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  • 1
    Publication Date: 2011-11-15
    Description: So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify 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 of odds (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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266855/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266855/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 10118/Cancer Research UK/United Kingdom -- 10589/Cancer Research UK/United Kingdom -- AR043369-14/AR/NIAMS NIH HHS/ -- C490/A11021/Cancer Research UK/United Kingdom -- C588/A10589/Cancer Research UK/United Kingdom -- C588/A4994/Cancer Research UK/United Kingdom -- C8197/A10123/Cancer Research UK/United Kingdom -- C8216/A6129/Cancer Research UK/United Kingdom -- CA88363/CA/NCI NIH HHS/ -- K24CA149202/CA/NCI NIH HHS/ -- P50CA9368/CA/NCI NIH HHS/ -- R01 AR043369/AR/NIAMS NIH HHS/ -- R01 CA-83115-01A2/CA/NCI NIH HHS/ -- R01 CA088363/CA/NCI NIH HHS/ -- R01 CA088363-09/CA/NCI NIH HHS/ -- R01 CA83115/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 13;480(7375):99-103. doi: 10.1038/nature10630.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080950" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Female ; Gene Expression Regulation, Neoplastic ; *Genetic Predisposition to Disease ; Humans ; Male ; Melanoma/*genetics ; Microphthalmia-Associated Transcription Factor/*genetics ; Middle Aged ; *Mutation ; Sumoylation/genetics ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-08-03
    Description: Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau ( VHL ) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.
    Keywords: Pediatric Hematology, Plenary Papers, Red Cells, Iron, and Erythropoiesis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2018-02-02
    Description: Objectives To assess the feasibility of delivering and evaluating a weight management (WM) programme for overweight patients with a family history (FH) of breast cancer (BC) or colorectal cancer (CRC). Study design A two-arm (intervention vs usual care) randomised controlled trial. Setting National Health Service (NHS) Tayside and NHS Grampian. Participants People with a FH of BC or CRC aged≥18 years and body mass index of ≥25 kg/m 2 referred to NHS genetic services. Intervention Participants were randomised to a control (lifestyle booklet) or 12-week intervention arm where they were given one face-to-face counselling session, four telephone consultations and web-based support. A goal of 5% reduction in body weight was set, and a personalised diet and physical activity (PA) programme was provided. Behavioural change techniques (motivational interviewing, action and coping plans and implementation intentions) were used. Primary outcome Feasibility measures: recruitment, programme implementation, fidelity measures, achieved measurements and retention, participant satisfaction assessed by questionnaire and qualitative interviews. Secondary outcomes Measured changes in weight and PA and reported diet and psychosocial measures between baseline and 12-week follow-up. Results Of 480 patients approached, 196 (41%) expressed interest in the study, and of those, 78 (40%) patients were randomised. Implementation of the programme was challenging within the time allotted and fidelity to the intervention modest (62%). Qualitative findings indicated the programme was well received. Questionnaires and anthropometric data were completed by 〉98%. Accelerometer data were attained by 84% and 54% at baseline and follow-up, respectively. Retention at 12 weeks was 76%. Overall, 36% of the intervention group (vs 0% in control) achieved 5% weight loss. Favourable increases in PA and reduction in dietary fat were also reported. Conclusions A lifestyle programme for people with a family history of cancer is feasible to conduct and acceptable to participants, and indicative results suggest favourable outcomes. Trial registration number ISRCTN13123470; Pre-results.
    Keywords: Public health, Open access, Patient-centred medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    ISSN: 1432-041X
    Keywords: Key words Lithium chloride ; Zebrafish ; Heart development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The molecular signalling mechanisms that are believed to govern the patterning of the heart early in embryonic development are not well understood. We have investigated the events which occur during patterning of the vertebrate heart by exposing gastrula stage zebrafish embryos to lithium, which is known to affect the phosphoinositol signalling pathway. Treatment of embryos at 50% epiboly (5.25 h after fertilization at 28.5°C) with 0.3 m LiCl for 5–15 min, results in embryos with defects which range from mild to severe, depending on the length of time the embryos are exposed to lithium. In the heart, defects appear progressively in the inflow tract, the sinus venosus and atrium. By using an antibody that recognizes an atrium-specific isoform of myosin, our results show that lithium treatment at gastrulation specifically affects the atrium and sinus venosus, and has little obvious effect on the ventricle. Defects induced by lithium differ from those induced by retinoic acid (RA) treatment of similarly staged embryos, and suggest that lithium and RA may affect the patterning signals important for establishment of the vertebrate heart by acting on different populations of cells or by influencing different patterning pathways.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Anaesthesia 49 (1994), S. 0 
    ISSN: 1365-2044
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: An obstetric epidural performed for analgesia showed a changing pattern of neurological block. The original features suggestive of a subdural block were complicated when aspiration of cerebrospinal fluid from the catheter became possible. Subsequent management as a continuous subarachnoid catheter allowed delivery.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2842
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Many variables are believed to affect the accurate measuring of metallic restoration electrical potentials. This study examined the effects of intra- versus extra-oral location of the reference electrode, the type of metallic probe used to make contact with the restoration, and scratching and brushing of the restoration surface. Dental amalgam restorations were measured in 40 human subjects. Results showed that only the location of the reference electrode affected the central tendency of the potential. The study discusses the significance of some experimental variables in the accurate measuring of metallic potentials and the need to consider individual subject differences when statistically analysing for the central tendency of a sample.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1434-6052
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We study an approximation to perturbative QCD in which all quarks (active and spectator) move along eikonal lines. These eikonal lines are described by matrix operatorsU defined by time-ordered and path-ordered integrals. All known examples of Bloch-Nordsieck cancellations follow simply from the unitary properties ofU. In particular, when the eikonal lines are space-like, the time-ordering can be omitted and the unitarity ofU is evident. In this model, it is possible to examine rather explicitly the soft and very-soft gluons whose effects must cancel if factorization is hold (to leading twist). We can show such cancellation if there is a smooth continuation from space-like eikonal lines to time-like ones. We give some examples relevant to this conjecture, but we are unable to prove it in general.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Mass spectrometric examinations of petroporphyrins have consistently shown them to be very complex mixtures7-9, and the assignment of the structure of these compounds to DPEP derivatives has been based solely on visible spectroscopy and molecular weight data. To our knowledge, the only exception to ...
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 30 (1974), S. 1216-1220 
    ISSN: 1600-5740
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 30 (1974), S. 1481-1484 
    ISSN: 1600-5740
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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