted in European and North American populations, while studies in Asian, Hispanic, and African populations are fewer. In most populations, many BRCA mutations were identified, which were distributed all over the genes. However, in some populations, a relatively small number of specific BRCA mutations are recurrent and account for the majority of all mutations in that population. Many of the recurrent mutations are founder mutations, which were derived from a common ancestor. Founder mutations are present in Ashkenazi Jewish, European, and Islander (Faroe, Easter, and Pitcairn populations. Such mutations have also been identified in patients from several Asian, South American, and African countries. Population-specific genetic risk assessment and genetic mutation screening have been facilitated at low costs. Given that mutations

  20. Novel Calmodulin (CALM2) Mutations Associated with Congenital Arrhythmia Susceptibility

    Science.gov (United States)

    Makita, Naomasa; Yagihara, Nobue; Crotti, Lia; Johnson, Christopher N.; Beckmann, Britt-Maria; Roh, Michelle S.; Shigemizu, Daichi; Lichtner, Peter; Ishikawa, Taisuke; Aiba, Takeshi; Homfray, Tessa; Behr, Elijah R.; Klug, Didier; Denjoy, Isabelle; Mastantuono, Elisa; Theisen, Daniel; Tsunoda, Tatsuhiko; Satake, Wataru; Toda, Tatsushi; Nakagawa, Hidewaki; Tsuji, Yukiomi; Tsuchiya, Takeshi; Yamamoto, Hirokazu; Miyamoto, Yoshihiro; Endo, Naoto; Kimura, Akinori; Ozaki, Kouichi; Motomura, Hideki; Suda, Kenji; Tanaka, Toshihiro; Schwartz, Peter J.; Meitinger, Thomas; Kääb, Stefan; Guicheney, Pascale; Shimizu, Wataru; Bhuiyan, Zahurul A.; Watanabe, Hiroshi; Chazin, Walter J.; George, Alfred L.

    2014-01-01

    Background Genetic predisposition to life-threatening cardiac arrhythmias such as in congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. Methods and Results We employed conventional and next-generation sequencing approaches including exome analysis in genotype-negative LQTS probands. We identified five novel de novo missense mutations in CALM2 in three subjects with LQTS (p.N98S, p.N98I, p.D134H) and two subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1–9 years. Three of five probands had cardiac arrest and one of these subjects did not survive. Although all probands had LQTS, two subjects also exhibited electrocardiographic features consistent with CPVT. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of five probands responded to β-blocker therapy whereas one subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within calcium binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced calcium binding affinity. Conclusions CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT. PMID:24917665

  1. A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection

    Directory of Open Access Journals (Sweden)

    Johanna Rhodes

    2017-04-01

    Full Text Available Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.

  2. Orbital periods of recurrent novae

    International Nuclear Information System (INIS)

    Schaefer, B.E.

    1990-01-01

    The class of recurrent novae (RN) with thermonuclear runaways contains only three systems (T Pyx, U Sco, and V394 CrA), for which no orbital periods are known. This paper presents a series of photometric observations where the orbital periods for all three systems are discovered. T Pyx is found to have sinusoidal modulation with an amplitude of 0.08 mag and a period of 2.3783 h (with a possible alias of 2.6403 h). U Sco is found to be an eclipsing system with an eclipse amplitude of roughly 1.5 mag and an orbital period of 1.2344 days. V394 CrA is found to have sinusoidal modulation with an amplitude of 0.5 mag and a period of 0.7577 days. Thus two out of three RN with thermonuclear runaways (or five out of six for all RN) have evolved companions. 16 refs

  3. Recurrent Priapism from Therapeutic Quetiapine

    Directory of Open Access Journals (Sweden)

    Omeed Saghafi

    2014-02-01

    Full Text Available Priapism is rarely related to use of non-erectile related medications. The objective was to educate about the multiple possible causes of priapism and to provide treatment recommendations for the different types of priapism. We present the case of a 43 year-old African American male with a history of schizoaffective disorder who presented to our emergency department multiple times over a three year period with priapism, each episode related to the ingestion of quetiapine. Following penile aspiration and intercavernosal injection of phenylephrine, this patient had resolution of his priapism. This case demonstrates an unusual case of recurrent priapism. [West J Emerg Med. 2014;15(1:114–116.

  4. Chronic recurrent multifocal osteomyelitis (CRMO)

    International Nuclear Information System (INIS)

    Schilling, F.

    1998-01-01

    Chronic recurrent multifocal osteomyelitis (CRMO) is an unusual clinical entity. More than 200 cases are described in the literature and it is presented here with special reference to its radiological aspects. It is an acquired disease of the skeleton which occurs predominantly during childhood and adolescence. About ten per cent of cases begin in early or, rarely, in later adult life. This variant is described here for the first time and is discussed as 'adult CRMO'. The underlying pathology is a bland, predominantly lympho-plasma cellular osteomyelitis which is self-limiting and leads to bone sclerosis (Garre). It probably involves an abnormal immune process which follows an infection but remains clinically latent and remains aseptic and sterile. In a quarter of cases there is an association with pustulosis palmo-plantaris and its relationship with psoriatic arthropathy is discussed. The clinical, histopathological and imaging features (radiological and particularly MRT) and the bone changes are described. (orig./AJ) [de

  5. Recurrent Primary Spinal Hydatid Cyst

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    Okan Turk

    2015-03-01

    Full Text Available Primary hydatid disease of spine is rare and spinal hydatitosis constitute only 1% of all hydatitosis. We report a case of recurrent primary intraspinal extradural hydatid cyst of the thoracic region causing progressive paraparesis. The patient was operated 16 years ago for primary spinal hydatid disease involvement and was instrumented dorsally for stabilization. The magnetic resonance imaging (MRI of thoracic spine showed a cystic lesion at T11-12 level and compressed spinal cord posterolaterally. Intraspinal cyst was excised through T11-12 laminectomy which made formerly. The early postoperative period showed a progressive improvement of his neurological deficit and he was discharged with antihelmintic treatment consisting of albendazole and amoxicillin-sulbactam combination. [Cukurova Med J 2015; 40(Suppl 1: 84-89

  6. Selection problems and objectives in mutation breeding

    International Nuclear Information System (INIS)

    Mac Key, J.

    1984-01-01

    In plant breeding, major genes are preferably handled by inbreeding, back-crosses and selection through the family/pedigree method. Polygenic systems need gene accumulation, i.e. handling in bulk allowing natural/recurrent selection to operate. The two types of genetic control normally occur together irrespective of whether the variation is created by crossing or by mutagenesis. Cross-breeding can conveniently work with both types of variation and offers a range of genetic backgrounds. Problems are the often enormous recombination potential risking the break-down of already accomplished genic constellations or undesirable linkages. Mutation induction implies a scattered mono- to oligo-factorial variation mostly functioning as a negative load. As a result, it will be difficult and unrealistic to try to explore micromutations, as defined by Gaul, in vegetatively propagated and autogamous crop plants. Quantitative analyses have not been able to give guidance since the induced variation includes disturbed vitality and main or side-effects of events that are possible to define as macro-mutations. The possibility of better exhausting the variation induced will mainly depend on the precision in selection techniques, i.e. by dividing complex traits into their components, by improving environmental conditions for selection, and/or by sharpening the screening technique. Contrary to recombination breeding, mutation-induced variation does not fit a plan encompassing overall agronomic traits simultaneously. The progress has to go step by step. Thus, even more than in cross-breeding, it is important that accurately outlined objectives be set. Some characters, such as flower colour, can easily be defined while others, such as yield, may be more interdependent, calling for compromises difficult to foresee. The complexity of the latter category of traits is illustrated by the interaction pattern in relation to grain yield in cereals where both shoot and root are considered

  7. Treatment of locally recurrent rectal cancer

    International Nuclear Information System (INIS)

    Kococik, Z.; Kococik, M.

    2007-01-01

    The suggested classifications of locally recurrent rectal cancer are based on the presence of symptoms and the degree of tumour fixation to the pelvic wall, or, otherwise, account for factor T in the TMN system. Although the results of rectal cancer treatment have improved, which may be attributed to total meso rectal excision and application of perioperative radiotherapy and radiochemotherapy, the ratio of cases of locally recurrent rectal cancer still amount from several to over a dozen percent. Among the available diagnostic methods for detecting locally recurrent rectal cancer after anterior rectal resection, endorectal sonography is of special importance. In the estimation of prognostic factors the lack of vascular invasion in recurrent cancer and the long period between the treatment of primary rectal cancer and the development of recurrence are a sign of good prognosis, while pain prior to recurrence treatment and male sex diminish the chances for cure. Locally recurrent rectal cancer impairs the patient's quality of life in all measurable aspects, but even after complete recovery we observe severe disturbances of sexual activity in most patients, and a number of patients require hygiene pads or suffer from chronic pain. Local recurrence of rectal cancer is more commonly qualified for excision after surgical treatment only, than after preoperative radiotherapy. The probability of total recurrent rectal cancer excision increases when the patient is younger, the primary tumours was less advanced and the first operation was sphincter-sparing surgery. Progress in the surgical treatment of recurrent rectal cancer was brought on by the introduction of the composite musculocutaneous flap to compensate the loss of perineal tissue. The application of intraoperative radiotherapy improves treatment results of recurrent rectal cancer, however at the cost of more frequent, serious postoperative complications and intense pain. In inoperable cases high dose regional

  8. Differential diagnosis of recurrent bronchitis in children

    Directory of Open Access Journals (Sweden)

    I. I. Zakirov

    2016-01-01

    Full Text Available The interest of the doctors — pediatricians to recurrent bronchitis is caused by its high specific weight in the structure of bronchopulmonary pathology in children, the complexity and the need to search the differential selection of an individual regimen and prevention. Recurrent bronchitis with bronchoobstructive syndromes patient is regarded as a predictor of asthma, however, erroneously consider these nosological forms as the stages of a single pathophysiological chain as congenital and acquired diseases of respiratory system, pathology of gastro-intestinal tract, cardio-vascular system can masquerade as recurrent bronchitis. The aim of this work — to analyze the current medical literature on the problem of differential search causes leading recurrent respiratory syndrome in children. Materials and methods. The review publications domestic and foreign authors studied data from clinical and epidemiological studies. Results and its discussion. Anatomical physiological characteristics of the respiratory tract, complicated premorbid background, the re-infection of the child respiratory infection contribute to the recurrent course of bronchitis. The most common recurrent bronchitis is transient, recurrent bronchitis episodes completely stoped with the age of the child. Recurrent respiratory infections can fix bronchial hyperreactivity and with the presence of aggravated allergic history lead to the development of asthma. Severe bronchitis, resistance to standard scheme of therapy, the frequent recurrence of respiratory syndrome dictate the need to expand the diagnostic research to clarify the leading cause of recurrent bronchitis. Conclusion. Recurrent bronchitis is considered as a separate nosological form. At the same time, by repeated episodes of respiratory infection may be masked by malformations, hereditary diseases of respiratory system, bronchus foreign body microaspiration syndrome, pathology of the cardio-vascular system. 

  9. Chemoradiotherapy response in recurrent rectal cancer

    International Nuclear Information System (INIS)

    Yu, Stanley K T; Bhangu, Aneel; Tait, Diana M; Tekkis, Paris; Wotherspoon, Andrew; Brown, Gina

    2014-01-01

    The efficacy of response to preoperative chemoradiotherapy (CRT) in recurrent versus primary rectal cancer has not been investigated. We compared radiological downsizing between primary and recurrent rectal cancers following CRT and determined the optimal size reduction threshold for response validated by survival outcomes. The proportional change in tumor length for primary and recurrent rectal cancers following CRT was compared using the independent sample t-test. Overall survival (OS) was calculated using the Kaplan–Meier product limit method and differences between survival for tumor size reduction thresholds of 30% (response evaluation criteria in solid tumors [RECIST]), 40%, and 50% after CRT in primary and recurrent rectal cancer groups. A total of 385 patients undergoing CRT were analyzed, 99 with recurrent rectal cancer and 286 with primary rectal cancer. The mean proportional reduction in maximum craniocaudal length was significantly higher for primary rectal tumors (33%) compared with recurrent rectal cancer (11%) (P < 0.01). There was no difference in OS for either primary or recurrent rectal cancer when ≤30% or ≤40% definitions were used. However, for both primary and recurrent tumors, significant differences in median 3-year OS were observed when a RECIST cut-off of 50% was used. OS was 99% versus 77% in primary and 100% versus 42% in recurrent rectal cancer (P = 0.002 and P = 0.03, respectively). Only patients that demonstrated >50% size reduction showed a survival benefit. Recurrent rectal cancer appears radioresistant compared with primary tumors for tumor size after CRT. Further investigation into improving/intensifying chemotherapy and radiotherapy for locally recurrent rectal cancer is justified

  10. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA.

    Science.gov (United States)

    Wang, Na; Liu, Tiantian; Sofiadis, Anastasios; Juhlin, C Christofer; Zedenius, Jan; Höög, Anders; Larsson, Catharina; Xu, Dawei

    2014-10-01

    The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis. The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit. The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival. TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup. © 2014 American Cancer Society.

  11. Mutation breeding in pepper

    Energy Technology Data Exchange (ETDEWEB)

    Daskalov, S [Plant Breeding Unit, Joint FAO/IAEA Division of Isotope and Radiation Applications of Atomic Energy for Food and Agricultural Development, Seibersdorf Laboratory, International Atomic Energy Agency, Vienna (Austria)

    1986-03-01

    Pepper (Capsicum sp.) is an important vegetable and spice crop widely grown in tropical as well as in temperate regions. Until recently the improvement programmes were based mainly on using natural sources of germ plasma, crossbreeding and exploiting the heterosis of F{sub 1} hybrids. However, interest in using induced mutations is growing. A great number of agronomically useful mutants as well as mutants valuable for genetic, cytological and physiological studies have been induced and described. In this review information is presented about suitable mutagen treatment procedures with radiation as well as chemicals, M{sub 1} effects, handling the treated material in M{sub 1}, M{sub 2} and subsequent generations, and mutant screening procedures. This is supplemented by a description of reported useful mutants and released cultivars. Finally, general advice is given on when and how to incorporate mutation induction in Capsicum improvement programmes. (author)

  12. Mutation breeding in pepper

    International Nuclear Information System (INIS)

    Daskalov, S.

    1986-01-01

    Pepper (Capsicum sp.) is an important vegetable and spice crop widely grown in tropical as well as in temperate regions. Until recently the improvement programmes were based mainly on using natural sources of germ plasma, crossbreeding and exploiting the heterosis of F 1 hybrids. However, interest in using induced mutations is growing. A great number of agronomically useful mutants as well as mutants valuable for genetic, cytological and physiological studies have been induced and described. In this review information is presented about suitable mutagen treatment procedures with radiation as well as chemicals, M 1 effects, handling the treated material in M 1 , M 2 and subsequent generations, and mutant screening procedures. This is supplemented by a description of reported useful mutants and released cultivars. Finally, general advice is given on when and how to incorporate mutation induction in Capsicum improvement programmes. (author)

  13. Screening of Duchenne muscular dystrophy (DMD mutations and investigating its mutational mechanism in Chinese patients.

    Directory of Open Access Journals (Sweden)

    Chen Chen

    Full Text Available Duchenne muscular dystrophy (DMD is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA and denaturing high performance liquid chromatography (DHPLC followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2% and 81 patients with DMD deletions/duplications (del/dup (68.1%, of which 64 (79.0% were deletions, 16 (19.8% were duplications, and one (1.2% was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot, we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43-55 and exon 10-23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.

  14. PMS2 gene mutation results in DNA mismatch repair system failure in a case of adult granulosa cell tumor

    OpenAIRE

    Wang, Wen-Chung; Lee, Ya-Ting; Lai, Yen-Chein

    2017-01-01

    Background Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable indolent growth with malignant potential and late recurrence. Approximately 95% are of adult type. Recent molecular studies have characterized the FOXL2 402C?>?G mutation in adult granulosa cell tumor. Our previous case report showed that unique FOXL2 402C?>?G mutation and defective DNA mismatch repair system are associated with the development of adult granulosa cell tumor. Findings In...

  15. Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events

    OpenAIRE

    Okolo, Onyemaechi N.; Katsanis, Emmanuel; Yun, Seongseok; Reveles, Candace Y.; Anwer, Faiz

    2017-01-01

    Objective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk o...

  16. A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated With BRAF Mutations

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahmcke, Christina M.; Dahl, Christina

    2015-01-01

    IMPORTANCE: Large studies investigating clinical presentation and treatment in primary conjunctival melanoma (CM) are rare. Clinicopathological characteristics of BRAF-mutated CM have not been studied thoroughly. OBJECTIVES: To determine the associations of clinicopathological tumor features...... and treatment with local recurrence, metastasis, and mortality and to determine the association of BRAF mutations with these features. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study at the Eye Pathology Institute, Copenhagen, Denmark. Participants included 139 patients with primary CM...

  17. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

    OpenAIRE

    Lohr, Jens G.; Stojanov, Petar; Lawrence, Michael S.; Auclair, Daniel; Chapuy, Bjoern; Sougnez, Carrie; Cruz-Gordillo, Peter; Knoechel, Birgit; Asmann, Yan W.; Slager, Susan L.; Novak, Anne J.; Dogan, Ahmet; Ansell, Stephen M.; Link, Brian K.; Zou, Lihua

    2012-01-01

    To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include...

  18. Heterozygous CAV1 frameshift mutations (MIM 601047 in patients with atypical partial lipodystrophy and hypertriglyceridemia

    Directory of Open Access Journals (Sweden)

    Alston Lindsay

    2008-01-01

    Full Text Available Abstract Background Mice with a deleted Cav1 gene encoding caveolin-1 develop adipocyte abnormalities and insulin resistance. From genomic DNA of patients with atypical lipodystrophy and hypertriglyceridemia who had no mutations in any known lipodystrophy gene, we used DNA sequence analysis to screen the coding regions of human CAV1 (MIM 601047. Results We found a heterozygous frameshift mutation in CAV1, designated I134fsdelA-X137, in a female patient who had atypical partial lipodystrophy, with subcutaneous fat loss affecting the upper part of her body and face, but sparing her legs, gluteal region and visceral fat stores. She had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis. In addition, she had some atypical features, including congenital cataracts and neurological findings. Her father was also heterozygous for this mutation, and had a similar pattern of fat redistribution, hypertriglyceridemia and congenital cataracts, with milder neurological involvement. An unrelated patient had a different heterozygous frameshift mutation in the CAV1 gene, designated -88delC. He also had a partial lipodystrophy phenotype, with subcutaneous fat loss affecting the arms, legs and gluteal region, but sparing his face, neck and visceral fat stores. He also had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis; however he had no clinically apparent neurological manifestations. The mutations were absent from the genomes of 1063 healthy individuals. Conclusion Thus, very rare CAV1 frameshift mutations appear to be associated with atypical lipodystrophy and hypertriglyceridemia.

  19. Mutated hilltop inflation revisited

    Science.gov (United States)

    Pal, Barun Kumar

    2018-05-01

    In this work we re-investigate pros and cons of mutated hilltop inflation. Applying Hamilton-Jacobi formalism we solve inflationary dynamics and find that inflation goes on along the {W}_{-1} branch of the Lambert function. Depending on the model parameter mutated hilltop model renders two types of inflationary solutions: one corresponds to small inflaton excursion during observable inflation and the other describes large field inflation. The inflationary observables from curvature perturbation are in tune with the current data for a wide range of the model parameter. The small field branch predicts negligible amount of tensor to scalar ratio r˜ O(10^{-4}), while the large field sector is capable of generating high amplitude for tensor perturbations, r˜ O(10^{-1}). Also, the spectral index is almost independent of the model parameter along with a very small negative amount of scalar running. Finally we find that the mutated hilltop inflation closely resembles the α -attractor class of inflationary models in the limit of α φ ≫ 1.

  20. Mutation breeding in jute

    International Nuclear Information System (INIS)

    Joshua, D.C.

    1980-01-01

    Mutagenic studies in jute in general dealt with the morphological abnormalities of the M 1 generation in great detail. Of late, induction of a wide spectrum of viable mutations have been reported in different varieties of both the species. Mutations affecting several traits of agronomic importance such as, plant height, time of flowering, fibre yield and quality, resistance to pests and diseases are also available. Cytological analysis of a large collection of induced mutants resulted in the isolation of seven trisomics in an olitorius variety. Several anatomical parameters which are the components of fibre yield, have also received attention. Some mutants with completely altered morphology were used for interpreting the evolution of leaf shape in Tiliaceas and related families. A capsularis variety developed using mutation breeding technique has been released for cultivation. Several others, including derivatives of inter-mutant hybridization have been found to perform well at different locations in the All India Coordinated Trials. Presently, chemical mutagenesis and induction of mutants of physiological significance are receiving considerable attention. The induced variability is being used in genetic and linkage studies. (author)

  1. Predictors for Recurrence of Chronic Subdural Hematoma.

    Science.gov (United States)

    Hammer, Alexander; Tregubow, Alexander; Kerry, Ghassan; Schrey, Michael; Hammer, Christian; Steiner, Hans-Herbert

    2017-01-01

    This prospective study was designed to analyze the dependence of different factors on the recurrence rate of chronic subdural hematoma (cSDH) after surgical treatment. Seventy-three consecutive patients, who were surgically treated at our department due to cSDH between 2009 and 2012, were included. The following parameters were analyzed: patient age and gender, occurrence of trauma, time between trauma and admission, neurological symptoms, presence of minor diseases, intake of anticoagulation medication. We classified the results of diagnostic imaging and determined the space-consuming effect via the cerebral midline shift. In addition, we scrutinized intraoperative findings and the dependence of the position of subdural drainage on the recurrence rate of cSDH. In our patient group, cSDH recurrence was significantly associated with aphasia (p=0.008). Moreover an increased cSDH recurrence rate was observed in the patient group that had a separated manifestation of the cSDH in the preoperative diagnostic imaging (p=0.048) and received no drainage implant (p=0.016). Homogeneous isodense cSDH was associated with no apparent recurrence (p=0.037). Within the scope of this study, we detected aphasia and separated cSDH as predictors of cSDH recurrence. Homogeneous isodense cSDH seems to be a good prognostic sign regarding the risk of recurrence development. Furthermore, our data clearly emphasize the importance of surgically applied drainage implants to prevent a recurrence of cSDH.

  2. Recurrent gastric lactobezoar in an infant

    OpenAIRE

    Castro, Leonor; Berenguer, Alberto; Pilar, Carla; Gon?alves, Rute; Nunes, Jos? L.

    2014-01-01

    Lactobezoars are a type of bezoar composed of undigested milk and mucus. The aetiology is likely multifactorial, being classically described in association with pre-term, low-birth weight infants fed with hyperconcentrated formula. The authors present a case of lactobezoar recurrence in a pre-term infant with oesophageal atresia. To our knowledge, this is the first report of recurrence of lactobezoar.

  3. 14 CFR 91.1107 - Recurrent training.

    Science.gov (United States)

    2010-01-01

    ..., as appropriate, including low-altitude windshear training and training on operating during ground... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Recurrent training. 91.1107 Section 91.1107... Management § 91.1107 Recurrent training. (a) Each program manager must ensure that each crewmember receives...

  4. Surgical Management of Recurrent Odontogenic Keratocyst

    OpenAIRE

    Semi, Ravinder Singh; Thapliyal, G. K.; Menon, Suresh

    2010-01-01

    The odontogenic keratocyst is a distinct entity arising from odontogenic epithelium. The unique histopathological appearance and the propensity for recurrence has made it management controversial in terms of the conservatism to be followed. This article describes the management of a case of recurrent odontogenic keratocyst with an aggressive therapy being adopted due to the nature of the pathology.

  5. Therapeutic resistance and cancer recurrence mechanisms

    Indian Academy of Sciences (India)

    Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. Thisbiological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy.Recent developments in the design of models reflecting cancer recurrence and in vivo imaging ...

  6. Association of recurrent pregnancy loss with chromosomal ...

    African Journals Online (AJOL)

    EB

    for recurrent pregnancy loss and these patients are the best candidates for offering prenatal genetic diagnosis by the help of which there is a possibility of obtaining a better reproductive outcome. Key words: chromosomal abnormality, recurrent pregnancy loss, thrombophilia. African Health Sciences 2013; 13(2): 447 - 452 ...

  7. Recurrence in Major Depression: A Conceptual Analysis

    Science.gov (United States)

    Monroe, Scott M.; Harkness, Kate L.

    2011-01-01

    Theory and research on major depression have increasingly assumed a recurrent and chronic disease model. Yet not all people who become depressed suffer recurrences, suggesting that depression is also an acute, time-limited condition. However, few if any risk indicators are available to forecast which of the initially depressed will or will not…

  8. Recurrent midgut volvulus following a Ladd procedure

    International Nuclear Information System (INIS)

    Panghaal, Vikash; Levin, Terry L.; Han, Bokyung

    2008-01-01

    We present a case of recurrent midgut volvulus in a 3-year-old girl with a history of midgut volvulus repair as an infant. Awareness of the possibility of recurrence even several years following an initial Ladd procedure is crucial to ensure prompt treatment in these children. (orig.)

  9. Recurrent midgut volvulus following a Ladd procedure

    Energy Technology Data Exchange (ETDEWEB)

    Panghaal, Vikash; Levin, Terry L.; Han, Bokyung [Montefiore Medical Center, Department of Radiology, Bronx, NY (United States)

    2008-04-15

    We present a case of recurrent midgut volvulus in a 3-year-old girl with a history of midgut volvulus repair as an infant. Awareness of the possibility of recurrence even several years following an initial Ladd procedure is crucial to ensure prompt treatment in these children. (orig.)

  10. Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

    Energy Technology Data Exchange (ETDEWEB)

    Caujolle, Jean-Pierre, E-mail: ncaujolle@aol.com [Department of Ophthalmology, Saint Roch Hospital, Nice Teaching Hospital, Nice (France); Paoli, Vincent [Department of Ophthalmology, Saint Roch Hospital, Nice Teaching Hospital, Nice (France); Chamorey, Emmanuel [Department of Radiation Oncology, Protontherapy Center, Centre Antoine Lacassagne, Nice (France); Department of Biostatistics and Epidemiology, Centre Antoine Lacassagne, Nice (France); Maschi, Celia; Baillif, Stéphanie [Department of Ophthalmology, Saint Roch Hospital, Nice Teaching Hospital, Nice (France); Herault, Joël [Department of Radiation Oncology, Protontherapy Center, Centre Antoine Lacassagne, Nice (France); Gastaud, Pierre [Department of Ophthalmology, Saint Roch Hospital, Nice Teaching Hospital, Nice (France); Hannoun-Levi, Jean Michel [Department of Radiation Oncology, Protontherapy Center, Centre Antoine Lacassagne, Nice (France)

    2013-04-01

    Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Five factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies.

  11. Local Recurrence After Uveal Melanoma Proton Beam Therapy: Recurrence Types and Prognostic Consequences

    International Nuclear Information System (INIS)

    Caujolle, Jean-Pierre; Paoli, Vincent; Chamorey, Emmanuel; Maschi, Celia; Baillif, Stéphanie; Herault, Joël; Gastaud, Pierre; Hannoun-Levi, Jean Michel

    2013-01-01

    Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT). Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model. Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Five factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences. Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies

  12. Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.

    Science.gov (United States)

    Louissaint, Abner; Schafernak, Kristian T; Geyer, Julia T; Kovach, Alexandra E; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G; Paxton, Christian N; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A; Neuberg, Donna S; South, Sarah T; Harris, Marian H; Hasserjian, Robert P; Hochberg, Ephraim P; Garraway, Levi A; Harris, Nancy Lee; Weinstock, David M

    2016-08-25

    Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. © 2016 by The American Society of Hematology.

  13. Detection of MPL mutations by a novel allele-specific PCR-based strategy.

    Science.gov (United States)

    Furtado, Larissa V; Weigelin, Helmut C; Elenitoba-Johnson, Kojo S J; Betz, Bryan L

    2013-11-01

    MPL mutation testing is recommended in patients with suspected primary myelofibrosis or essential thrombocythemia who lack the JAK2 V617F mutation. MPL mutations can occur at allelic levels below 15%, which may escape detection by commonly used mutation screening methods such as Sanger sequencing. We developed a novel multiplexed allele-specific PCR assay capable of detecting most recurrent MPL exon 10 mutations associated with primary myelofibrosis and essential thrombocythemia (W515L, W515K, W515A, and S505N) down to a sensitivity of 2.5% mutant allele. Test results were reviewed from 15 reference cases and 1380 consecutive specimens referred to our laboratory for testing. Assay performance was compared to Sanger sequencing across a series of 58 specimens with MPL mutations. Positive cases consisted of 45 with W515L, 6 with S505N, 5 with W515K, 1 with W515A, and 1 with both W515L and S505N. Seven cases had mutations below 5% that were undetected by Sanger sequencing. Ten additional cases had mutation levels between 5% and 15% that were not consistently detected by sequencing. All results were easily interpreted in the allele-specific test. This assay offers a sensitive and reliable solution for MPL mutation testing. Sanger sequencing appears insufficiently sensitive for robust MPL mutation detection. Our data also suggest the relative frequency of S505N mutations may be underestimated, highlighting the necessity for inclusion of this mutation in MPL test platforms. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  14. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.

    Science.gov (United States)

    Lenato, Gennaro M; Lastella, Patrizia; Di Giacomo, Marilena C; Resta, Nicoletta; Suppressa, Patrizia; Pasculli, Giovanna; Sabbà, Carlo; Guanti, Ginevra

    2006-02-01

    Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation. 2006 Wiley-Liss, Inc.

  15. 6th International Symposium on Recurrence Plots

    CERN Document Server

    Jr, Jr; Ioana, Cornel; Marwan, Norbert

    2016-01-01

    The chapters in this book originate from the research work and contributions presented at the Sixth International Symposium on Recurrence Plots held in Grenoble, France in June 2015. Scientists from numerous disciplines gathered to exchange knowledge on recent applications and developments in recurrence plots and recurrence quantification analysis. This meeting was remarkable because of the obvious expansion of recurrence strategies (theory) and applications (practice) into ever-broadening fields of science. It discusses real-world systems from various fields, including mathematics, strange attractors, applied physics, physiology, medicine, environmental and earth sciences, as well as psychology and linguistics. Even readers not actively researching any of these particular systems will benefit from discovering how other scientists are finding practical non-linear solutions to specific problems. The book is of interest to an interdisciplinary audience of recurrence plot users and researchers interested in time...

  16. Effect of BRCA germline mutations on breast cancer prognosis

    Science.gov (United States)

    Baretta, Zora; Mocellin, Simone; Goldin, Elena; Olopade, Olufunmilayo I.; Huo, Dezheng

    2016-01-01

    Abstract Background: The contribution of BRCA germline mutational status to breast cancer patients’ prognosis is unclear. We aimed to systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast cancer, those with Ashkenazi Jewish ancestry, and patients with stage I–III disease. Methods: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated using random-effect models. Results: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11–1.52) and worse BCSS than sporadic/BRCA-negative cases among patients with stage I–III breast cancer (HR 1.45, 95% CI: 1.01–2.07). BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03–1.62), although they have similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR 0.49, 95% CI: 0.26–0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast cancer (HR 1.44, 95% CI: 1.05–1.97) and of distant metastases (HR 1.82, 95% CI: 1.05–3.16) than sporadic/BRCA-negative patients. Conclusion: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline mutations to better define the prognosis of breast cancer in these patients. PMID:27749552

  17. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Bonaventure, J.; Rousseau, F.; Legeai-Mallet, L.; LeMerrer, M.; Munnich, A.; Maroteaux, P. [INSERM, Paris (France)

    1996-05-03

    The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases; in our series, seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder. 31 refs., 4 figs., 2 tabs.

  18. Patients at high risk of tuberculosis recurrence

    Directory of Open Access Journals (Sweden)

    Mehdi Mirsaeidi

    2018-01-01

    Full Text Available Recurrent tuberculosis (TB continues to be a significant problem and is an important indicator of the effectiveness of TB control. Recurrence can occur by relapse or exogenous reinfection. Recurrence of TB is still a major problem in high-burden countries, where there is lack of resources and no special attention is being given to this issue. The rate of recurrence is highly variable and has been estimated to range from 4.9% to 47%. This variability is related to differences in regional epidemiology of recurrence and differences in the definitions used by the TB control programs. In addition to treatment failure from noncompliance, there are several key host factors that are associated with high rates of recurrence. The widely recognized host factors independent of treatment program that predispose to TB recurrence include gender differences, malnutrition; comorbidities such as diabetes, renal failure, and systemic diseases, especially immunosuppressive states such as human immunodeficiency virus; substance abuse; and environmental exposures such as silicosis. With improved understanding of the human genome, proteome, and metabolome, additional host-specific factors that predispose to recurrence are being identified. Information on temporal and geographical trends of TB cases as well as studies with whole-genome sequencing might provide further information to enable us to fully understand TB recurrence and discriminate between reactivation and new infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care. Continued improvement in diagnosis, treatment approaches, and an understanding of host-specific factors are needed to fully understand the clinical epidemiological and social determinants of TB recurrence.

  19. Patients at high risk of tuberculosis recurrence.

    Science.gov (United States)

    Mirsaeidi, Mehdi; Sadikot, Ruxana T

    2018-01-01

    Recurrent tuberculosis (TB) continues to be a significant problem and is an important indicator of the effectiveness of TB control. Recurrence can occur by relapse or exogenous reinfection. Recurrence of TB is still a major problem in high-burden countries, where there is lack of resources and no special attention is being given to this issue. The rate of recurrence is highly variable and has been estimated to range from 4.9% to 47%. This variability is related to differences in regional epidemiology of recurrence and differences in the definitions used by the TB control programs. In addition to treatment failure from noncompliance, there are several key host factors that are associated with high rates of recurrence. The widely recognized host factors independent of treatment program that predispose to TB recurrence include gender differences, malnutrition; comorbidities such as diabetes, renal failure, and systemic diseases, especially immunosuppressive states such as human immunodeficiency virus; substance abuse; and environmental exposures such as silicosis. With improved understanding of the human genome, proteome, and metabolome, additional host-specific factors that predispose to recurrence are being identified. Information on temporal and geographical trends of TB cases as well as studies with whole-genome sequencing might provide further information to enable us to fully understand TB recurrence and discriminate between reactivation and new infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care. Continued improvement in diagnosis, treatment approaches, and an understanding of host-specific factors are needed to fully understand the clinical epidemiological and social determinants of TB recurrence.

  20. Chemoradiotherapy response in recurrent rectal cancer.

    Science.gov (United States)

    Yu, Stanley K T; Bhangu, Aneel; Tait, Diana M; Tekkis, Paris; Wotherspoon, Andrew; Brown, Gina

    2014-02-01

    The efficacy of response to preoperative chemoradiotherapy (CRT) in recurrent versus primary rectal cancer has not been investigated. We compared radiological downsizing between primary and recurrent rectal cancers following CRT and determined the optimal size reduction threshold for response validated by survival outcomes. The proportional change in tumor length for primary and recurrent rectal cancers following CRT was compared using the independent sample t-test. Overall survival (OS) was calculated using the Kaplan-Meier product limit method and differences between survival for tumor size reduction thresholds of 30% (response evaluation criteria in solid tumors [RECIST]), 40%, and 50% after CRT in primary and recurrent rectal cancer groups. A total of 385 patients undergoing CRT were analyzed, 99 with recurrent rectal cancer and 286 with primary rectal cancer. The mean proportional reduction in maximum craniocaudal length was significantly higher for primary rectal tumors (33%) compared with recurrent rectal cancer (11%) (P rectal cancer when ≤30% or ≤40% definitions were used. However, for both primary and recurrent tumors, significant differences in median 3-year OS were observed when a RECIST cut-off of 50% was used. OS was 99% versus 77% in primary and 100% versus 42% in recurrent rectal cancer (P = 0.002 and P = 0.03, respectively). Only patients that demonstrated >50% size reduction showed a survival benefit. Recurrent rectal cancer appears radioresistant compared with primary tumors for tumor size after CRT. Further investigation into improving/intensifying chemotherapy and radiotherapy for locally recurrent rectal cancer is justified. © 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  1. Recurrent Childhood Animal Cruelty and Its Link to Recurrent Adult Interpersonal Violence.

    Science.gov (United States)

    Trentham, Caleb E; Hensley, Christopher; Policastro, Christina

    2018-06-01

    In the early 1960s, researchers began to examine the potential link between childhood animal cruelty and future interpersonal violence. Findings since then have been inconsistent in establishing a relationship between the two. This may be due to researchers failing to measure the recurrency of childhood animal abuse and the recurrency of later violent acts committed in adulthood. The current study, using data from 257 inmates at a medium-security prison in a Southern state, is a replication of research conducted by Tallichet and Hensley, and Hensley, Tallichet, and Dutkiewicz, which examined this recurrency issue. The only statistically significant predictor of recurrent adult interpersonal violence in this study was recurrent childhood animal cruelty. Inmates who engaged in recurrent childhood animal cruelty were more likely to commit recurrent adult interpersonal violence. Respondents' race, education, and childhood residence were not significant predictors of the outcome variable.

  2. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

    Science.gov (United States)

    Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

    2017-01-01

    Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular

  3. Wiskott-Aldrich Syndrome. A Report of a New Mutation

    Directory of Open Access Journals (Sweden)

    Nelva Lizbeth Guillén-Rocha

    2014-06-01

    Full Text Available Wiskott-Aldrich syndrome was rst reported clinically in 1937, and in 1954 the classic triad was identified: eccema, recurrent infections and thrombocytopenia with an X-linked transmission. Its incidence is estimated at 1 to 10 in one million live births per year. Wiskott Aldrich syndrome is caused by mutations in a gene in the short arm of chromosome X that encodes the Wiskott-Aldrich syndrome protein (WASp, which identi cation and sequencing was rst performed in 1994, and since then about 300 mutations have been reported. This paper describes the case of a boy with Wiskott-Aldrich syndrome, with clinical and genetic diagnosis, with a considerable diagnostic delay attributable to an atypical presentation misdiagnosed as immune thrombocytopenia.

  4. Aneurysm Recurrence Volumetry Is More Sensitive than Visual Evaluation of Aneurysm Recurrences.

    Science.gov (United States)

    Schönfeld, M H; Schlotfeldt, V; Forkert, N D; Goebell, E; Groth, M; Vettorazzi, E; Cho, Y D; Han, M H; Kang, H-S; Fiehler, J

    2016-03-01

    Considerable inter-observer variability in the visual assessment of aneurysm recurrences limits its use as an outcome parameter evaluating new coil generations. The purpose of this study was to compare visual assessment of aneurysm recurrences and aneurysm recurrence volumetry with an example dataset of HydroSoft coils (HSC) versus bare platinum coils (BPC). For this retrospective study, 3-dimensional time-of-flight magnetic resonance angiography datasets acquired 6 and 12 months after endovascular therapy using BPC only or mainly HSC were analyzed. Aneurysm recurrence volumes were visually rated by two observersas well as quantified by subtraction of the datasets after intensity-based rigid registration. A total of 297 aneurysms were analyzed (BPC: 169, HSC: 128). Recurrences were detected by aneurysm recurrence volumetry in 9 of 128 (7.0 %) treated with HSC and in 24 of 169 (14.2 %) treated with BPC (odds ratio: 2.39, 95 % confidence interval: 1.05-5.48; P = 0.039). Aneurysm recurrence volumetry revealed an excellent correlation between observers (Cronbach's alpha = 0.93). In contrast, no significant difference in aneurysm recurrence was found for visual assessment (3.9 % in HSC cases and 4.7 % in BPC cases). Recurrences were observed in aneurysms smaller than the sample median in 10 of 33 (30.3 %) by aneurysm recurrence volumetry and in 1 of 13 (7.7 %) by visual assessment. Aneurysm recurrences were detected more frequently by aneurysm recurrence volumetry when compared with visual assessment. By using aneurysm recurrence volumetry, differences between treatment groups were detected with higher sensitivity and inter-observer validity probably because of the higher detection rate of recurrences in small aneurysms.

  5. [Identification of novel pathogenic gene mutations in pediatric acute myeloid leukemia by whole-exome resequencing].

    Science.gov (United States)

    Shiba, Norio

    2015-12-01

    A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations.

  6. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families.

    Science.gov (United States)

    Konstantopoulou, I; Tsitlaidou, M; Fostira, F; Pertesi, M; Stavropoulou, A-V; Triantafyllidou, O; Tsotra, E; Tsiftsoglou, A P; Tsionou, C; Droufakou, S; Dimitrakakis, C; Fountzilas, G; Yannoukakos, D

    2014-01-01

    We have screened 473 breast/ovarian cancer patients with family history, aiming to define the prevalence and enrich the spectrum of BRCA1/2 pathogenic mutations occurring in the Greek population. An overall mutation prevalence of 32% was observed. Six BRCA1 recurrent/founder mutations dominate the observed spectrum (58.5% of all mutations found). These include three mutations in exon 20 and three large genomic deletions. Of the 44 different deleterious mutations found in both genes, 16 are novel and reported here for the first time. Correlation with available histopathology data showed that 80% of BRCA1 carriers presented a triple-negative breast cancer phenotype while 82% of BRCA2 carriers had oestrogen receptor positive tumours. This study provides a comprehensive view of the frequency, type and distribution of BRCA1/2 mutations in the Greek population as well as an insight of the screening strategy of choice for patients of Greek origin. We conclude that the Greek population has a diverse mutation spectrum influenced by strong founder effects. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

    Science.gov (United States)

    Heinzen, Erin L.; Swoboda, Kathryn J.; Hitomi, Yuki; Gurrieri, Fiorella; Nicole, Sophie; de Vries, Boukje; Tiziano, F. Danilo; Fontaine, Bertrand; Walley, Nicole M.; Heavin, Sinéad; Panagiotakaki, Eleni; Fiori, Stefania; Abiusi, Emanuela; Di Pietro, Lorena; Sweney, Matthew T.; Newcomb, Tara M.; Viollet, Louis; Huff, Chad; Jorde, Lynn B.; Reyna, Sandra P.; Murphy, Kelley J.; Shianna, Kevin V.; Gumbs, Curtis E.; Little, Latasha; Silver, Kenneth; Ptác̆ek, Louis J.; Haan, Joost; Ferrari, Michel D.; Bye, Ann M.; Herkes, Geoffrey K.; Whitelaw, Charlotte M.; Webb, David; Lynch, Bryan J.; Uldall, Peter; King, Mary D.; Scheffer, Ingrid E.; Neri, Giovanni; Arzimanoglou, Alexis; van den Maagdenberg, Arn M.J.M.; Sisodiya, Sanjay M.; Mikati, Mohamad A.; Goldstein, David B.; Nicole, Sophie; Gurrieri, Fiorella; Neri, Giovanni; de Vries, Boukje; Koelewijn, Stephany; Kamphorst, Jessica; Geilenkirchen, Marije; Pelzer, Nadine; Laan, Laura; Haan, Joost; Ferrari, Michel; van den Maagdenberg, Arn; Zucca, Claudio; Bassi, Maria Teresa; Franchini, Filippo; Vavassori, Rosaria; Giannotta, Melania; Gobbi, Giuseppe; Granata, Tiziana; Nardocci, Nardo; De Grandis, Elisa; Veneselli, Edvige; Stagnaro, Michela; Gurrieri, Fiorella; Neri, Giovanni; Vigevano, Federico; Panagiotakaki, Eleni; Oechsler, Claudia; Arzimanoglou, Alexis; Nicole, Sophie; Giannotta, Melania; Gobbi, Giuseppe; Ninan, Miriam; Neville, Brian; Ebinger, Friedrich; Fons, Carmen; Campistol, Jaume; Kemlink, David; Nevsimalova, Sona; Laan, Laura; Peeters-Scholte, Cacha; van den Maagdenberg, Arn; Casaer, Paul; Casari, Giorgio; Sange, Guenter; Spiel, Georg; Boneschi, Filippo Martinelli; Zucca, Claudio; Bassi, Maria Teresa; Schyns, Tsveta; Crawley, Francis; Poncelin, Dominique; Vavassori, Rosaria

    2012-01-01

    Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene. PMID:22842232

  8. [Gene mutation analysis and prenatal diagnosis of a family with Bartter syndrome].

    Science.gov (United States)

    Li, Long; Ma, Na; Li, Xiu-Rong; Gong, Fei; DU, Juan

    2016-08-01

    To investigate the mutation of related genes and prenatal diagnosis of a family with Bartter syndrome (BS). The high-throughput capture sequencing technique and PCR-Sanger sequencing were used to detect pathogenic genes in the proband of this family and analyze the whole family at the genomic level. After the genetic cause was clarified, the amniotic fluid was collected from the proband's mother who was pregnant for 5 months for prenatal diagnosis. The proband carried compound heterozygous mutations of c.88C>T(p.Arg30*) and c.968+2T>A in the CLCNKB gene; c.88C>T(p.Arg30*) had been reported as a pathogenic mutation, and c.968+2T>A was a new mutation. Pedigree analysis showed that the two mutations were inherited from the mother and father, respectively. Prenatal diagnosis showed that the fetus did not inherit the mutations from parents and had no mutations at the two loci. The follow-up visit confirmed that the infant was in a healthy state, which proved the accuracy of genetic diagnosis and prenatal diagnosis. The compound heterozygous mutations c.88C>T(p.Arg30*) and c.968+2T>A in the CLCNKB gene are the cause of BS in the proband, and prenatal diagnosis can prevent the risk of recurrence of BS in this family.

  9. The prognostic value of BRAF mutation and lymph node metastases in patients with papillary thyroid cancer

    International Nuclear Information System (INIS)

    Takacsova, E.

    2015-01-01

    Full text of publication follows. Aim: To assess the prognostic significance of BRAF mutation and lymph node metastases in patients with papillary thyroid cancer. Method: between January 2010 and March 2012, we retrospectively analysed 172 patients after total thyroidectomy with neck dissection for papillary thyroid cancer. Mutation in the BRAF gene (V600E) was assessed in all of the enrolled patients. According to TNM classification, 56 (33%) patients were in low risk group and 116 (67%) patients in high risk group. Among high risk group, 105 out of 116 (90%) patients were presented with lymph node metastases. Thyroid ablation with radioactive iodine was performed in all of the patients enrolled in the study. Persistent or recurrent disease was diagnosed in 42 (24%) patients during radioiodine therapy. Results and conclusion: BRAF mutation did not appear to be significant unfavourable prognostic factor in our cohort: it was present in 55% of low risk patients, in 48% of high risk patients and in 46% of patients with lymph node metastases. In patients with persistent or recurrent disease, BRAF mutation was found in 48%. But we confirmed that the presence of lymph node metastases in time of initial surgery (61% of all patients) appeared to be significant: neck dissection enabled a more precise classification of patients into the high risk group - up to 95% of patients with persistent or recurrent disease diagnosed during radioiodine therapy belonged to the high risk group in the beginning of therapy. (author)

  10. Recurrent laughter-induced syncope.

    Science.gov (United States)

    Gaitatzis, Athanasios; Petzold, Axel

    2012-07-01

    Syncope is a common presenting complaint in Neurology clinics or Emergency departments, but its causes are sometimes difficult to diagnose. Apart from vasovagal attacks, other benign, neurally mediated syncopes include "situational" syncopes, which occur after urination, coughing, swallowing, or defecation. A healthy 42-year-old male patient presented to the neurology clinic with a long history of faints triggered by spontaneous laughter, especially after funny jokes. Physical and neurological examination, and electroencephalography and magnetic resonance imaging were unremarkable. There was no evidence to suggest cardiogenic causes, epilepsy, or cataplexy and a diagnosis of laughing syncope was made. Laughter-induced syncope is usually a single event in the majority of cases, but may present as recurrent attacks as in our case. Some cases occur in association with underlying neurological conditions. Prognosis is good in the case of neurally mediated attacks. Laughter may not be recognized by physicians as a cause of syncope, which may lead to unnecessary investigations or misdiagnosis, and affect patients' quality of life.

  11. MDX-010 in Treating Patients With Recurrent or Refractory Lymphoma

    Science.gov (United States)

    2014-05-22

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  12. Hereditary thrombophilia and recurrent pregnancy loss: a retrospective cohort study of pregnancy outcome and obstetric complications

    DEFF Research Database (Denmark)

    Lund, M; Nielsen, H S; Hviid, T V

    2010-01-01

    was found to be associated with FVL/PT mutations. CONCLUSIONS: In the unadjusted analysis, FVL and PT mutations have a negative prognostic impact on the live birth rate in women with RPL; however, when adjusting for significant covariates, the results no longer reach statistical significance. Strong......-mutation carriers and 6 were PT-mutation carriers. The unadjusted live birth rate was 45.7% in FVL/PT carriers versus 63.4% in FVL/PT non-carriers, P = 0.04. The adjusted odds ratio for live birth in FVL/PT carriers was 0.48 (95% CI = 0.23-1.01), P = 0.05. Among the obstetric complications, only excessive bleeding......BACKGROUND: The association among hereditary thrombophilia, recurrent pregnancy loss (RPL) and obstetric complications is yet uncertain. The objective of the study was to assess the prognostic value of the factor V Leiden (FVL) and prothrombin (PT) mutations for the subsequent chance of live birth...

  13. Application of molecular imaging combined with genetic screening in diagnosing MELAS, diabetes and recurrent pancreatitis.

    Science.gov (United States)

    Zhiping, W; Quwen, L; Hai, Z; Jian, Z; Peiyi, G

    2016-01-01

    We report molecular imaging combined with gene diagnosis in a family with 7 members who carried an A3243G mutation in mitochondrial tRNA and p.Thr 137 Met in cationic trypsinogen (PRSS1) gene presented with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), diabetes, and recurrent pancreatitis. DNA sequencing was used to detect and validate mitochondrial DNA and PRSS1. We also verified that mitochondrial heterozygous mutations and c.410 C>T mutation causing p.Thr 137 Met could be detected in oral epithelial cells or in urine sediment cells. In addition, molecular imaging was carried out in the affected family members. In this pedigree, MELAS syndrome accompanied by pancreatitis was an important clinical feature, followed by diabetes. Heteroplasmy of the mtDNA A3243G and c.410 C>T mutation of PRSS1 was found in all tissue samples of these patients, but no mutations were found in 520 normal control and normal individuals of the family. However, based on molecular imaging observations, patients with relatively higher lactate/pyruvate levels had more typical and more severe symptoms, particularly those of pancreatic disease (diabetes or pancreatitis). MELAS syndrome may be associated with pancreatitis. For the diagnosis, it is more reasonable to perform molecular imaging combined with gene diagnosis.

  14. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    2009-01-01

    Chickpea is an important food legume in Turkey. Turkey is one of the most important gene centers in the world for legumes. The most widely known characteristic of chickpea is that it is an important vegetable protein source used in human and animal nutrition. However, the dry grains of chickpea, has 2-3 times more protein than our traditional food of wheat. In addition, cheakpea is also energy source because of its high carbohydrate content. It is very rich in some vitamin and mineral basis. In the plant breeding, mutation induction has become an effective way of supplementing existing germplasm and improving cultivars. Many successful examples of mutation induction have proved that mutation breeding is an effective and important approach to food legume improvement. The induced mutation technique in chickpea has proved successful and good results have been attained. Realizing the potential of induced mutations, a mutation breeding programme was initiated at the Nuclear Agriculture Section of the Saraykoey Nuclear Research and Training Center in 1994. The purpose of the study was to obtain high yielding chickpea mutants with large seeds, good cooking quality and high protein content. Beside this some characters such as higher adaptation ability, tolerant to cold and drought, increased machinery harvest type, higher yield, resistant to diseases especially to antracnose and pest were investigated too. Parents varieties were ILC-482, AK-7114 and AKCIN-91 (9 % seed moisture content and germination percentage 98 %) in these experiments. The irradiation doses were 0 (control), 50, 100, 150, 200, 250, 300, 350, 400, 500 ve 600 Gy for greenhouse experiments and 0 (control), 50, 100, 150, 200, 250, 300, 350 ve 400 Gy for field experiments, respectively. One thousand seeds for per treatment were sown in the field for the M 1 . At maturity, 3500 single plants were harvested and 20 seeds were taken from each M 1 plant and planted in the following season. During plant growth

  15. Inguinal hernia recurrence: Classification and approach

    Directory of Open Access Journals (Sweden)

    Campanelli Giampiero

    2006-01-01

    Full Text Available The authors reviewed the records of 2,468 operations of groin hernia in 2,350 patients, including 277 recurrent hernias updated to January 2005. The data obtained - evaluating technique, results and complications - were used to propose a simple anatomo-clinical classification into three types which could be used to plan the surgical strategy:Type R1: first recurrence ′high,′ oblique external, reducible hernia with small (< 2 cm defect in non-obese patients, after pure tissue or mesh repairType R2: first recurrence ′low,′ direct, reducible hernia with small (< 2 cm defect in non-obese patients, after pure tissue or mesh repairType R3: all the other recurrences - including femoral recurrences; recurrent groin hernia with big defect (inguinal eventration; multirecurrent hernias; nonreducible, linked with a controlateral primitive or recurrent hernia; and situations compromised from aggravating factors (for example obesity or anyway not easily included in R1 or R2, after pure tissue or mesh repair.

  16. Vocal fold hemorrhage: factors predicting recurrence.

    Science.gov (United States)

    Lennon, Christen J; Murry, Thomas; Sulica, Lucian

    2014-01-01

    Vocal fold hemorrhage is an acute phonotraumatic injury treated with voice rest; recurrence is a generally accepted indication for surgical intervention. This study aims to identify factors predictive of recurrence based on outcomes of a large clinical series. Retrospective cohort. Retrospective review of cases of vocal fold hemorrhage presenting to a university laryngology service. Demographic information was compiled. Videostroboscopic exams were evaluated for hemorrhage extent, presence of varix, mucosal lesion, and/or vocal fold paresis. Vocal fold hemorrhage recurrence was the main outcome measure. Follow-up telephone survey was used to complement clinical data. Forty-seven instances of vocal fold hemorrhage were evaluated (25M:22F; 32 professional voice users). Twelve of the 47 (26%) patients experienced recurrence. Only the presence of varix demonstrated significant association with recurrence (P = 0.0089) on multivariate logistic regression. Vocal fold hemorrhage recurred in approximately 26% of patients. Varix was a predictor of recurrence, with 48% of those with varix experiencing recurrence. Monitoring, behavioral management and/or surgical intervention may be indicated to treat patients with such characteristics. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  17. Factors associated with recurrent bacterial empyema thoracis

    Directory of Open Access Journals (Sweden)

    Apichat Tantraworasin

    2018-07-01

    Full Text Available Summary: Background: Empyema thoracis (ET is one of the common thoracic diseases frequently found in developing countries. In the past, only a few studies have analyzed recurrent ET, and none had clearly identified the prognostic factors for recurrence. The aim of this study is to identify the prognostic factors of recurrent ET in Northern Thailand. Methods: A retrospective cohort study was conducted. All patients diagnosed with Stage II and III ET at Maharaj Nakorn Chiang Mai Hospital (a tertiary-care hospital in northern Thailand between January 1, 2007 and November 31, 2012 were enrolled in this study. All clinical data were extracted from the medical recording system. The primary outcome was recurrent disease. Multivariable Cox’s proportion hazard model was used to identify the independent prognostic factors for recurrence. Results: There were 382 patients enrolled in this study, and 34 patients (8.9% had recurrent disease. The most common gram-positive and gram-negative pathogens found were Staphylococcus aureus and Acinetobacter baumannii, respectively. Three independent prognostic factors for recurrent disease were nonsepsis status prior to the surgery [hazard ratio (HR = 12.3; 95% confidence interval (CI, 4.25–35.43], nonperforming decortication (HR = 5.4; 95% CI, 1.82–15.92, and persistent pleural spaces (HR = 4.1; 95% CI, 1.93–8.68. Conclusions: Clinical characteristics, surgical procedure, and persistent pleural spaces were independent prognostic factors for ET recurrence in this study. Decortication and early thoracoplasty in patients who had persistent pleural space should be considered. Large cohort studies are warranted to support these findings. Keywords: empyema thoracis, incidence, prognostic factor, pyothorax, recurrence

  18. Salvage photodynamic therapy for recurrent nasopharyngeal carcinoma.

    Science.gov (United States)

    Succo, Giovanni; Rosso, S; Fadda, G L; Fantini, M; Crosetti, Erika

    2014-06-01

    To evaluate the feasibility of photodynamic therapy (NP-PDT) in the palliative management of recurrent/persistent nasopharyngeal cancer (NFC). Six patients with persistent/recurrent NPC underwent PDT with palliative intent. NP-PDT was delivered by three different methods depending on the localization, size and depth of the lesion: type I NP-PDT: transnasal direct illumination of postero-superior recurrence; type II NP-PDT: transnasal direct illumination of the whole nasopharynx; type III NP-PDT: transoral direct or interstitial illumination of lateral recurrence. In this case, the ENT-magnetic navigation system (MNS) was extremely useful in identifying the tumor and its distance from the ICA. Both patients treated with NP-PDT type I are free from disease at 38 and 71 months after treatment; both patients treated with NP-PDT type II experienced further local and loco-regional recurrence of disease within 16 months; one died of the disease while the second underwent a second palliative treatment, NP-PDT type I, and is currently living with the disease; of the two patients who underwent NP-PDT type III, one died as a result of regional and systemic recurrence without local recurrence while the second experienced a superficial recurrence. He underwent a second NP-PDT type III treatment and is currently free from disease at 21 months. NP-PDT is a non-invasive and simple treatment modality that may have an important role in the treatment of selected cases of persistent/recurrent NPC in its early stage, not suitable for a conventional therapeutic protocol. Coupling NP-PDT with the ENT-MNS can be an effective strategy to obtain more precise light delivery within the tumor, particularly in lateral and parapharyngeal localization. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Risk factors for recurrent spontaneous epistaxis.

    Science.gov (United States)

    Abrich, Victor; Brozek, Annabelle; Boyle, Timothy R; Chyou, Po-Huang; Yale, Steven H

    2014-12-01

    To identify risk factors associated with spontaneous recurrent epistaxis. This was a retrospective cohort study assessing patients in the Marshfield Clinic system diagnosed as having epistaxis between January 1, 1991, and January 1, 2011. There were 461 cases with at least 2 episodes of spontaneous epistaxis within 3 years and 912 controls with only 1 episode in the same time frame. More than 50 potential risk factors were investigated, including demographic features, substance use, nasal anatomical abnormalities, nasal infectious and inflammatory processes, medical comorbidities, medications, and laboratory values. A Cox proportional hazards regression modeling approach was used to calculate hazard ratios of epistaxis recurrence. Traditional risk factors for epistaxis, including nasal perforation, nasal septum deviation, rhinitis, sinusitis, and upper respiratory tract infection, did not increase the risk of recurrence. Significant risk factors for recurrent epistaxis included congestive heart failure, diabetes mellitus, hypertension, and a history of anemia. Warfarin use increased the risk of recurrence, independent of international normalized ratio. Aspirin and clopidogrel were not found to increase the risk of recurrence. Few major adverse cardiovascular events were observed within 30 days of the first epistaxis event. Congestive heart failure is an underappreciated risk factor for recurrent epistaxis. Hypertension and diabetes mellitus may induce atherosclerotic changes in the nasal vessels, making them friable and more at risk for bleeding. Patients with recurrent epistaxis may also be more susceptible to developing anemia. Physicians should promote antiplatelet and antithrombotic medication adherence despite an increased propensity for recurrent epistaxis to prevent major adverse cardiovascular events. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  20. Induced mutations in citrus

    International Nuclear Information System (INIS)

    Spiegel-Roy, P.; Vardi, Aliza

    1990-01-01

    Full text: Parthenocarpic tendency is an important prerequisite for successful induction of seedlessness in breeding and especially in mutation breeding. A gene for asynapsis and accompanying seedless fruit has been found by us in inbred progeny of cv. 'Wilking'. Using budwood irradiation by gamma rays, seedless mutants of 'Eureka' and 'Villafranca' lemon (original clone of the latter has 25 seeds) and 'Minneola' tangelo have been obtained. Ovule sterility of the three mutants is nearly complete, with some pollen fertility still remaining. A semi-compact mutant of Shamouti orange has been obtained by irradiation. A programme for inducing seedlessness in easy peeling citrus varieties and selections has been initiated. (author)

  1. Induced skeletal mutations

    International Nuclear Information System (INIS)

    Selby, P.B.

    1979-01-01

    This paper describes a large-scale experiment that, by means of breeding tests, confirmed that many dominant skeletal mutations are induced by large-dose radiation exposure. The author also discusses: (1) the major advantages and disadvantages of the skeletal method in improving estimates of genetic hazard to man; (2) future uses of the skeletal method; (3) direct estimation of risk beyond the first generation using the skeletal method; and (4) the possibility of using the skeletal method as a quick and easy screen for chemical mutagens

  2. Recurrence determinism and Li-Yorke chaos for interval maps

    OpenAIRE

    Špitalský, Vladimír

    2017-01-01

    Recurrence determinism, one of the fundamental characteristics of recurrence quantification analysis, measures predictability of a trajectory of a dynamical system. It is tightly connected with the conditional probability that, given a recurrence, following states of the trajectory will be recurrences. In this paper we study recurrence determinism of interval dynamical systems. We show that recurrence determinism distinguishes three main types of $\\omega$-limit sets of zero entropy maps: fini...

  3. Mutation Breeding Newsletter. No. 39

    International Nuclear Information System (INIS)

    1992-01-01

    This newsletter contains brief articles on the use of radiation to induce mutations in plants; radiation-induced mutants in Chrysanthemum; disrupting the association between oil and protein content in soybean seeds; mutation studies on bougainvillea; a new pepper cultivar; and the use of mutation induction to improve the quality of yam beans. A short review of the seminar on the use of mutation and related biotechnology for crop improvement in the Middle East and Mediterranean regions, and a description of a Co-ordinated Research Programme on the application of DNA-based marker mutations for the improvement of cereals and other sexually reproduced crop species are also included. Two tables are given: these are based on the ''FAO/IAEA Mutant Varieties Database'' and show the number of mutated varieties and the number of officially released mutant varieties in particular crops/species. Refs and tabs

  4. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukemia

    Science.gov (United States)

    Gaikwad, Amos; Rye, Cassia L.; Devidas, Meenakshi; Heerema, Nyla A.; Carroll, Andrew J.; Izraeli, Shai; Plon, Sharon E.; Basso, Giuseppe; Pession, Andrea; Rabin, Karen R.

    2009-01-01

    Summary Recurrent, prognostically significant chromosomal abnormalities occur in approximately 75% of pediatric acute lymphoblastic leukemia (ALL), but only infrequently in children with Down syndrome (DS) and ALL. Recently, novel somatic activating mutations in Janus kinase 2 (JAK2) were reported in 18% of DS ALL. Here we report identification and clinical correlates of JAK2 mutations in an independent cohort. JAK2 activating mutations occurred in 10 of 53 DS ALL cases (18.9%). Mutations were overrepresented in males (p<0.03), occurred once in association with high hyperdiploidy, and were not significantly correlated with age, initial white blood count, or event-free survival. Our results confirm significance of JAK-STAT pathway activation in DS ALL. PMID:19120350

  5. Irradiation-induced mutation experiments with eiploid and tetraploid tomato plants

    International Nuclear Information System (INIS)

    Boda, J.

    1979-01-01

    Tomato mutation experiments are described. The tomatoes used in the experiment were the diploid Reziszta and its autotetraploid variety. The experimental plants were exposed to an irradiation of 5000 rsd for 1-2 days, and after transplantation into the gamma field, to chronic irradiation during the whole growing season. The chronic treatment heavily reduced fertility in the generations of tetraploid tomato plants. Recurrent treatment of tetraploid led to further deterioration in fertility. Several berries were formed with few seeds or with no seeds at all. After three irradiations, the chlorophyll mutation frequency increased in the diploid and tetraploid tomato plants. For diploids, treatment applied at the seedling stage gave a lower chlorophyll mutation frequency. With tetraploids the same treatment induced similar chlorophyll mutation frequency. As regards to phenotypic variability of quantitative characteristics in diploid and tetraploid tomatoes, the single and repeated chronic irradiation induced no increase in the variability of properties like flowering time, weight, height etc. (author)

  6. Prognostic significance of IDH 1 mutation in patients with glioblastoma multiforme.

    Science.gov (United States)

    Khan, Inamullah; Waqas, Muhammad; Shamim, Muhammad Shahzad

    2017-05-01

    Focus of brain tumour research is shifting towards tumour genesis and genetics, and possible development of individualized treatment plans. Genetic analysis shows recurrent mutation in isocitrate dehydrogenase (IDH1) gene in most Glioblastoma multiforme (GBM) cells. In this review we evaluated the prognostic significance of IDH 1 mutation on the basis of published evidence. Multiple retrospective clinical analyses correlate the presence of IDH1 mutation in GBM with good prognostic outcomes compared to wild-type IDH1. A systematic review reported similar results. Based on the review of current literature IDH1 mutation is an independent factor for longer overall survival (OS) and progression free survival (PFS) in GBM patients when compared to wild-type IDH1. The prognostic significance opens up new avenues for treatment.

  7. Biochemical characterization of P4-ATPase mutations associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine

    Progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1 that flips phospholipid from the exoplasmic leaflet to the cytoplasmic leaflet of canalicular membranes. It is hypothesized...... that PFIC1 mutations are the most disturbing with respect to expression, structural stability and/or function. Although recent data indicates that the specific phospholipid substrate of ATP8B1 is phosphatidylcholine (PC) [1] whereas ATP8A2 flips phosphatidylserine (PS) and phosphatidylethanolamine (PE......), there may be several mechanistic similarities between ATP8B1 and ATP8A2, and here we investigate known disease mutations using our well-functioning methodology for expression, affinity purification and assay of the partial reactions of ATP8A2. Mutations I91P (L127P in ATP8B1) and L308F (I344F) are located...

  8. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

    DEFF Research Database (Denmark)

    Schubert, J.; Siekierska, A.; Langlois, M.

    2014-01-01

    Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding...... syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations...... and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature...

  9. Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin | Office of Cancer Genomics

    Science.gov (United States)

    Morin et al. describe recurrent somatic mutations in EZH2, a polycomb group oncogene. The mutation, found in the SET domain of this gene encoding a histone methyltransferase, is found only in a subset of lymphoma samples. Specifically, EZH2 mutations are found in about 12% of follicular lymphomas (FL) and almost 23% of diffuse large B-cell lymphomas (DLBCL) of germinal center origin. This paper goes on to demonstrate that altered EZH2 proteins, corresponding to the most frequent mutations found in human lymphomas, have reduced activity using in vitro histone methylation assays.

  10. Mutations induced in plant breeding

    International Nuclear Information System (INIS)

    Barriga B, P.

    1984-01-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented. (Author)

  11. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)

    1984-10-01

    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  12. Mutation breeding newsletter. No. 43

    International Nuclear Information System (INIS)

    1997-10-01

    This issue of the Newsletter includes articles dealing with radiation induced mutation based plant breeding research findings aimed at improving productivity, disease resistance and tolerance of stress conditions

  13. Mutation breeding in mangosteen

    International Nuclear Information System (INIS)

    Mohd Khalid Mohd Zain

    2002-01-01

    Mangosteen the queen of the tropical fruits is apomitic and only a cultivar is reported and it reproduces asexually. Conventional breeding is not possible and the other methods to create variabilities are through genetic engineering and mutation breeding. The former technique is still in the infantry stage in mangosteen research while the latter has been an established tool in breeding to improve cultivars. In this mutation breeding seeds of mangosteen were irradiated using gamma rays and the LD 50 for mangosteen was determined and noted to be very low at 10 Gy. After sowing in the seedbed, the seedlings were transplanted in polybags and observed in the nursery bed for about one year before planted in the field under old oil palm trees in Station MARDI, Kluang. After evaluation and screening, about 120 mutant mangosteen plants were selected and planted in Kluang. The plants were observed and some growth data taken. There were some mutant plants that have good growth vigour and more vigorous that the control plants. The trial are now in the fourth year and the plants are still in the juvenile stage. (Author)

  14. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    Sagel, Z.; Tutluer, M. I.; Peskircioglu, H.; Kantoglu, Y.; Kunter, B.

    2009-01-01

    Chickpea is an important food legume in Turkey. Turkey is one of the most important gene centers in the world for legumes. Realizing the potential of induced mutations, a mutation breeding programme was initiated at the Nuclear Agriculture Section of the Saraykoy Nuclear Research and Training Center in 1994. The purpose of the study was to obtain high yielding chickpea mutants with large seeds, good cooking quality and high protein content. Beside this some characters such as higher adaptation ability, tolerant to cold and drought, increased machinery harvest type, higher yield, resistant to diseases especially to antracnose and pest were investigated too. Parent varieties were ILC-482, AK-7114 and AKCIN-91 had been used in these experiments. The irradiation doses were 0 (control), 50, 100, 150, 200, 250, 300, 350 and 400 Gy for field experiments, respectively. As a result of these experiments, two promising mutant lines were chosen and given to the Seed Registration and Certification Center for official registration These two promising mutants were tested at five different locations of Turkey, in 2004 and 2005 years. After 2 years of registration experiments one of outstanding mutants was officially released as mutant chickpea variety under the name TAEK-SAGEL, in 2006. Some basic characteristics of this mutant are; earliness (95-100 day), high yield capacity (180-220 kg/da), high seed protein (22-25 %), first pot height (20-25 cm), 100 seeds weight (42-48 g), cooking time (35-40 min) and resistance to Ascochyta blight.

  15. Ethanol ablation of predominantly cystic thyroid nodules: Evaluation of recurrence rate and factors related to recurrence

    International Nuclear Information System (INIS)

    Suh, C.H.; Baek, J.H.; Ha, E.J.; Choi, Y.J.; Lee, J.H.; Kim, J.K.; Chung, K.-W.; Kim, T.Y.; Kim, W.B.; Shong, Y.K.

    2015-01-01

    Aim: To evaluate recurrence rate and associated risk factors for recurrence after ethanol ablation (EA) in patients with predominantly cystic thyroid nodules. Materials and methods: This observational study was approved by the Ethics Committee of the Institutional Review Board and informed consent for procedures was obtained. From April 2009 to April 2013, 107 consecutive patients with predominantly cystic nodules were treated using EA. Recurrence was defined as nodules showing a residual solid portion with internal vascularity, cosmetic problems remaining, or persistent symptoms, and patients who requested additional therapy to resolve their symptomatic or cosmetic problems. Delayed recurrence was defined as treated nodules that showed no recurrent features at 1 month, but showed newly developed recurrent features during the longer follow-up period. Multivariate analysis was used for variables to demonstrate the independent factors related to volume reduction. Results: One month after EA, 18.7% of patients (20/107) showed recurrence. Among 87 patients with non-recurrence, 24.1% (21/87) showed delayed recurrence. The total recurrence rate was 38.3% (41/107). Patients with recurrence (n = 41) were treated using radiofrequency ablation (n = 28), second EA (n = 4), and refused further treatment (n = 9). These patients responded well to repeat EA and radiofrequency ablation. Multivariate analysis demonstrated that the initial nodule volume (>20 ml; p < 0.036) and vascularity (grade >1; p < 0.049) were independent predictors of volume reduction at last follow-up. Conclusions: The results revealed that although EA seemed to be effective during the initial period, delayed recurrence should be considered during longer-term follow-up. The independent predictors of recurrence were initial volume (>20 ml) and vascularity. - Highlights: • Ethanol ablation showed unsatisfactory results in 18.7% of patient at one month. • Delayed recurrence was observed in 24

  16. Identification of ribonucleotide reductase mutation causing temperature-sensitivity of herpes simplex virus isolates from whitlow by deep sequencing.

    Science.gov (United States)

    Daikoku, Tohru; Oyama, Yukari; Yajima, Misako; Sekizuka, Tsuyoshi; Kuroda, Makoto; Shimada, Yuka; Takehara, Kazuhiko; Miwa, Naoko; Okuda, Tomoko; Sata, Tetsutaro; Shiraki, Kimiyasu

    2015-06-01

    Herpes simplex virus 2 caused a genital ulcer, and a secondary herpetic whitlow appeared during acyclovir therapy. The secondary and recurrent whitlow isolates were acyclovir-resistant and temperature-sensitive in contrast to a genital isolate. We identified the ribonucleotide reductase mutation responsible for temperature-sensitivity by deep-sequencing analysis.

  17. Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma

    NARCIS (Netherlands)

    Majdak, EJ; Debniak, J; Milczek, T; Cornelisse, CJ; Devilee, P; Emerich, J; Jassem, J; De Bock, GH

    2005-01-01

    BACKGROUND. The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS. A consecutive series of

  18. Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Sanem Eren Akarcan

    2017-01-01

    Full Text Available Chronic Mucocutaneous Candidiasis (CMC is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF (c.1154 C>T, p.Thr385Met in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

  19. Poincaré recurrences of DNA sequences

    Science.gov (United States)

    Frahm, K. M.; Shepelyansky, D. L.

    2012-01-01

    We analyze the statistical properties of Poincaré recurrences of Homo sapiens, mammalian, and other DNA sequences taken from the Ensembl Genome data base with up to 15 billion base pairs. We show that the probability of Poincaré recurrences decays in an algebraic way with the Poincaré exponent β≈4 even if the oscillatory dependence is well pronounced. The correlations between recurrences decay with an exponent ν≈0.6 that leads to an anomalous superdiffusive walk. However, for Homo sapiens sequences, with the largest available statistics, the diffusion coefficient converges to a finite value on distances larger than one million base pairs. We argue that the approach based on Poncaré recurrences determines new proximity features between different species and sheds a new light on their evolution history.

  20. Surgical treatment for residual or recurrent strabismus

    Directory of Open Access Journals (Sweden)

    Tao Wang

    2014-12-01

    Full Text Available Although the surgical treatment is a relatively effective and predictable method for correcting residual or recurrent strabismus, such as posterior fixation sutures, medial rectus marginal myotomy, unilateral or bilateral rectus re-recession and resection, unilateral lateral rectus recession and adjustable suture, no standard protocol is established for the surgical style. Different surgical approaches have been recommended for correcting residual or recurrent strabismus. The choice of the surgical procedure depends on the former operation pattern and the surgical dosages applied on the patients, residual or recurrent angle of deviation and the operator''s preference and experience. This review attempts to outline recent publications and current opinion in the management of residual or recurrent esotropia and exotropia.

  1. Mitochondrial trifunctional protein deficiency with recurrent rhabdomyolysis

    NARCIS (Netherlands)

    Scheuerman, Oded; Wanders, Ronald J. A.; Waterham, Hans R.; Dubnov-Raz, Gal; Garty, Ben-Zion

    2009-01-01

    Rhabdomyolysis is an important clinical diagnosis. The differential diagnosis is extensive and includes various etiologies, such as infection, inflammation, trauma, endocrinopathies, and congenital muscular and metabolic disorders. Reported here is the case of an infant with recurrent rhabdomyolysis

  2. Recurrence quantification analysis theory and best practices

    CERN Document Server

    Jr, Jr; Marwan, Norbert

    2015-01-01

    The analysis of recurrences in dynamical systems by using recurrence plots and their quantification is still an emerging field.  Over the past decades recurrence plots have proven to be valuable data visualization and analysis tools in the theoretical study of complex, time-varying dynamical systems as well as in various applications in biology, neuroscience, kinesiology, psychology, physiology, engineering, physics, geosciences, linguistics, finance, economics, and other disciplines.   This multi-authored book intends to comprehensively introduce and showcase recent advances as well as established best practices concerning both theoretical and practical aspects of recurrence plot based analysis.  Edited and authored by leading researcher in the field, the various chapters address an interdisciplinary readership, ranging from theoretical physicists to application-oriented scientists in all data-providing disciplines.

  3. Recurrent encephalic hemorrhage associated with cocaine abuse

    International Nuclear Information System (INIS)

    Pumar, J.; Otero, E.; Castineira, A.; Arrojo, L.; Linares, M.; Castineira, J.A.; Vidal, J.

    1994-01-01

    We report a case of recurrent intracerebral hemorrhage secondary to cocaine abuse in a patient with no other predisposing factors. The hemorrhages were located both supra- and infratentorially. (orig.)

  4. Ocean wave forecasting using recurrent neural networks

    Digital Repository Service at National Institute of Oceanography (India)

    Mandal, S.; Prabaharan, N.

    , merchant vessel routing, nearshore construction, etc. more efficiently and safely. This paper describes an artificial neural network, namely recurrent neural network with rprop update algorithm and is applied for wave forecasting. Measured ocean waves off...

  5. Postoperative recurrence after VATS for spontaneous pneumothorax

    International Nuclear Information System (INIS)

    Katsuno, Gotaro; Tsumura, Makoto; Kokudo, Yasutaka; Muraoka, Atsushi; Tsuruno, Masaki

    2003-01-01

    A total of 88 cases of 81 patients with spontaneous pneumothorax treated at the hospital from March 1992 to August 2001 were subjected to a study of examining preoperative chest CT and thoracographic findings from the standpoint of postoperative recurrence. Preoperative chest CT and thoracography were conducted in 82 cases and 41 cases (including 25 cases with continuous air leakage), respectively. Eight (9.1%) patients developed recurrence of pneumothorax, and three patients of them underwent reoperation. Considering the intraoperative findings, newly formed bullae appeared to be a cause of recurrence. Resulting from these examinations, we conclude that it is difficult to predict the risk factor for postoperative recurrence at this time, in addition, it is important that the area of air leakage can be confirmed by thoracoscopic findings. (author)

  6. Recurrent autoassociative networks and holistic computations

    NARCIS (Netherlands)

    Stoianov, [No Value; Amari, SI; Giles, CL; Gori, M; Piuri,

    2000-01-01

    The paper presents an experimental study of holistic computations over distributed representations (DRs) of sequences developed by the Recurrent Autoassociative Networks (KAN). Three groups of holistic operators are studied: extracting symbols at fixed position, extracting symbols at a variable

  7. Studies on recurrence of colorectal carcinoma

    International Nuclear Information System (INIS)

    Kobayashi, Masayuki; Nosaki, Tadaharu; Murai, Tomoya; Ooshita, Ikuo; Kobayashi, Suzuo

    1989-01-01

    Recurrence patterns of colorectal carcinoma were studied in 402 patients followed up for 5 years or more after surgery. Recurrence was observed in 23% for colon cancer and 38% for rectal canccer. The most frequent site of recurrence or relapse in cases of colon cancer was the liver, followed by multiple organs and a local region; and in the case of rectal cancer, it was multiple organs, followed by a local region, the liver, lung, and bone. The rate of recurrence or relapse tended to be higher in patients with lymph node metastases or more advanced clinical stage. Liver relapse was seen in 13% for colon cancer and 12% for rectal cancer, occurring within 48 months after surgery. Since CT can detect liver relapse within 24 months, abdominal CT and chest plain roentgenography should be performed in the first 6 months, 12 months, and 24 months after surgery. (Namekawa, K)

  8. ON SOME RECURRENCE TYPE SMARANDACHE SEQUENCES

    OpenAIRE

    MAJUMDAR, A.A.K.; GUNARTO, H.

    2000-01-01

    In this paper, we study some properties of ten recurrence type Smarandache sequences, namely, the Smarandache odd, even, prime product, square product, higher-power product, permutation, consecutive, reverse, symmetric, and pierced chain sequences.

  9. Things Fall Apart: A Recurrence of Tiling

    Science.gov (United States)

    Rogers, Douglas G.

    2005-01-01

    A study investigates recurrence relations, sequences in which each term is determined by one or more previous terms. Results provide another approach to the problem of finding closed forms for recursively-defined sequences.

  10. Errata :Chromosomal Abnormalities in Couples with Recurrent ...

    African Journals Online (AJOL)

    Chromosomal Abnormalities in Couples with Recurrent Abortions in Lagos, Nigeria. Akinde OR, Daramola A O, Taiwo I A, Afolayan M O and Akinsola Af. Sonographic Mammary Gland Density Pattern in Women in Selected ommunities of Southern Nigeria.

  11. Recurrent Bilateral Breast Abscesses after Sternotomy

    Directory of Open Access Journals (Sweden)

    Hamza Cinar

    2012-01-01

    Full Text Available Median sternotomy is the most commonly used incision in cardiothoracic procedures. Development of breast abscess after sternotomy is a very rare situation. We present a case of sternal wound infection with recurrent bilateral breast abscess after sternotomy. Our case is the first and only case in the literature due to the presence of sternal wound infection with recurrent bilateral breast abscess after sternotomy.

  12. Recurrence of non-Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Watanabe, Toshikazu; Oguchi, Masahiko; Niibe, Hideo; Horiuchi, Junichi; Kaneta, Koichi; Morita, Kozo; Masaki, Norie; Hayabuchi, Naofumi.

    1988-01-01

    From 1972 to 1982, 563 patients with Stage I and II non-Hodgkin's lymphoma received radiation therapy in the department of radiology which belongs to the JLRTS group. Local control failures were seen in only 5 cases (0.9 %). The regional recurrences were found in 30 cases (5 %). 17 of recurrences occured during the first 5 years. 17 cases had remissions again, and 5 cases had 5 year survivals. (author)

  13. Current surgery of retinal detachment recurrence. Review

    Directory of Open Access Journals (Sweden)

    V. D. Zakharov

    2012-01-01

    Full Text Available this review presents a detailed analysis and an experience of surgical treatment of retinal detachment recurrence associated with light silicone oil tamponade of vitreous cavity. Approaches and variants of treatment were described in the historical aspect and till now. there are considered general and particular issues in case of retinal detachment recurrence appearance, expediency and volume of intraoperative manipulations, time of operation and choice of temporary substitute of vitreous body for a purpose of postoperative tamponade of vitreous cavity.

  14. Recurrence risk of ictal asystole in epilepsy.

    Science.gov (United States)

    Hampel, Kevin G; Thijs, Roland D; Elger, Christian E; Surges, Rainer

    2017-08-22

    To determine the recurrence risk of ictal asystole (IA) and its determining factors in people with epilepsy. We performed a systematic review of published cases with IA in 3 databases and additionally searched our local database for patients with multiple seizures simultaneously recorded with ECG and EEG and at least one IA. IA recurrence risk was estimated by including all seizures without knowledge of the chronological order. Various clinical features were assessed by an individual patient data meta-analysis. A random mixed effect logistic regression model was applied to estimate the average recurrence risk of IA. Plausibility of the calculated IA recurrence risk was checked by analyzing the local dataset with available information in chronological order. Eighty patients with 182 IA in 537 seizures were included. Recurrence risk of IA amounted to 40% (95% confidence interval [CI] 32%-50%). None of the clinical factors (age, sex, type and duration of epilepsy, hemispheric lateralization, duration of IA per patient) appeared to have a significant effect on the short-term recurrence risk of IA. When considering the local dataset only, IA recurrence risk was estimated to 30% (95% CI 14%-53%). Information whether IA coincided with symptoms (i.e., syncope) or not was given in 60 patients: 100 out of 142 IAs were symptomatic. Our data suggest that in case of clinically suspected IA, the recording of 1 or 2 seizures is not sufficient to rule out IA. Furthermore, the high short-term recurrence risk favors aggressive treatment, including pacemaker implantation if seizure freedom cannot be achieved. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  15. To the non-recurrence nature

    International Nuclear Information System (INIS)

    Somsikov, V.

    1999-01-01

    On the example of a hard-disk system the non-recurrence problem have been investigated. Some of the properties of differential equation for the motion of hard-disk system have been analyzed. Using the suggestions of all disk pairs occur simultaneously within a rather small period τ, asymptotic properties of the non-equilibrium hard-disk system when t→∞ have been studied. The explanation of non-recurrence nature have been submitted. (author)

  16. Recurrence of amblyopia after occlusion therapy.

    Science.gov (United States)

    Bhola, Rahul; Keech, Ronald V; Kutschke, Pamela; Pfeifer, Wanda; Scott, William E

    2006-11-01

    To determine the stability of visual acuity (VA) after a standardized occlusion regimen in children with strabismic and/or anisometropic amblyopia. Retrospective, population-based, consecutive observational case series. Four hundred forty-nine patients younger than 10 years who underwent an occlusion trial for amblyopia and were observed until there was a recurrence of amblyopia or for a maximum of 1 year after decrease or cessation of occlusion therapy. We performed a retrospective chart review of all patients treated by occlusion therapy for strabismic and/or anisometropic amblyopia at our institution over a 34-year period. Of the 1621 patients identified in our database, 449 met the eligibility criteria and were included in this study. Patients having at least a 2 logarithm of the minimum angle of resolution (logMAR)-level improvement in VA by optotypes or a change from unmaintained to maintained fixation preference during the course of occlusion therapy were included. A recurrence of amblyopia was defined as > or =2 logMAR levels of VA reduction or reversal of fixation preference within 1 year after a decrease or cessation of occlusion therapy. Recurrence of amblyopia after a decrease or cessation of occlusion therapy and its relationship with patient age and VA of the amblyopic eye at the time of decrease or cessation of occlusion therapy. Of 653 occlusion trials, 179 (27%) resulted in recurrence of amblyopia. The recurrence was found to be inversely correlated with patient age. There was no statistically significant association between the recurrence of amblyopia and VA of the amblyopic eye at the end of maximal occlusion therapy. There is a clinically important risk of amblyopia recurrence when occlusion therapy is decreased before the age of 10 years. The risk of recurrence is inversely correlated with age (P<0.0001).

  17. Prevention of Recurrent Staphylococcal Skin Infections

    OpenAIRE

    Creech, C. Buddy; Al-Zubeidi, Duha N.; Fritz, Stephanie A.

    2015-01-01

    Staphylococcus aureus infections pose a significant health burden. The emergence of community-associated methicillin-resistant S. aureus has resulted in an epidemic of skin and soft tissue infections (SSTI), and many patients experience recurrent SSTI. As S. aureus colonization is associated with subsequent infection, decolonization is recommended for patients with recurrent SSTI or in settings of ongoing transmission. S. aureus infections often cluster within households and asymptomatic carr...

  18. Heterogeneous recurrence monitoring and control of nonlinear stochastic processes

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hui, E-mail: huiyang@usf.edu; Chen, Yun [Complex Systems Monitoring, Modeling and Analysis Laboratory, University of South Florida, Tampa, Florida 33620 (United States)

    2014-03-15

    Recurrence is one of the most common phenomena in natural and engineering systems. Process monitoring of dynamic transitions in nonlinear and nonstationary systems is more concerned with aperiodic recurrences and recurrence variations. However, little has been done to investigate the heterogeneous recurrence variations and link with the objectives of process monitoring and anomaly detection. Notably, nonlinear recurrence methodologies are based on homogeneous recurrences, which treat all recurrence states in the same way as black dots, and non-recurrence is white in recurrence plots. Heterogeneous recurrences are more concerned about the variations of recurrence states in terms of state properties (e.g., values and relative locations) and the evolving dynamics (e.g., sequential state transitions). This paper presents a novel approach of heterogeneous recurrence analysis that utilizes a new fractal representation to delineate heterogeneous recurrence states in multiple scales, including the recurrences of both single states and multi-state sequences. Further, we developed a new set of heterogeneous recurrence quantifiers that are extracted from fractal representation in the transformed space. To that end, we integrated multivariate statistical control charts with heterogeneous recurrence analysis to simultaneously monitor two or more related quantifiers. Experimental results on nonlinear stochastic processes show that the proposed approach not only captures heterogeneous recurrence patterns in the fractal representation but also effectively monitors the changes in the dynamics of a complex system.

  19. Recurrence interval analysis of trading volumes.

    Science.gov (United States)

    Ren, Fei; Zhou, Wei-Xing

    2010-06-01

    We study the statistical properties of the recurrence intervals τ between successive trading volumes exceeding a certain threshold q. The recurrence interval analysis is carried out for the 20 liquid Chinese stocks covering a period from January 2000 to May 2009, and two Chinese indices from January 2003 to April 2009. Similar to the recurrence interval distribution of the price returns, the tail of the recurrence interval distribution of the trading volumes follows a power-law scaling, and the results are verified by the goodness-of-fit tests using the Kolmogorov-Smirnov (KS) statistic, the weighted KS statistic and the Cramér-von Mises criterion. The measurements of the conditional probability distribution and the detrended fluctuation function show that both short-term and long-term memory effects exist in the recurrence intervals between trading volumes. We further study the relationship between trading volumes and price returns based on the recurrence interval analysis method. It is found that large trading volumes are more likely to occur following large price returns, and the comovement between trading volumes and price returns is more pronounced for large trading volumes.

  20. Recurrence quantity analysis based on matrix eigenvalues

    Science.gov (United States)

    Yang, Pengbo; Shang, Pengjian

    2018-06-01

    Recurrence plots is a powerful tool for visualization and analysis of dynamical systems. Recurrence quantification analysis (RQA), based on point density and diagonal and vertical line structures in the recurrence plots, is considered to be alternative measures to quantify the complexity of dynamical systems. In this paper, we present a new measure based on recurrence matrix to quantify the dynamical properties of a given system. Matrix eigenvalues can reflect the basic characteristics of the complex systems, so we show the properties of the system by exploring the eigenvalues of the recurrence matrix. Considering that Shannon entropy has been defined as a complexity measure, we propose the definition of entropy of matrix eigenvalues (EOME) as a new RQA measure. We confirm that EOME can be used as a metric to quantify the behavior changes of the system. As a given dynamical system changes from a non-chaotic to a chaotic regime, the EOME will increase as well. The bigger EOME values imply higher complexity and lower predictability. We also study the effect of some factors on EOME,including data length, recurrence threshold, the embedding dimension, and additional noise. Finally, we demonstrate an application in physiology. The advantage of this measure lies in a high sensitivity and simple computation.

  1. Recurrence relations for spin foam vertices

    International Nuclear Information System (INIS)

    Bonzom, Valentin; Livine, Etera R; Speziale, Simone

    2010-01-01

    We study recurrence relations for various Wigner 3nj-symbols and the non-topological 10j-symbol. For the 6j- and the 15j-symbols which correspond to basic amplitudes of 3d and 4d topological spin foam models, recurrence relations are obtained from the invariance under Pachner moves and can be interpreted as quantizations of the constraints of the underlying classical field theories. We also derive recurrences from the action of holonomy operators on spin network functionals, making a more precise link between the topological Pachner moves and the classical constraints. Interestingly, our recurrence relations apply to any SU(2) invariant symbol, depending on the cycles of the corresponding spin network graph. Another method is used for non-topological objects such as the 10j-symbol and pseudo-isosceles 6j-symbols. The recurrence relations are also interpreted in terms of elementary geometric properties. Finally, we discuss the extension of the recurrences to take into account boundary states which leads to equations similar to Ward identities for correlation functions in the Barrett-Crane model.

  2. Studies on mutation techniques in rice breeding

    International Nuclear Information System (INIS)

    Wang Cailian; Chen Qiufang; Jin Wei

    2001-01-01

    Synthetical techniques for improving rice mutation breeding efficiency were studied. The techniques consist of corresponding relationship between radiosensitivity and mutation frequency, choosing appropriate materials, combination of physical and chemical mutagens, mutagenic effects of the new mutagenic agents as proton, ions, synchronous irradiation and space mutation. These techniques and methods for inducing mutations are very valuable to increase inducing mutation efficiency and breeding level

  3. Identification of miRNAs associated with recurrence of stage II colorectal cancer

    DEFF Research Database (Denmark)

    Christensen, Lise Lotte; Tobiasen, Heidi; Schepeler, Troels

    2011-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer deaths. Twenty-five percent of the patients radically treated for a stage II CRC (no lymph node or distant metastasis) later develop recurrence and dies from the disease. MicroRNAs (miRNAs) are aberrantly expressed or mutated in human...... target prediction and transcript profiling. Initially, miRNA over-expression in HCT116 cells was followed by transcriptional profiling of transfected cells using GeneChip Human Exon 1.0 ST Arrays. Three in silico predicted miRNA targets showing differential mRNA expression upon miRNA up-regulation were...... cancers, and function either as tumour suppressors or oncogenes. Additionally, they also appear to have both diagnostic and prognostic significance. The aim of the present study was to identify miRNAs associated with recurrence of stage II CRC, followed up by an investigation of how these potential...

  4. The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer.

    Science.gov (United States)

    Lorusso, Domenica; Fontanella, Caterina; Maltese, Giuseppa; Lepori, Stefano; Tripodi, Elisa; Bogani, Giorgio; Raspagliesi, Francesco

    2017-06-01

    Recurrence is a common event in endothelial ovarian cancer (EOC) patients, and the choice of the most appropriate treatment is driven by the platinum-free interval, molecular characteristics of the disease such as BRCA mutational status, previous treatments and toxicity. Areas covered: This review focuses on the main hematologic and non-hematologic toxicities correlated with the use of licensed antiangiogenic agents and PARP inhibitors in recurrent platinum-sensitive EOC, providing recommendations for their management. Expert opinion: The clinical research over the next years will be focused on a more precise characterization of molecular pathways underlying tumorigenesis of the five ovarian tumors, to improve the decision-making process in these rare diseases. For this purpose, new study designs and international collaborations will become mandatory. Immunotherapy, antiangiogenic agents and PARP inhibitors will be combined to build a treatment strategy algorithm which will allow patients to receive all the available treatment option, in the more appropriate sequence.

  5. An evaluation of factors predicting breast recurrence and prognosis after recurrence, on distinguishing intramammary and extramammary recurrence, in breast-conserving surgery

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Reiki; Nagao, Kazuharu; Miyayama, Haruhiko [Kumamoto City Hospital (Japan)] (and others)

    2001-06-01

    Recurrence of cancer in the breast is an important problem in breast-conserving therapy. We evaluated risk factors for recurrence from the viewpoint of recurrence type and outcome after recurrence. Of 533 cases of breast cancer treated with breast-conserving surgery from April 1989 through July 2000, disease in 66 recurred (12.4%) and were classified as 23 cases of breast recurrence only, 16 cases of both breast recurrence and distant metastasis, and 27 cases of distant metastasis only. The clinical factors examined included age, lymphatic invasion, nodal status, extensive intraductal component (EIC), proliferative activity, and estrogen receptor (ER) status. Of the 39 cases of breast recurrence, 19 had intramammary tumors and 20 had extramammary tumors of the skin, subcutaneous tissue, or muscle, including 8 cases with inflammatory breast recurrence. Multivariate analysis showed that factors correlated with breast recurrence were age, ER status, proliferative activity, and surgical margin. EIC-comedo was related to intramammary recurrence, whereas lymphatic invasion and nodal status were related to extramammary recurrence. Postoperative irradiation was an effective treatment for tumors in young women and tumors with positive margins or a comedo component. Outcome after breast recurrence depended on nodal status at primary operation, and survival rates were worst in patients with inflammatory breast recurrence. In conclusion, age, EIC-comedo status, the surgical margin, and negative ER status were correlated with breast recurrence. Countermeasures against these factors should be investigated. (author)

  6. An evaluation of factors predicting breast recurrence and prognosis after recurrence, on distinguishing intramammary and extramammary recurrence, in breast-conserving surgery

    International Nuclear Information System (INIS)

    Nishimura, Reiki; Nagao, Kazuharu; Miyayama, Haruhiko

    2001-01-01

    Recurrence of cancer in the breast is an important problem in breast-conserving therapy. We evaluated risk factors for recurrence from the viewpoint of recurrence type and outcome after recurrence. Of 533 cases of breast cancer treated with breast-conserving surgery from April 1989 through July 2000, disease in 66 recurred (12.4%) and were classified as 23 cases of breast recurrence only, 16 cases of both breast recurrence and distant metastasis, and 27 cases of distant metastasis only. The clinical factors examined included age, lymphatic invasion, nodal status, extensive intraductal component (EIC), proliferative activity, and estrogen receptor (ER) status. Of the 39 cases of breast recurrence, 19 had intramammary tumors and 20 had extramammary tumors of the skin, subcutaneous tissue, or muscle, including 8 cases with inflammatory breast recurrence. Multivariate analysis showed that factors correlated with breast recurrence were age, ER status, proliferative activity, and surgical margin. EIC-comedo was related to intramammary recurrence, whereas lymphatic invasion and nodal status were related to extramammary recurrence. Postoperative irradiation was an effective treatment for tumors in young women and tumors with positive margins or a comedo component. Outcome after breast recurrence depended on nodal status at primary operation, and survival rates were worst in patients with inflammatory breast recurrence. In conclusion, age, EIC-comedo status, the surgical margin, and negative ER status were correlated with breast recurrence. Countermeasures against these factors should be investigated. (author)

  7. Mutation breeding in soybean

    International Nuclear Information System (INIS)

    Baradjanegara, A.A.

    1983-01-01

    In Indonesia, soybean is one of the important crop after rice. It is generally cultivated in the lowlands and rarely in the highlands. Seeds of soybean variety ORBA were treated with various doses of fast neutrons, gamma rays, EMS and NaN 3 with the aims of studying the mutagen effects in M-1 and M-2 generations and also to select mutants adapted to highland conditions. D-50 doses for gamma rays, fast neutrons and EMS were around 23 krad, 2,300 rad, 0.3%, respectively. Much higher chlorophyll mutation frequency was observed in EMS treatment of 0.3%. Seven mutants were shorter and four early mutants matured from 4 to 20 days earlier than the control plants. Two early mutants were quite adaptable in both the low and highlands and produced better yields than the parental material. (author)

  8. Founder Mutations in Xeroderma Pigmentosum

    Science.gov (United States)

    Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.

    2012-01-01

    In this issue, Soufir et al. report a founder mutation in the XPC DNA repair gene in 74% of families with xeroderma pigmentosum (XP) in the Maghreb region (Algeria, Morocco, and Tunisia) of northern Africa. These patients have a high frequency of skin cancer. The presence of this founder mutation provides an opportunity for genetic counseling and early diagnosis of XP. PMID:20463673

  9. Mutations causative of familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Benn, Marianne; Watts, Gerald F; Tybjærg-Hansen, Anne

    2016-01-01

    causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study. METHODS AND RESULTS: We genotyped for LDLR[W23X;W66G;W556S] and APOB[R3500Q] accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information......-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L. CONCLUSION: Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria....... The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH...

  10. MPL mutations in myeloproliferative disorders

    DEFF Research Database (Denmark)

    Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.

    2008-01-01

    Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet c......DNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F......(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin...

  11. Mutation induction by heavy ions

    Science.gov (United States)

    Kiefer, J.; Stoll, U.; Schneider, E.

    1994-10-01

    Mutation induction by heavy ions is compared in yeast and mammalian cells. Since mutants can only be recovered in survivors the influence of inactivation cross sections has to be taken into account. It is shown that both the size of the sensitive cellular site as well as track structure play an important role. Another parameter which influences the probability of mutation induction is repair: Contrary to naive assumptions primary radiation damage does not directly lead to mutations but requires modification to reconstitute the genetic machinery so that mutants can survive. The molecular structure of mutations was analyzed after exposure to deuterons by amplification with the aid of polymerase chain reaction. The results-although preliminary-demonstrate that even with densely ionizing particles a large fraction does not carry big deletions which suggests that point mutations may also be induced by heavy ions.

  12. Mutation breeding in ornamental plants

    International Nuclear Information System (INIS)

    Datta, S.K.

    1990-01-01

    Full text: Mutation induction produced a large number of new promising varieties in ornamental species. 37 new mutants of Chrysanthemum and 14 of rose have been developed by mutations and released for commercialisation. The mutations in flower colour/shape were detected as chimeras in M 1 V 1 , M 1 V 2 , M 1 V 3 generations. The mutation frequency varied with the cultivar and exposure to gamma rays. Comparative analysis of original cultivars and their respective induced mutants on cytomorphological, anatomical and biochemical characters are being carried out for better understanding of the mechanism involved in the origin and evolution of somatic flower colour/shape mutations. Cytological analysis with reference to chromosomal aberrations, chromosome number, ICV, INV and DNA content gave no differences between the original and mutant cultivars. Analysis of florets/petal pigments by TLC and spectrophotometric methods indicated both qualitative and quantitative changes. (author)

  13. Biological significance of TERT promoter mutation in papillary urothelial neoplasm of low malignant potential.

    Science.gov (United States)

    Wang, Chung-Chieh; Huang, Chao-Yuan; Jhuang, Yu-Lin; Chen, Chih-Chi; Jeng, Yung-Ming

    2018-04-01

    Mutations in FGFR3 and the promoter region of the telomerase reverse transcriptase (TERT) gene have been found frequently in urothelial carcinoma of the urinary bladder. However, related data for papillary urothelial neoplasm of low malignant potential (PUNLMP) are limited. In this study, we investigated the mutation status of the TERT promoter, FGFR3 and HRAS in low-grade papillary urothelial neoplasms and evaluated their prognostic significance. The cases included in this study comprised 21 inverted papillomas, 30 PUNLMPs and 34 low-grade non-invasive papillary urothelial carcinomas (NIPUCs). TERT promoter mutations were observed in 10 (33%) PUNLMPs and 17 (50%) low-grade NIPUCs, but not in any inverted papilloma. FGFR3 mutations were observed more frequently in PUNLMP and low-grade NIPUC than in inverted papillomas (P = 0.009), whereas the opposite trend was noted for HRAS mutations (P low-grade NIPUC (P = 0.530). Notably, PUNLMP cases with TERT promoter mutations had a similar recurrence rate to that in low-grade NIPUC cases (P = 0.487). Our results suggest that the status of the TERT promoter mutation may serve as a biomarker of prognostic stratification in patients with PUNLMP. © 2017 John Wiley & Sons Ltd.

  14. Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia.

    Science.gov (United States)

    Schneider, Adele; Bardakjian, Tanya; Reis, Linda M; Tyler, Rebecca C; Semina, Elena V

    2009-12-01

    SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and identified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families.

  15. Domain-restricted mutation analysis to identify novel driver events in human cancer

    Directory of Open Access Journals (Sweden)

    Sanket Desai

    2017-10-01

    Full Text Available Analysis of mutational spectra across various cancer types has given valuable insights into tumorigenesis. Different approaches have been used to identify novel drivers from the set of somatic mutations, including the methods which use sequence conservation, geometric localization and pathway information. Recent computational methods suggest use of protein domain information for analysis and understanding of the functional consequence of non-synonymous mutations. Similarly, evidence suggests recurrence at specific position in proteins is robust indicators of its functional impact. Building on this, we performed a systematic analysis of TCGA exome derived somatic mutations across 6089 PFAM domains and significantly mutated domains were identified using randomization approach. Multiple alignment of individual domain allowed us to prioritize for conserved residues mutated at analogous positions across different proteins in a statistically disciplined manner. In addition to the known frequently mutated genes, this analysis independently identifies low frequency Meprin and TRAF-Homology (MATH domain in Speckle Type BTB/POZ (SPOP protein, in prostate adenocarcinoma. Results from this analysis will help generate hypotheses about the downstream molecular mechanism resulting in cancer phenotypes.

  16. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

    Science.gov (United States)

    Horvath, Rita; Hudson, Gavin; Ferrari, Gianfrancesco; Fütterer, Nancy; Ahola, Sofia; Lamantea, Eleonora; Prokisch, Holger; Lochmüller, Hanns; McFarland, Robert; Ramesh, V; Klopstock, Thomas; Freisinger, Peter; Salvi, Fabrizio; Mayr, Johannes A; Santer, Rene; Tesarova, Marketa; Zeman, Jiri; Udd, Bjarne; Taylor, Robert W; Turnbull, Douglass; Hanna, Michael; Fialho, Doreen; Suomalainen, Anu; Zeviani, Massimo; Chinnery, Patrick F

    2006-07-01

    Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

  17. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru.

    Science.gov (United States)

    Abugattas, J; Llacuachaqui, M; Allende, Y Sullcahuaman; Velásquez, A Arias; Velarde, R; Cotrina, J; Garcés, M; León, M; Calderón, G; de la Cruz, M; Mora, P; Royer, R; Herzog, J; Weitzel, J N; Narod, S A

    2015-10-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Total pancreatectomy and autoislet transplant for chronic recurrent pancreatitis in a 5-year-old boy

    Directory of Open Access Journals (Sweden)

    Shaheed Merani

    2016-10-01

    Full Text Available Childhood chronic pancreatitis is a rare disorder, which can lead to a chronically debilitating condition. The etiology of recurrent hereditary pancreatitis, which previously was classified as idiopathic, has now been attributed in certain cases to specific genetic mutations including abnormalities in the PRSS gene. We describe here the use of total pancreatectomy and autoislet transplant in a 5-year-old with chronic pancreatitis. This represents the youngest patient undergoing the procedure at our institution. The early successful outcomes for this patient, both of symptom relief and glycemic control are detailed.

  19. Investigation on feasibility of recurrence quantification analysis for ...

    African Journals Online (AJOL)

    The RQA parameters such as percent recurrence (REC), trapping time (TT), percent laminarity (LAM) and entropy (ENT), and also the recurrence plots color patterns for different flank wear, can be used in detecting insert wear in face milling. Keywords: milling, flank wear, recurrence plot, recurrence quantification analysis.

  20. Young patient's age determines pterygium recurrence after surgery.

    African Journals Online (AJOL)

    2014-03-01

    Mar 1, 2014 ... and degree of fleshiness, and laterality were compared between recurrent and no recurrent pterygia. ... was performed to determine the predictors of pterygium recurrence. Recurrence rates after surgery were compared between. CAT and LCAT. Results. ... obstruction of vision, disfigurement, or frequent.

  1. Wiskott-Aldrich Syndrome With Normal-Sized Platelets in an Eighteen-Month-Old Boy: A Rare Mutation

    Directory of Open Access Journals (Sweden)

    Jayitri Mazumdar

    2015-07-01

    Full Text Available Introduction: Wiskott-Aldrich syndrome (WAS is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and recurrent infections. The disease is usually associated with small defective platelets. Case Presentation: We described an 18-month-old boy who presented with lower gastrointestinal bleeding, eczema, and recurrent infections. There was pancytopenia with normal-sized platelets. In addition, the CD4 count was significantly low and serum IgA and IgE levels were increased. The diagnosis of WAS was confirmed by detecting a mutation of WAS gene, which was due to a deletion mutation resulting in frameshift (c.177DelT. Conclusions: Usually microplatelets with mean platelet volume of 4-5 fL are seen in WAS, but in this case, the patient had normal-sized platelets with a rare mutation of WAS gene. Therefore, high index of clinical suspicion is needed to diagnose WAS.

  2. Muckle-Wells syndrome in an Indian family associated with NLRP3 mutation

    Directory of Open Access Journals (Sweden)

    M C Abdulla

    2015-01-01

    Full Text Available Muckle - Wells syndrome (MWS is a rare autosomal dominant disease that belongs to a group of hereditary periodic fever syndromes. It is part of the wider spectrum of the cryopyrin-associated periodic syndrome (CAPS which has only rarely been described in non-Caucasian individuals. It is characterized by recurrent self-limiting episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis from childhood. Progressive sensorineural hearing loss and amyloidosis are two late complications. MWS is caused by gain of function mutations in the NLRP3 gene, which encodes cryopyrin, a protein involved in regulating the production of proinflammatory cytokines. We report two patients with MWS in an Indian family associated with the p.D303N mutation in the NLRP3 gene. These findings promote awareness of these hereditary periodic fever syndromes as a cause for recurrent fevers from childhood in the Indian population.

  3. Different clinical phenotypes in familial severe congenital neutropenia cases with same mutation of the ELANE gene.

    Science.gov (United States)

    Cho, Hye-Kyung; Jeon, In Sang

    2014-03-01

    Severe congenital neutropenia (SCN) is a heterogeneous group of disorders with a defect in granulopoiesis causing marked neutropenia and severe bacterial infections. A 17-month-old girl (patient 1) was admitted due to cervical lymphadenitis caused by methicillin-resistant Staphylococcus aureus, with neutropenia. She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. Her sister, a 37-month-old girl (patient 2), had recurrent stomatitis with profound neutropenia, and her mother, a 32-yr-old woman (patient 3), had had recurrent stomatitis until her early 20s with neutropenia. We found an ELANE gene mutation (c.597+1G > A) from them in direct DNA sequencing analysis. Patients 1 and 2 did not respond to granulocyte colony stimulating factor and patient 1 was treated with prolonged antibiotics and excision. We demonstrated inherited SCN cases showing different severity even with the same mutation of the ELANE gene in a family.

  4. Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.

    Directory of Open Access Journals (Sweden)

    Alexandra V Stavropoulou

    Full Text Available Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24. In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6% of familial cancer cases and in 27/592 (4.6% of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%. The majority of BRCA1 carriers (71.2% presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.

  5. The rate of beneficial mutations surfing on the wave of a range expansion.

    Directory of Open Access Journals (Sweden)

    Rémi Lehe

    Full Text Available Many theoretical and experimental studies suggest that range expansions can have severe consequences for the gene pool of the expanding population. Due to strongly enhanced genetic drift at the advancing frontier, neutral and weakly deleterious mutations can reach large frequencies in the newly colonized regions, as if they were surfing the front of the range expansion. These findings raise the question of how frequently beneficial mutations successfully surf at shifting range margins, thereby promoting adaptation towards a range-expansion phenotype. Here, we use individual-based simulations to study the surfing statistics of recurrent beneficial mutations on wave-like range expansions in linear habitats. We show that the rate of surfing depends on two strongly antagonistic factors, the probability of surfing given the spatial location of a novel mutation and the rate of occurrence of mutations at that location. The surfing probability strongly increases towards the tip of the wave. Novel mutations are unlikely to surf unless they enjoy a spatial head start compared to the bulk of the population. The needed head start is shown to be proportional to the inverse fitness of the mutant type, and only weakly dependent on the carrying capacity. The precise location dependence of surfing probabilities is derived from the non-extinction probability of a branching process within a moving field of growth rates. The second factor is the mutation occurrence which strongly decreases towards the tip of the wave. Thus, most successful mutations arise at an intermediate position in the front of the wave. We present an analytic theory for the tradeoff between these factors that allows to predict how frequently substitutions by beneficial mutations occur at invasion fronts. We find that small amounts of genetic drift increase the fixation rate of beneficial mutations at the advancing front, and thus could be important for adaptation during species invasions.

  6. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Yu Chaowen

    2011-12-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: PKD1 (16p13.3 and PKD2 (4q21. Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of PKD1 gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both PKD1 and PKD2 genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC. Methods Both PKD1 and PKD2 genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources. Results A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65. About 69% (20/29 of the mutations are first reported with a recurrent mutation rate of 31%. Conclusions Mutation study of PKD1 and PKD2 genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.

  7. Mutational meltdown in laboratory yeast populations

    NARCIS (Netherlands)

    Zeyl, C.; Mizesko, M.; Visser, de J.A.G.M.

    2001-01-01

    In small or repeatedly bottlenecked populations, mutations are expected to accumulate by genetic drift, causing fitness declines. In mutational meltdown models, such fitness declines further reduce population size, thus accelerating additional mutation accumulation and leading to extinction. Because

  8. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

    International Nuclear Information System (INIS)

    Palomba, Grazia; Tanda, Francesco; Farris, Antonio; Orrù, Sandra; Floris, Carlo; Pisano, Marina; Lovicu, Mario; Santona, Maria Cristina; Landriscina, Gennaro; Crisponi, Laura; Palmieri, Giuseppe; Loi, Angela; Monne, Maria; Uras, Antonella; Fancello, Patrizia; Piras, Giovanna; Gabbas, Attilio; Cossu, Antonio; Budroni, Mario; Contu, Antonio

    2009-01-01

    In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764-8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations

  9. VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.

    Science.gov (United States)

    Jia, Peilin; Zhao, Zhongming

    2014-02-01

    A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.

  10. A new assay to identify recurrent mutations in acute myeloid leukemia using next-generation sequencing

    Directory of Open Access Journals (Sweden)

    Coriu Daniel

    2014-03-01

    Full Text Available Introducere: Leucemia acută mieloblastică (LAM este o boală heterogenă caracterizată prin debut la vârstă avansată, fenotip agresiv şi prognostic nefavorabil în special în grupul de vârstă de peste 65 de ani. Pentru stratificarea pacienţilor în grupe de risc se utilizează citogenetica clasică împreună cu metodele moleculare pentru identificarea mutaţiilor punctiforme. În acest articol descriem o nouă metodă de identificare a mutaţiilor în 5 gene implicate în LAM: RUNX1, FLT3, DNMT3A, IDH1 şi IDH2 utilizând secvenţierea de nouă generaţie. Materiale şi metode: Au fost secvenţiate probe de la 40 de pacienţi cu LAM cu cariotip normal internaţi în Institutul Clinic Fundeni. Design-ul de primeri a fost efectuat utilizând LaserGene Genomics suit. Secvenţierea de nouă generaţie a fost efectuată pe platforma MiSeq de la Illumina. Rezultatele au fost analizate utilizând LaserGene Genomics suit. Rezultatele obţinute prin secvenţierea de nouă generaţie au fost comparate cu secvenţierea Sanger. Rezultate: Nu au fost identificate mutaţii adiţionale în probele de la nouă pacienţi pozitivi pentru mutaţiile FLT3-ITD şi / sau NPM1. În probele de la 25 din 31 de pacienţi, cu cariotip normal şi fără mutaţii FLT3-ITD şi NPM1, au fost identificate mutaţii în una din cele 5 gene studiate. Toate aceste mutaţii, identificate prin secvenţierea de nouă generaţie, au fost confirmate prin metoda de secvenţiere clasică Sanger. Concluzii: În acest studiu am validat o metodă de identificare a mutaţiilor apărute la pacienţii cu LAM utilizând secvenţierea de nouă generaţie. Această metodă prezintă o serie de avantaje: este mai ieftină ca in cazul secvenţierii Sanger, prezintă o sensibilitate crescută pentru detectarea mutaţiilor, a fost descrisă ca fiind cantitativă şi în cazul nostru a permis stratificarea în grupe de risc a majorităţii pacienţilor cu cariotip normal şi fără mutaţiile FLT3-ITD şi NPM1.

  11. Systematic reconstruction of autism biology from massive genetic mutation profiles.

    Science.gov (United States)

    Luo, Weijun; Zhang, Chaolin; Jiang, Yong-Hui; Brouwer, Cory R

    2018-04-01

    Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.

  12. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.

    Directory of Open Access Journals (Sweden)

    Fabiola Traina

    Full Text Available We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM. SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04 and sole TET2 mutations (P<0.001. In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

  13. Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.

    Science.gov (United States)

    Orrico, A; Galli, L; Faivre, L; Clayton-Smith, J; Azzarello-Burri, S M; Hertz, J M; Jacquemont, S; Taurisano, R; Arroyo Carrera, I; Tarantino, E; Devriendt, K; Melis, D; Thelle, T; Meinhardt, U; Sorrentino, V

    2010-02-01

    Mutations in the FGD1 gene have been shown to cause Aarskog-Scott syndrome (AAS), or facio-digito-genital dysplasia (OMIM#305400), an X-linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any evidence for phenotype-genotype correlations between type and position of mutations and clinical features. In addition to the well-established phenotypic features of AAS, other clinical features are also reported and discussed. Copyright 2010 Wiley-Liss, Inc.

  14. Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells

    OpenAIRE

    Luca Mologni; Mariantonia Costanza; Geeta Geeta Sharma; Michela Viltadi; Luca Massimino; Stefania Citterio; Stefania Purgante; Hima Raman; Alessandra Pirola; Massimo Zucchetti; Rocco Piazza; Carlo Gambacorti-Passerini

    2018-01-01

    BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current frontline therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion w...

  15. Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence.

    Science.gov (United States)

    Ferguson, Margaret D; Dong, Lei; Wan, Jim; Deneve, Jeremiah L; Dickson, Paxton V; Behrman, Stephen W; Shibata, David; Martin, Mike G; Glazer, Evan S

    2018-02-10

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations-gene mutations, variations in copy number, and changes in gene expression-has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student's t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson's χ 2 . Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p molecular alterations warrants further investigation.

  16. Structure of a PKA RIα Recurrent Acrodysostosis Mutant Explains Defective cAMP-Dependent Activation.

    Science.gov (United States)

    Bruystens, Jessica Gh; Wu, Jian; Fortezzo, Audrey; Del Rio, Jason; Nielsen, Cole; Blumenthal, Donald K; Rock, Ruth; Stefan, Eduard; Taylor, Susan S

    2016-12-04

    Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing. The crystal structure of a monomeric form of this mutant (RIα92-365) bound to the catalytic (C)-subunit reveals the dysfunctional regions of the RIα subunit. Beyond the missing residues, the entire capping motif is disordered (residues 357-379) and explains the disrupted cAMP binding. Moreover, the effects of the mutation extend far beyond the CNB-B domain and include the active site and N-lobe of the C-subunit, which is in a partially open conformation with the C-tail disordered. A key residue that contributes to this crosstalk, D267, is altered in our structure, and we confirmed its functional importance by mutagenesis. In particular, the D267 interaction with Arg241, a residue shown earlier to be important for allosteric regulation, is disrupted, thereby strengthening the interaction of D267 with the C-subunit residue Arg194 at the R:C interface. We see here how the switch between active (cAMP-bound) and inactive (holoenzyme) conformations is perturbed and how the dynamically controlled crosstalk between the helical domains of the two CNB domains is necessary for the functional regulation of PKA activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Meningeal infiltration in recurrent nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Chong, V.F.H.; Fan, Y.-F.

    2000-01-01

    Permeative infiltration of the meninges appears to be a distinct form of recurrent nasopharyngeal carcinoma (NPC). The present report of eight patients with recurrent NPC illustrates meningeal infiltration following basal foramina extension. Seven of the eight patients (88%) showed jugular foramen involvement. Three patients had concomitant infiltration of the foramen magnum. There was one patient showing spread through the foramen lacerum. Only four (50%) of these patients had clinically detectable tumour in the nasopharynx, while the other half showed deep submucosal recurrence with endoscopically unremarkable findings. Permeative meningeal infiltration appears to be a distinct form of NPC recurrence. It is important to recognize this phenomenon so as to optimize the treatment options. The imaging studies were reviewed and the following features were recorded: local nasopharyngeal recurrence, the manner of intracranial spread and site of meningeal infiltration. Four patients had only MRI, two had only CT and two patients had both CT and MRI. The presence or absence of intracranial tumour before treatment was also recorded. Two observers reviewed the images and results were arrived at by consensus. Copyright (1999) Blackwell Science Pty Ltd

  18. CT findings in recurrent pyogenic cholangitis

    International Nuclear Information System (INIS)

    Jung, Seung Hye; Lim, Jae Hoon; Ko, Young Tae; Lee, Dong Ho

    1991-01-01

    Recurrent pyogenic cholangitis is characterized clinically by recurrent attacks of right upper abdominal pain, fever and jaundice, and pathologically by chronic inflammation of the bile ducts with or without pigment bile duct stones. We analyzed the CT findings of 33 cases with recurrent pyogenic cholangitis. Twenty-four cases were confirmed by operation, and 9 cases were diagnosed clinically and cholangiographically. The CT findings of recurrent pyogenic cholangitis were dilatation of the intrahepatic ducts (n = 30), dilatation of the extrahepatic ducts (n = 24) intrahepatic stones (n = 16), extrahepatic stones (n = 12), stricture of the bile ducts (n = 10), wall enhancement of the bile ducts (n = 8), gallstones (n = 8), segmental atrophy of the liver (n = 7), pneumobilia (n = 4), abscess (n = 3), and segmental enhancement (n = 1) of the liver. A CT is considered helpful when sectional imaging is needed, but sonographic findings are equivocal or not confirmative; space-occupying lesions complicated with recurrent pyogenic cholangitis: hepatic resection is planned; and imaging guidance is needed for complex drainage procedures

  19. Local recurrence risk after previous salvage mastectomy.

    Science.gov (United States)

    Tanabe, M; Iwase, T; Okumura, Y; Yoshida, A; Masuda, N; Nakatsukasa, K; Shien, T; Tanaka, S; Komoike, Y; Taguchi, T; Arima, N; Nishimura, R; Inaji, H; Ishitobi, M

    2016-07-01

    Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136). Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Recurrent urinary tract infections in women.

    Science.gov (United States)

    Aydin, Abdullatif; Ahmed, Kamran; Zaman, Iftikhar; Khan, Muhammad Shamim; Dasgupta, Prokar

    2015-06-01

    Recurrent urinary tract infections (UTIs) are more common in women and are frequently defined as ≥2 episodes in the last 6 months or ≥3 episodes in the last 12 months. In a primary care setting, 53 % of women above the age of 55 years and 36 % of younger women report a recurrence within 1 year. Thus, management and prevention of recurrent UTI is of utmost significance. This review aims to highlight the latest research in prevention strategies and suggest a management pathway. A search was conducted on MEDLINE, Embase and the Cochrane Database of Systematic Reviews databases for the latest systematic reviews and high-quality randomized controlled trials. Special emphasis was placed on the remit "recurrent" and strongly adhered to. Furthermore, a Google search was conducted for current guidelines on the management of UTIs. Current prevention strategies include eliminating risk factors that increase the risk of acquiring recurrent UTI and continuous, post-coital and self-initiated antimicrobial prophylaxis. Other prospective preventative strategies, currently under trial, include use of vaccinations, D-mannose and lactobacillus (probiotics). Although risk factors should be identified and addressed accordingly, individualized antibiotic prophylaxis remains the most effective method of management. Non-antibiotic prevention strategies such as cranberry, vitamin C and methenamine salts lack strong evidence to be introduced as routine management options and as alternatives to antibiotics. Based on current evidence and guidelines, a management pathway is recommended. Emerging therapies require further evaluation before they can be recommended.

  1. Learning State Space Dynamics in Recurrent Networks

    Science.gov (United States)

    Simard, Patrice Yvon

    Fully recurrent (asymmetrical) networks can be used to learn temporal trajectories. The network is unfolded in time, and backpropagation is used to train the weights. The presence of recurrent connections creates internal states in the system which vary as a function of time. The resulting dynamics can provide interesting additional computing power but learning is made more difficult by the existence of internal memories. This study first exhibits the properties of recurrent networks in terms of convergence when the internal states of the system are unknown. A new energy functional is provided to change the weights of the units in order to the control the stability of the fixed points of the network's dynamics. The power of the resultant algorithm is illustrated with the simulation of a content addressable memory. Next, the more general case of time trajectories on a recurrent network is studied. An application is proposed in which trajectories are generated to draw letters as a function of an input. In another application of recurrent systems, a neural network certain temporal properties observed in human callosally sectioned brains. Finally the proposed algorithm for stabilizing dynamics around fixed points is extended to one for stabilizing dynamics around time trajectories. Its effects are illustrated on a network which generates Lisajous curves.

  2. Allelic deletions of cell growth regulators during progression of bladder cancer

    DEFF Research Database (Denmark)

    Primdahl, H; von der Maase, H; Christensen, M

    2000-01-01

    Cell growth regulators include proteins of the p53 pathway encoded by the genes CDKN2A (p16, p14arf), MDM2, TP53, and CDKN1A (p21) as well as proteins encoded by genes like RB1, E2F, and MYCL. In the present study we investigated allelic deletions of all these genes in each recurrent bladder tumor...... difference in the numbers of gene loci hit by deletions muscle-invasive versus noninvasive tumors (P = 0.0000002), with the genes most often hit by deletions in muscle-invasive tumors being TP53, RB1, and MYCL. A number of novel findings were made. Losses of MYCL and RB1 alleles were more pronounced...... that a characteristic difference between recurrent noninvasive and recurrent progressing bladder tumors is loss of cell cycle-regulatory genes in the latter group....

  3. Minisequencing mitochondrial DNA pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Carracedo Ángel

    2008-04-01

    Full Text Available Abstract Background There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations. Methods We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease. Results We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain patients carrying haplogroup J lineages (Fisher's Exact test, P-value Conclusion We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories.

  4. Mutation breeding in malting barley

    Energy Technology Data Exchange (ETDEWEB)

    Hiraki, Makoto; Sanada, Matsuyoshi

    1984-03-01

    The released varieties of malting barley through mutation breeding is more than ten in number, including foreign varieties. In Japan four varieties has been released so far. We started mutation breeding in 1956 together with cross breeding that we employed before. Until now, Gamma 4, Amagi Nijo 1 and Fuji Nijo 2 have been produced from the direct use of induced mutations and Nirasaki Nijo 8 from the indirect use of them. Mutation breeding has been used mainly in the partial improvement of agronomic characteristics since the selection for malting quality was very complicated. As the variety bred by induced mutation is usually equivalent to the original variety in malting quality, both this new variety and the original one could be cultivated in the same area without any problem on later malt production. Particularly when one farmer cultivates barley in an extensive acreage, he can harvest at the best time according to the different maturing time of each variety. From these points of view, mutation breeding is an efficient tool in malting barley breeding. Mutagens we have used so far are X-rays, ..gamma..-rays, neutron and chemicals such as dES. From our experience in selection, the low dose of radiation and chemical mutagens are more effective in selection of point mutation than the high dose of radiation which tends to produce many abnormal but few practical mutants. (author).

  5. HNPCC: Six new pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Epplen Joerg T

    2004-06-01

    Full Text Available Abstract Background Hereditary non-polyposis colorectal cancer (HNPCC is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR. HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6. Methods Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out. Results We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6 resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702], three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298] and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]. All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H. Conclusions HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.

  6. Factor V Leiden Mutation and PT 20210 Mutation Test

    Science.gov (United States)

    ... Disorders Fibromyalgia Food and Waterborne Illness Fungal Infections Gout Graves Disease Guillain-Barré Syndrome Hashimoto Thyroiditis Heart ... Tested? To determine whether you have an inherited gene mutation that increases your risk of developing a ...

  7. [A case of colchicine-responsive Mollaret's meningitis with MEFV gene mutation].

    Science.gov (United States)

    Kinohshita, Tomomi; Matsushima, Akira; Satoh, Shunichi; Hoshi, Kenichi; Kishida, Dai; Yahikozawa, Hiroyuki

    2014-01-01

    A 66-year-old woman was admitted to our hospital with recurrent meningitis. She presented with 10 episodes of meningitis in 10 months. Examination of cerebrospinal fluid demonstrated pleocytosis, with neutrophils dominant at the early stage, and lymphocytes dominant at the late stage. Mollaret cells were found and the level of IL-6 was increased in cerebrospinal fluid. Several antibiotics and antiviral agents failed to prevent relapse. However, colchicine therapy successfully prevented the recurrence of meningitis. Genetic testing for familial Mediterranean fever (FMF) showed a mutation in the MEFV gene. It is difficult to diagnose the cause of Mollaret's meningitis in some patients. FMF, neuro-Behçet's disease, and neuro-Sweet disease should be included in the differential diagnosis of recurrent meningitis. In addition, colchicine therapy can prevent the relapse of meningitis in such cases.

  8. Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation.

    Science.gov (United States)

    Hagebeuk, Eveline E O; Marcelis, Carlo L; Alders, Mariëlle; Kaspers, Ageeth; de Weerd, Al W

    2015-10-01

    This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. Even though both siblings showed a typical CDKL5 phenotype, their presentation is different. From birth, the oldest daughter had a severe developmental delay, feeding problems, and hypotonia and experienced daily refractory seizures. The youngest daughter appeared to be normal until age 3 months. At that age seizures started, deterioration and regression became evident, and an epileptic encephalopathy developed. This report of familial recurrence, with suspected germline mosaicism in a healthy parent, has important consequences for genetic counseling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased. © The Author(s) 2015.

  9. Mutations induced by ultraviolet light

    International Nuclear Information System (INIS)

    Pfeifer, Gerd P.; You, Young-Hyun; Besaratinia, Ahmad

    2005-01-01

    The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA

  10. Laboratory practice guidelines for detecting and reporting JAK2 and MPL mutations in myeloproliferative neoplasms: a report of the Association for Molecular Pathology.

    Science.gov (United States)

    Gong, Jerald Z; Cook, James R; Greiner, Timothy C; Hedvat, Cyrus; Hill, Charles E; Lim, Megan S; Longtine, Janina A; Sabath, Daniel; Wang, Y Lynn

    2013-11-01

    Recurrent mutations in JAK2 and MPL genes are genetic hallmarks of BCR-ABL1-negative myeloproliferative neoplasms. Detection of JAK2 and MPL mutations has been incorporated into routine diagnostic algorithms for these diseases. This Special Article summarizes results from a nationwide laboratory survey of JAK2 and MPL mutation analysis. Based on the current practice pattern and the literature, this Special Article provides recommendations and guidelines for laboratory practice for detection of mutations in the JAK2 and MPL genes, including clinical manifestations for prompting the mutation analysis, current and recommended methodologies for testing the mutations, and standardization for reporting the test results. This Special Article also points to future directions for genomic testing in BCR-ABL1-negative myeloproliferative neoplasms. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  11. Radiation mutation breeding

    International Nuclear Information System (INIS)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek

    1998-04-01

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected

  12. Radiation mutation breeding

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek

    1998-04-01

    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected.

  13. Mutation breeding in wheat

    International Nuclear Information System (INIS)

    Amer, I.M.

    2002-01-01

    The study aims to improve the productivity of wheat by using gamma ray (100 - 600 Gy) in mutation breading. Five local varieties were used and the program continued for the Sakha 69 for seven generations. Seeds irradiated with 600 Gy were not germinated in the field, while low doses (100-150 Gy) stimulated the root growth and spike length. The higher doses caused gradual decrease of growth with differences in varieties response. in the second generation, a genetic differences were noticed in most varieties using doses of 100-300 Gy, and the dispike was disappeared when 250 Gy was used. 79 plants from irradiated Sakha 69 were selected according to spike length and the number of grains and planted with the control to test the third generation. differences between the varieties were noticed and 8 mutants with high productivity were selected and evaluated in the fourth and fifth generations with the local variety. The mutants improve the productivity and in particular the mutants Nos.. (19-1), (14-3), and (30-2). The experiment showed the relation between the planting sites and the mutants in the sixth and seven generations

  14. Induced mutations in castor

    International Nuclear Information System (INIS)

    Ganesan, K.; Javad Hussain, H.S.; Vindhiyavarman, P.

    2001-01-01

    Castor (Ricinus communis L.) is an important oilseed crop in India. To create variability mutations were induced in two cultivars 'TMV5' (maturing in 130-140 days) and 'CO1' (perennial type). Gamma rays and diethyl sulphate and ethidium bromide were used for seed treatment. Ten doses, from 100 to 1000 Gy were employed. For chemical mutagenesis five concentrations of mutagenes from 10 to 50 mM were tried. No economic mutants could be isolated after treatment with the chemical mutagens. The following economic mutants were identified in the dose 300 Gy of gamma rays. Annual types from perennial CO 1 castor CO 1 is a perennial variety (8-10 years) with bold seeds (100 seed weight 90 g) and high oil content (57%). Twenty-one lines were isolated with annual types (160-180 days) with high yield potential as well as bold seeds and high oil content. These mutants, identified in M 3 generation were bred true in subsequent generations up to M 8 generation. Critical evaluation of the mutants in yield evaluation trials is in progress

  15. Recurrent intramedullary epidermoid cyst of conus medullaris.

    LENUS (Irish Health Repository)

    Fleming, Christina

    2011-01-01

    Spinal intramedullary epidermoid cyst is a rare condition. Recurrent epidermoid cyst in the spine cord is known to occur. The authors describe a case of recurrent conus medullaris epidermoid cyst in a 24-year-old female. She initially presented at 7 years of age with bladder disturbance in the form of diurnal enuresis and recurrent urinary tract infection. MRI lumbar spine revealed a 4 cm conus medullaris epidermoid cyst. Since the initial presentation, the cyst had recurred seven times in the same location and she underwent surgical intervention in the form of exploration and debulking. This benign condition, owing to its anatomical location, has posed a surgical and overall management challenge. This occurrence is better managed in a tertiary-care centre requiring multi-disciplinary treatment approach.

  16. Recurrence analysis of ant activity patterns.

    Directory of Open Access Journals (Sweden)

    Felipe Marcel Neves

    Full Text Available In this study, we used recurrence quantification analysis (RQA and recurrence plots (RPs to compare the movement activity of individual workers of three ant species, as well as a gregarious beetle species. RQA and RPs quantify the number and duration of recurrences of a dynamical system, including a detailed quantification of signals that could be stochastic, deterministic, or both. First, we found substantial differences between the activity dynamics of beetles and ants, with the results suggesting that the beetles have quasi-periodic dynamics and the ants do not. Second, workers from different ant species varied with respect to their dynamics, presenting degrees of predictability as well as stochastic signals. Finally, differences were found among minor and major caste of the same (dimorphic ant species. Our results underscore the potential of RQA and RPs in the analysis of complex behavioral patterns, as well as in general inferences on animal behavior and other biological phenomena.

  17. Recurrence quantification analysis of global stock markets

    Science.gov (United States)

    Bastos, João A.; Caiado, Jorge

    2011-04-01

    This study investigates the presence of deterministic dependencies in international stock markets using recurrence plots and recurrence quantification analysis (RQA). The results are based on a large set of free float-adjusted market capitalization stock indices, covering a period of 15 years. The statistical tests suggest that the dynamics of stock prices in emerging markets is characterized by higher values of RQA measures when compared to their developed counterparts. The behavior of stock markets during critical financial events, such as the burst of the technology bubble, the Asian currency crisis, and the recent subprime mortgage crisis, is analyzed by performing RQA in sliding windows. It is shown that during these events stock markets exhibit a distinctive behavior that is characterized by temporary decreases in the fraction of recurrence points contained in diagonal and vertical structures.

  18. Recurrent Hypothenar Hammer Syndrome: A Case Report.

    Science.gov (United States)

    Adams, Nicholas S; Ford, Ronald D

    2016-10-01

    Hypothenar hammer syndrome (HHS) is a rare cause of digital ischemia and pain caused from repetitive trauma to the palm. Often related to occupational practices, thrombosis and embolization can occur. Treatment is often surgical and involves excision with or without reconstruction. We describe a 55 year-old, male pipe fitter previously diagnosed and treated for HHS with excision and repair using a reversed interpositional vein graft in the mid-1980's. He continued to work in the profession, which he regularly used his palm as a hammer and returned approximately 30 years later with recurrent symptoms of cold intolerance and pain. Angiography confirmed occlusion of the ulnar artery with emboli present distally. The patient was again treated with excision and reconstruction. HHS is an uncommon cause of digital ischemia. Its recurrence is even more rare. To our knowledge, this is the first described case of diagnosed and treated recurrent HHS.

  19. Laparoscopic Surgery for Recurrent Crohn's Disease

    Directory of Open Access Journals (Sweden)

    Antonino Spinelli

    2012-01-01

    Full Text Available In spite of the recent improvements in drug therapy, surgery still represents the most frequent treatment for Crohn's disease (CD complications. Laparoscopy has been widely applied over the last twenty years in colorectal surgery and was associated with lower postoperative pain, shorter hospitalization, faster return to daily activities, and better cosmetic results. Laparoscopy experienced a slower diffusion in inflammatory bowel disease surgery than in oncologic colorectal surgery, but proved to be safe and effective, and is currently considered the gold standard for the treatment of primary uncomplicated ileocolic CD. Indications for laparoscopy in CD have recently been widened to embrace more complicated or recurrent CD. This paper reviews the available data on the subset of recurrent CD patients. The reported results indicate that laparoscopy may be safely applied even in selected recurrent CD cases in hands of IBD surgeons with broad laparoscopic experience.

  20. Recurrent Admissions for Diabetic Foot Complications

    Directory of Open Access Journals (Sweden)

    Ang CL

    2013-07-01

    Full Text Available Diabetic foot complications are a significant source of morbidity and mortality. Patients who undergo recurrent admissions for the same diabetic foot problems represent a difficult subgroup to treat. From July 2007 to June 2008, there were 38 such patients who were admitted recurrently. Eighteen patients (47% were re-admitted because of previous refusal of surgical treatment. Eighteen patients (47% received treatment as necessary but were still readmitted for recurrent infection at the same wound site. Assessment of patients’ compliance to outpatient treatment was found to be generally lacking. As a significant proportion were re-admitted because of previous refusal of surgery, a trained counselor may be suitable in counselling patients for debridement or amputation surgery.