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Sample records for henry lynch heredity

  1. Regularities of radiation heredity

    International Nuclear Information System (INIS)

    Skakov, M.K.; Melikhov, V.D.

    2001-01-01

    One analyzed regularities of radiation heredity in metals and alloys. One made conclusion about thermodynamically irreversible changes in structure of materials under irradiation. One offers possible ways of heredity transmittance of radiation effects at high-temperature transformations in the materials. Phenomenon of radiation heredity may be turned to practical use to control structure of liquid metal and, respectively, structure of ingot via preliminary radiation treatment of charge. Concentration microheterogeneities in material defect structure induced by preliminary irradiation represent the genetic factor of radiation heredity [ru

  2. Distinct Gene Expression Signatures in Lynch Syndrome and Familial Colorectal Cancer Type X

    DEFF Research Database (Denmark)

    Valentin, Mev; Therkildsen, Christina; Veerla, Srinivas

    2013-01-01

    Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.......Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects....

  3. Lynching Luther

    DEFF Research Database (Denmark)

    Backe, Hans-Joachim

    2016-01-01

    , cerebral detective – two character-types traditionally rather juxtaposed as irreconcilable opposites. In this fashion, the overall story arc meshes together elements from Thomas Harris-style serial killer fiction and intuitive detection in the tradition of George Simenon’s Maigret. Similarly......, the individual episodes oscillate between carefully plotted psychology and lurid plot-holes. In other words: taken at face value, Luther is as interesting as it is messy. This paper proposes a reading of Luther that reconciles its many inconsistencies by treating it as if it was a David Lynch movie. If one...

  4. Mike Lynch

    DEFF Research Database (Denmark)

    Horst, Maja; Irwin, Alan

    associated with this position and especially its relationship to STS traditions of policy relevance and engagement. What does it mean for STS to do its job? Or rather, what does it mean for us to do our jobs? Taking inspiration both from Lynch’s published work and the different ways he has performed his STS...... jobs, this presentation will discuss the relationship between vacation, work, professional ethos and personal contribution in the context of STS.......In ’Science as a vacation’, Michael Lynch argues that ’STS might aim for something other than the serious job of doing business’. In so doing, he makes a strong case for an STS that does not aim to be useful but instead does ‘its own job’. In our presentation, we will explore some of the challenges...

  5. Heredity before genetics: a history.

    Science.gov (United States)

    Cobb, Matthew

    2006-12-01

    Two hundred years ago, biologists did not recognize that there was such a thing as 'heredity'. By the 1830s, however, insights from medicine and agriculture had indicated that something is passed from generation to generation, creating the context for the brilliant advances of Mendel and Darwin. Recent work on the history and philosophy of science has shed light on how seventeenth-, eighteenth- and nineteenth-century thinkers sought to understand similarities between parents and offspring.

  6. Extracolonic Manifestations of Lynch Syndrome

    OpenAIRE

    Bansidhar, Brian J.

    2012-01-01

    Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolon...

  7. Lynch syndrome: the patients' perspective

    NARCIS (Netherlands)

    Seppen, Jurgen; Bruzzone, Linda

    2013-01-01

    People with Lynch syndrome have a high lifetime risk for the development of colorectal, endometrial and several other types of cancer. Lynch syndrome is caused by germline mutations in genes encoding DNA mismatch repair proteins. In this review, issues that concern Lynch patients are highlighted

  8. Diagnosing Lynch Syndrome

    LENUS (Irish Health Repository)

    Gleeson, J

    2016-11-01

    Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is a hereditary condition that increases an individual’s risk of developing a constellation of cancers. These most commonly arise in the colon, but also involve other solid organs such as the endometrium and ovaries in women, the stomach, brain and the skin. Ireland’s small population offers an opportunity to identify all those with Lynch Syndrome (LS) in the country, which would represent a powerful preventive opportunity to meaningfully impact on the incidence of cancer in Ireland.

  9. Vanglateenistuse enesekaitsekoolitus / Henri Palm

    Index Scriptorium Estoniae

    Palm, Henri

    2014-01-01

    Vanglateenistus korraldab Tartus, Tallinnas ja Jõhvis enesekaitsekoolitusi gümnaasiumiõpilastele. Jakob Westholmi abiturient Henri Palm on osalenud treeningutel osalenud kolm aastat ning jagab kogemusi

  10. Interview with Henry Jenkins

    OpenAIRE

    TWC Editor

    2008-01-01

    An interview with Henry Jenkins focussing on Transformative Works and Cultures (TWC), the Organization for Transformative Works (OTW), and Jenkins' academic research into fan and participatory cultures.

  11. Interview with Henry Jenkins

    Directory of Open Access Journals (Sweden)

    TWC Editor

    2008-09-01

    Full Text Available An interview with Henry Jenkins focussing on Transformative Works and Cultures (TWC, the Organization for Transformative Works (OTW, and Jenkins' academic research into fan and participatory cultures.

  12. Henry Ford Health Systems

    Science.gov (United States)

    Henry Ford Health Systems evolved from a hospital into a system delivering care to 2.5 million patients and includes the Cancer Epidemiology, Prevention and Control Program, which focuses on epidemiologic and public health aspects of cancer.

  13. Lynch Syndrome: An Updated Review

    Directory of Open Access Journals (Sweden)

    Rishabh Sehgal

    2014-06-01

    Full Text Available Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.

  14. Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

    Directory of Open Access Journals (Sweden)

    Bartuma Katarina

    2012-05-01

    Full Text Available Abstract Background A growing number of individuals are diagnosed with hereditary cancer. Though increased levels of anxiety and depression have been demonstrated around the time of genetic counselling, most individuals handle life at increased risk well. Data have, however, been collected on individual basis, which led us to focus on family perspectives of hereditary cancer. Methods Lynch syndrome represents a major type of hereditary colorectal and gynaecological cancer. We preformed open-ended interviews with 27 informants from 9 Lynch syndrome families. Inductive content analysis revealed three major themes: transition to a risk family, patterns of communication and influence on family relations and individual roles. Results Family members described how learning about Lynch syndrome shifted focus from daily issues to concerns about cancer. Changes in communication related to difficulties in talking to children about heredity and informing new family members and distant relatives about an increased risk of cancer. Influence on relations was exemplified by family members taking on different roles, e.g. females often being responsible for coordinating information about heredity and providing support. Families in which members had experienced cancer at young age typically informed children soon after learning about heredity and at young age, whereas families with experience of cancer at higher age postponed information and thereby also genetic counselling. Conclusions Three major family perspectives are described in Lynch syndrome families; becoming a risk family, patterns of communication and influence on family relations. Since these issues are central, our findings suggests that such family perspectives should be considered during genetic counselling in order to contribute to information spread, help family members cope with the increased risk, and motivate family members at risk to undergo surveillance.

  15. Neuron-Based Heredity and Human Evolution

    Directory of Open Access Journals (Sweden)

    Don Marshall Gash

    2015-06-01

    Full Text Available Abstract:Abstract: It is widely recognized that human evolution has been driven by two systems of heredity: one DNA-based and the other based on the transmission of behaviorally acquired information via nervous system functions. The genetic system is ancient, going back to the appearance of life on Earth. It is responsible for the evolutionary processes described by Darwin. By comparison, the nervous system is relatively newly minted and in its highest form, responsible for ideation and mind-to-mind transmission of information. Here the informational capabilities and functions of the two systems are compared. While employing quite different mechanisms for encoding, storing and transmission of information, both systems perform these generic hereditary functions. Three additional features of neuron-based heredity in humans are identified: the ability to transfer hereditary information to other members of their population, not just progeny; a selection process for the information being transferred; and a profoundly shorter time span for creation and dissemination of survival-enhancing information in a population. The mechanisms underlying neuron-based heredity involve hippocampal neurogenesis and memory and learning processes modifying and creating new neural assemblages changing brain structure and functions. A fundamental process in rewiring brain circuitry is through increased neural activity (use strengthening and increasing the number of synaptic connections. Decreased activity in circuitry (disuse leads to loss of synapses. Use and disuse modifying an organ to bring about new modes of living, habits and functions are processes are in line with Neolamarckian concepts of evolution (Packard, 1901. Evidence is presented of bipartite evolutionary processes – Darwinian and Neolamarckian – driving human descent from a common ancestor shared with the great apes.

  16. Henry Gray's Anatomy.

    Science.gov (United States)

    Pearce, J M S

    2009-04-01

    Little is generally known of Henry Gray, the author of Gray's Anatomy, and even less of his colleague Henry Vandyke Carter, who played a vital role in the dissections and illustrations leading to the production of the first volume in 1859. This essay attempts to sketch briefly the salient, know aspects of these two men and their divergent careers. It traces succinctly the subsequent fate of the unique anatomy book that has influenced and instructed almost every student of medicine. (c) 2009 Wiley-Liss, Inc.

  17. Darbishire expands his vision of heredity from Mendelian genetics to inherited memory.

    Science.gov (United States)

    Wood, Roger J

    2015-10-01

    The British biologist A.D. Darbishire (1879-1915) responded to the rediscovery in 1900 of Mendel's theory of heredity by testing it experimentally, first in Oxford, then in Manchester and London. He summarised his conclusions in a textbook 'Breeding and the Mendelian Discovery' (1911), in which he questioned whether Mendelism alone could explain all aspects of practical breeding experience. Already he had begun to think about an alternative theory to give greater emphasis to the widely held conviction among breeders regarding the inheritance of characteristics acquired during an individual's life. Redefining heredity in terms of a germ-plasm based biological memory, he used vocabulary drawn partly from sources outside conventional science, including the metaphysical/vitalistic writings of Samuel Butler and Henri Bergson. An evolving hereditary memory fitted well with the conception of breeding as a creative art aimed at greater economic efficiency. For evolution beyond human control he proposed a self-modifying process, claiming it to surpass in efficiency the chancy mechanism of natural selection proposed by Darwin. From his writings, including early chapters of an unfinished book entitled 'An Introduction to a Biology', we consider how he reached these concepts and how they relate to later advances in understanding the genome and the genetic programme. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Lynch syndrome-associated neoplasms

    DEFF Research Database (Denmark)

    Shia, Jinru; Holck, Susanne; Depetris, Giovanni

    2013-01-01

    It was a century ago that Warthin, a pathologist, first described the clinical condition now known as Lynch syndrome. One hundred years later, our understanding of this syndrome has advanced significantly. Much of the progress took place over the last 25 years and was marked by a series...... of interacting developments from the disciplines of clinical oncology, pathology, and molecular genetics, with each development serving to guide or enhance the next. The advancement of our understanding about the pathology of Lynch syndrome associated tumors exemplifies such intimate interplay among disciplines....... Today, accumulative knowledge has enabled surgical pathologists to detect tumors that are likely to be associated with Lynch syndrome, and the pathologist is playing an increasingly more important role in the care of these patients. The pathologist's ability is afforded primarily by information gained...

  19. HENRY'S "HAND OF GOD"

    Directory of Open Access Journals (Sweden)

    Željko Kaluđerović

    2014-04-01

    Full Text Available In this paper the author discusses the views and statements of the French football player Thierry Henry he gave after his illegal play during the playoff match between France and the Republic of Ireland to claim one of the final spots in the World Cup 2010 in South Africa. First, by controlling the ball with his hand before passing it on for the goal Henry has shown disregard for the constitutive rules of football. Then, by stating that he is "not a referee" he demonstrated that for some players rules are not inherent to football and that they can be relativized, given that for them winning is the goal of the highest ontological status. Furthermore, he has rejected the rules of sportsmanship, thus expressing his opinion that the opponents are just obstacles which have to be removed in order to achieve your goals. Henry's action has disrupted major moral values, such as justice, honesty, responsibility and beneficence. The rules of fair play have totally been ignored both in Henry's action and in the Football Association of France's unwillingness to comment on whether a replay should take place. They have ignored one of the basic principles stated in the "Declaration of the International Fair Play Committee", according to which, fair play is much more than playing to the rules of the game; it's about the attitude of the sportsperson. It's about respecting your opponent and preserving his or her physical and psychological integrity. Finally, the author believes that the rules, moral values and fair play in football are required for this game to become actually possible to play

  20. HENRY'S "HAND OF GOD"

    Directory of Open Access Journals (Sweden)

    Željko Kaluđerović

    2014-04-01

    Full Text Available In this paper the author discusses the views and statements of the French football player Thierry Henry he gave after his illegal play during the playoff match between France and the Republic of Ireland to claim one of the final spots in the World Cup 2010 in South Africa. First, by controlling the ball with his hand before passing it on for the goal Henry has shown disregard for the constitutive rules of football. Then, by stating that he is "not a referee" he demonstrated that for some players rules are not inherent to football and that they can be relativized, given that for them winning is the goal of the highest ontological status. Furthermore, he has rejected the rules of sportsmanship, thus expressing his opinion that the opponents are just obstacles which have to be removed in order to achieve your goals. Henry's action has disrupted major moral values, such as justice, honesty, responsibility and beneficence. The rules of fair play have totally been ignored both in Henry's action and in the Football Association of France's unwillingness to comment on whether a replay should take place. They have ignored one of the basic principles stated in the "Declaration of the International Fair Play Committee", according to which, fair play is much more than playing to the rules of the game; it's about the attitude of the sportsperson. It's about respecting your opponent and preserving his or her physical and psychological integrity. Finally, the author believes that the rules, moral values and fair play in football are required for this game to become actually possible to play.

  1. [Graft hybridization and the specificity of heredity in fruit trees].

    Science.gov (United States)

    Liu, Yong-Sheng; Li, Bao-Yin; Li, Gui-Rong; Zhou, Xiu-Mei

    2004-09-01

    Emphatically discusses the relationship between graft hybridization and the specificity of heredity in fruit trees on the basis of introducing the recent achievements in plant graft hybridization. We propose that genetic materials in rootstock being translocated and integrated into the genome of the germ cells and embryonic cells in scion are the main reasons why the majority of the hybrid seedlings have wild properties and the heredity of fruit trees violate Mendel's laws of heredity. The potential of graft hybridization in fruit breeding are also discussed.

  2. Genetics Home Reference: Lynch syndrome

    Science.gov (United States)

    ... Genetic Changes Variations in the MLH1 , MSH2 , MSH6 , PMS2 , or EPCAM gene increase the risk of developing Lynch syndrome . The MLH1 , MSH2 , MSH6 , and PMS2 genes are involved in the repair of errors ...

  3. Exploring podcasting in heredity and evolution teaching.

    Science.gov (United States)

    Almeida-Aguiar, Cristina; Carvalho, Ana Amélia

    2016-09-10

    Podcasts are digital files very popular in several and very distinct areas. In higher education, they have been explored in a multitude of ways mainly to support teaching and learning processes. The study here described focuses the integration of podcasts in Heredity and Evolution, a course from the Biology and Geology Degree Program at University of Minho, Portugal. It aimed to introduce podcasts in the teaching/learning context, to empirically study different dimensions of podcasting, and to evaluate students' acceptance and receptiveness to the pedagogical use of this technology. Five informative podcasts and three with feedback were produced and delivered. All the students listened to the audio files and considered the episodes audible and clear, their preference going to episodes of short or moderate length and containing summaries, study guidelines or syllabus contents. Students judged extremely valuable the integration of this technology in learning and showed receptiveness to podcasting in other courses. Curiously, in spite of owning mobile devices, students clearly favored the use of personal computers to listen to the podcasts. This student acceptance and openness to podcasting has been encouraging its pedagogical application in other teaching courses. The episodes produced often maintain the characteristics identified as the best by the students of this study but the pedagogical approach has been moving to a more student-centered learning situation, with students as podcasts producers. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):429-432, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

  4. Heredity of acne in Korean patients.

    Science.gov (United States)

    Cho, Eun Byul; Ha, Ji Min; Park, Eun Joo; Kim, Kwang Ho; Kim, Kwang Joong

    2014-10-01

    Acne is a chronic inflammatory disease of the pilocebaceous unit that presents with various spectrum and severity. Genetic backgrounds and environmental factors are also considered to be relevant, but few studies have focused on Korean patients. A cross-sectional epidemiologic study on family history of Korean acne patients was performed to analyze family history of acne, and to compare the severity and characteristics of acne in association with family history. A total of 221 patients were enrolled, 98 male (44.3%) and 123 female (55.7%). Patients were grouped as patients with (A+) or without (A-) family history of acne. In a second analysis, patients with any experience of acne treatment were evaluated. Severity of acne was measured with Burton's grading system and Korean Acne Grading System (KAGS). Female patients had a higher tendency to have family history than males (P = 0.002). Group A+ had statistically significant earlier onset of acne (P = 0.002). In inexperienced patients, patients with family history showed a relatively earlier onset (P = 0.084). This study confirmed the role of heredity in acne. Family history of acne is associated with earlier onset of the disease, and more non-inflammatory lesions. © 2014 Japanese Dermatological Association.

  5. Milestones of Lynch syndrome: 1895-2015.

    Science.gov (United States)

    Lynch, Henry T; Snyder, Carrie L; Shaw, Trudy G; Heinen, Christopher D; Hitchins, Megan P

    2015-03-01

    Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.

  6. Henry Gray, plagiarist.

    Science.gov (United States)

    Richardson, Ruth

    2016-03-01

    The first edition of Anatomy Descriptive and Surgical (1858) was greeted with accolades, but also provoked serious controversy concerning Henry Gray's failure to acknowledge the work of earlier anatomists. A review in the Medical Times (1859) accused Gray of intellectual theft. The journal took the unusual step of substantiating its indictment by publishing twenty parallel texts from Gray and from a pre-existing textbook, Quain's Anatomy. At the recent "Vesalius Continuum" conference in Zakynthos, Greece (2014) Professor Brion Benninger disputed the theft by announcing from the floor the results of a computer analysis of both texts, which he reported exonerated Gray by revealing no evidence of plagiarism. The analysis has not been forthcoming, however, despite requests. Here the historian of Gray's Anatomy supplements the argument set out in the Medical Times 150 years ago with data suggesting unwelcome personality traits in Henry Gray, and demonstrating the utility of others' work to his professional advancement. Fair dealing in the world of anatomy and indeed the genuineness of the lustre of medical fame are important matters, but whether quantitative evidence has anything to add to the discussion concerning Gray's probity can be assessed only if Benninger makes public his computer analysis. © 2015 Wiley Periodicals, Inc.

  7. Lynch syndrome-related small intestinal adenocarcinomas.

    Science.gov (United States)

    Jun, Sun-Young; Lee, Eui-Jin; Kim, Mi-Ju; Chun, Sung Min; Bae, Young Kyung; Hong, Soon Uk; Choi, Jene; Kim, Joon Mee; Jang, Kee-Taek; Kim, Jung Yeon; Kim, Gwang Il; Jung, Soo Jin; Yoon, Ghilsuk; Hong, Seung-Mo

    2017-03-28

    Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

  8. Modernization and Lynching in the New South

    Directory of Open Access Journals (Sweden)

    Mattias Smångs

    2016-09-01

    Full Text Available This article evaluates an emerging body of historical scholarship that challenges prevailing views of the primacy of rural conditions in southern lynching by positing that it was symbiotically associated with the processes of modernization underway in the region in the decades around 1900. Statistical analyses of lynching data that differentiate among events according to communal participation, support, and ceremony in Georgia and Louisiana from 1882 to 1930 and local-level indices of modernization (urbanization, rural depopulation, industrialization, agricultural commercialization, and dissolution of traditional family roles yield results that both support and contradict such a modernization thesis of lynching. The findings imply that the consequences of the social transformation in the South coinciding with the lynching era were not uniform throughout the region with regard to racial conflict and violence and that broad arguments proposing an intrinsic connection between modernization and lynchings therefore are overstated.

  9. Diagnosis of Lynch Syndrome: Genetic Testing Identifies a Potentially Deadly Hereditary Disease

    Science.gov (United States)

    ... of Lynch Syndrome Follow us A Diagnosis of Lynch Syndrome Genetic testing identifies a potentially deadly hereditary disease ... helped Jack learn what was wrong. Jack had Lynch Syndrome—an inherited disorder. Lynch Syndrome increases the risk ...

  10. Human heredity after 1945: moving populations centre stage.

    Science.gov (United States)

    Bangham, Jenny; de Chadarevian, Soraya

    2014-09-01

    The essays in this issue look at the contested history of human heredity after 1945 from a new analytical angle, that of populations and the ways in which they were constructed and studied. One consequence of this approach is that we do not limit our attention to the disciplinary study of genetics. After the Second World War, populations became a central topic for an array of fields, including demography, anthropology, epidemiology, and public health. Human heredity had a role in all of these: demographers carried out mental surveys in efforts to distinguish hereditary from environmental factors, doctors screened newborns and tested pregnant women for chromosome disorders; anthropologists collected blood from remote locations to gain insights into the evolutionary history of human populations; geneticists monitored people exposed to radiation. Through this work, populations were labelled as clinical, normal, primitive, pure, vulnerable or exotic. We ask: how were populations chosen, who qualified as members, and how was the study of human heredity shaped by technical, institutional and geopolitical conditions? By following the practical and conceptual work to define populations as objects of research, the essays trace the circulation of practices across different fields and contexts, bringing into view new actors, institutions, and geographies. By doing so the collection shows how human heredity research was linked to the broader politics of the postwar world, one profoundly conditioned by Cold War tensions, by nationalist concerns, by colonial and post-colonial struggles, by modernisation projects and by a new internationalism. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome.

    Science.gov (United States)

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

    2015-11-01

    Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Henry David Thoreau's Spiritual World

    Institute of Scientific and Technical Information of China (English)

    马云

    2013-01-01

    Henry David Thoreau was wholeheartedly in love with nature and he devoted almost all his life time to observation, appreciation and study of nature. Thus he formed a deep understanding of nature. In 1845, Thoreau began a two-year and two-month residence at Walden Pond. His life was lonely but full of fragrance. He wanted to live meaningfully, confront the essential facts of life and live a simple life. Based on the review of the literature related to this topic, this paper aims to study Henry David Thoreau’s spiritual world, especially reflected in his famous book-Walden.

  13. Synthetic genetic polymers capable of heredity and evolution

    DEFF Research Database (Denmark)

    Pinheiro, Vitor B; Taylor, Alexander I; Cozens, Christopher

    2012-01-01

    in and recovered from six alternative genetic polymers based on simple nucleic acid architectures not found in nature [xeno-nucleic acids (XNAs)]. We also select XNA aptamers, which bind their targets with high affinity and specificity, demonstrating that beyond heredity, specific XNAs have the capacity......Genetic information storage and processing rely on just two polymers, DNA and RNA, yet whether their role reflects evolutionary history or fundamental functional constraints is currently unknown. With the use of polymerase evolution and design, we show that genetic information can be stored...... for Darwinian evolution and folding into defined structures. Thus, heredity and evolution, two hallmarks of life, are not limited to DNA and RNA but are likely to be emergent properties of polymers capable of information storage....

  14. The Life of Henry Eyring

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 17; Issue 7. The Life of Henry Eyring - From Mines to Molecules. Deepika Janakiraman. General Article Volume 17 Issue 7 July 2012 pp 625-634. Fulltext. Click here to view fulltext PDF. Permanent link:

  15. Henry Taube and Coordination Chemistry

    Science.gov (United States)

    dropdown arrow Site Map A-Z Index Menu Synopsis Henry Taube and Coordination Chemistry Resources with Professor of Chemistry, Emeritus, at Stanford University, received the 1983 Nobel Prize in Chemistry " there from 1940-41. "I became deeply interested in chemistry soon after I came to Berkeley,"

  16. Phrenology, heredity and progress in George Combe's Constitution of Man.

    Science.gov (United States)

    Jenkins, Bill

    2015-09-01

    The Constitution of Man by George Combe (1828) was probably the most influential phrenological work of the nineteenth century. It not only offered an exposition of the phrenological theory of the mind, but also presented Combe's vision of universal human progress through the inheritance of acquired mental attributes. In the decades before the publication of Darwin's Origin of Species, the Constitution was probably the single most important vehicle for the dissemination of naturalistic progressivism in the English-speaking world. Although there is a significant literature on the social and cultural context of phrenology, the role of heredity in Combe's thought has been less thoroughly explored, although both John van Wyhe and Victor L. Hilts have linked Combe's views on heredity with the transformist theories of Jean-Baptiste Lamarck. In this paper I examine the origin, nature and significance of his ideas and argue that Combe's hereditarianism was not directly related to Lamarckian transformism but formed part of a wider discourse on heredity in the early nineteenth century.

  17. Lynch Syndrome: Genomics Update and Imaging Review.

    Science.gov (United States)

    Cox, Veronica L; Saeed Bamashmos, Anas A; Foo, Wai Chin; Gupta, Shiva; Yedururi, Sireesha; Garg, Naveen; Kang, Hyunseon Christine

    2018-01-01

    Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites. Over time, the accumulation of mutations in microsatellites and elsewhere in the genome can affect the production of important cellular proteins, spurring tumorigenesis. Universal testing of colorectal tumors for microsatellite instability (MSI) is now recommended to (a) prevent cases of Lynch syndrome being missed owing to the use of clinical criteria alone, (b) reduce morbidity and mortality among the relatives of affected individuals, and (c) guide management decisions. Organ-specific cancer risks and associated screening paradigms vary according to the sex of the affected individual and the type of germline DNA alteration causing the MSI. Furthermore, Lynch syndrome-associated cancers have different pathologic, radiologic, and clinical features compared with their sporadic counterparts. Most notably, Lynch syndrome-associated tumors tend to be more indolent than non-Lynch syndrome-associated neoplasms and thus may respond differently to traditional chemotherapy regimens. The high MSI in cases of colorectal cancer reflects a difference in the biologic features of the tumor, possibly with a unique susceptibility to immunotherapy. © RSNA, 2018.

  18. Role for Genetic Anticipation in Lynch Syndrome

    DEFF Research Database (Denmark)

    Nilbert, Mef; Timshel, Susanne; Bernstein, Inge

    2009-01-01

    PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA...... mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS: In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290....... The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. CONCLUSION: The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need...

  19. Lynch syndrome: still not a familiar picture

    Directory of Open Access Journals (Sweden)

    Hes Frederik J

    2008-02-01

    Full Text Available Abstract Background Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems. Case presentation A large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history. Conclusion Hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.

  20. Henry Morgenthau's voice in history.

    Science.gov (United States)

    Steiner, Pamela

    2015-01-01

    Henry Morgenthau (1856-1946) distinguished himself as the U.S. Ambassador to the Ottoman Empire, 1913-1916, and as the chairman of the League of Nations Refugee Settlement Commission (RSC) for Greece, 1923-24. I describe aspects of his early life that shaped the man he became, his accomplishments in these two posts, and his feelings about himself over time. At the end I briefly describe his attitude toward a possible Jewish state in Palestine.

  1. The Lynch syndrome: a management dilemma.

    Science.gov (United States)

    Palumbo, Piergaspare; Amatucci, Chiara; Perotti, Bruno; Dezzi, Claudia; Girolami, Marco; Illuminati, Giulio; Angelici, Alberto M

    2013-05-01

    The case of a familial Lynch syndrome is reported. The criteria for early diagnosis, management and surveillance are briefly reviewed. A germline mutation of genes responsible for mismatch repair is at the basis of the Lynch syndrome. Carriers are predisposed to colorectal cancer and other tumors. Two members of the presently reported family developed colorectal cancer, whereas two others developed other neoplasms. The syndrome was confirmed in members of the same family with appropriate genetic workup. Clinical examination and endoscopy were consequently scheduled once-a-year. Given the high risk of neoplastic disease, such yearly controls can be proposed as the standard follow-up of this condition.

  2. Evolving concepts of heredity and genetics in orthodontics.

    Science.gov (United States)

    Carlson, David S

    2015-12-01

    The field of genetics emerged from the study of heredity early in the 20th century. Since that time, genetics has progressed through a series of defined eras based on a number of major conceptual and technical advances. Orthodontics also progressed through a series of conceptual stages over the past 100 years based in part on the ongoing and often circular debate about the relative importance of heredity (nature) and the local environment (nurture) in the etiology and treatment of malocclusion and dentofacial deformities. During the past 20 years, significant advancements in understanding the genomic basis of craniofacial development and the gene variants associated with dentofacial deformities have resulted in a convergence of the principles and concepts in genetics and in orthodontics that will lead to significant advancement of orthodontic treatments. Fundamental concepts from genetics and applied translational research in orthodontics provide a foundation for a new emphasis on precision orthodontics, which will establish a modern genomic basis for major improvements in the treatment of malocclusion and dentofacial deformities as well as many other areas of concern to orthodontists through the assessment of gene variants on a patient-by-patient basis. Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  3. Twenty hanging Dolls and a Lynching:

    DEFF Research Database (Denmark)

    Risør, Helene

    2010-01-01

    The article sets lynching of presumed criminals in the city of El Alto, Bolivia, in relation to both everyday experiences of insecurity about crime and violence and the enactment of neighborliness as a grounded notion of citizenship. Focusing on the experience and management of insecurity and its...

  4. Value-based healthcare in Lynch syndrome

    NARCIS (Netherlands)

    Hennink, Simone D; Hofland, N.; Gopie, J.P.; van der Kaa, C.; de Koning, K.; Nielsen, M.; Tops, C.; Morreau, H.; de Vos Tot Nederveen Cappel, W.H.; Langers, A.M.; Hardwick, J.C.; Gaarenstroom, K.N.; Tollenaar, R.A.; Veenendaal, R.A.; Tibben, A.; Wijnen, J.; van Heck, M.; van Asperen, C.; Roukema, J.A.; Hommes, D.W.; Hes, F.J.; Vasen, H.F.A.

    2013-01-01

    Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare

  5. 100 years lynch syndrome

    DEFF Research Database (Denmark)

    Bleiker, Eveline M A; Esplen, Mary Jane; Meiser, Bettina

    2013-01-01

    In the care of patients with Lynch Syndrome (LS), a range of psychosocial issues are encountered, which significantly affect patient outcomes. A brief historical background of 'psycho-onco-genetics' (the domain where psychology, oncology and genetics meet) in relation to LS is presented, followed...

  6. Genetic counseling and cascade genetic testing in Lynch syndrome.

    Science.gov (United States)

    Hampel, Heather

    2016-07-01

    Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers. Individuals with Lynch syndrome have a 10-80 % lifetime risk for colorectal cancer and a 15-60 % lifetime risk for endometrial cancer. Both cancers are preventable through chemoprevention, intensive cancer surveillance, and risk-reducing surgery options. Efforts to identify as many individuals with Lynch syndrome as possible will prevent cancers and save lives. This includes the traditional cancer genetic counseling model whereby individuals with and without cancer are evaluated for a possible Lynch syndrome diagnosis based on their personal and family history of colon polyps and cancers. It also includes universal tumor screening for Lynch syndrome whereby all individuals with colorectal or endometrial cancer are screened for tumor features of Lynch syndrome at the time of diagnosis. Those with tumors suspicious for Lynch syndrome are referred for cancer genetic counseling regardless of their family history of cancer. This two approaches must be maximized to attain high patient reach. Finally, and perhaps most importantly, cascade testing among the at-risk relatives of those diagnosed with Lynch syndrome is critically important to maximize the diagnosis of individuals with Lynch syndrome. In fact, the cost-effectiveness of universal tumor screening for Lynch syndrome relies entirely on counseling and testing as many at-risk individuals as possible since young unaffected individuals stand to benefit the most from an early diagnosis of Lynch syndrome. This approach must be optimized to achieve high family reach. It will take a concerted effort from patients, clinicians and public health officials to improve current approaches to the diagnosis of Lynch syndrome and the prevention and treatment of Lynch syndrome-associated cancer but these lessons can be applied to other conditions as the ultimate example of personalized medicine.

  7. Childhood cancers in families with and without Lynch syndrome.

    Science.gov (United States)

    Heath, John A; Reece, Jeanette C; Buchanan, Daniel D; Casey, Graham; Durno, Carol A; Gallinger, Steven; Haile, Robert W; Newcomb, Polly A; Potter, John D; Thibodeau, Stephen N; Le Marchand, Loïc; Lindor, Noralane M; Hopper, John L; Jenkins, Mark A; Win, Aung Ko

    2015-12-01

    Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.

  8. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

    Science.gov (United States)

    Carethers, John M; Stoffel, Elena M

    2015-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management. PMID:26309352

  9. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer.

    Science.gov (United States)

    Carethers, John M; Stoffel, Elena M

    2015-08-21

    Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

  10. Structural heredity influence upon principles of strain wave hardening

    Science.gov (United States)

    Kiricheck, A. V.; Barinov, S. V.; Yashin, A. V.

    2017-02-01

    It was established experimentally that by penetration of a strain wave through material hardened not only the technological modes of processing, but also a technological heredity - the direction of the fibers of the original macrostructure have an influence upon the diagram of microhardness. By penetration of the strain wave along fibers, the degree of hardening the material is less, however, a product is hardened throughout its entire section mainly along fibers. In the direction of the strain waves across fibers of the original structure of material, the degree of material hardening is much higher, the depth of the hardened layer with the degree of hardening not less than 50% makes at least 3 mm. It was found that under certain conditions the strain wave can completely change the original structure of the material. Thus, a heterogeneously hardened structure characterized by the interchange of harder and more viscous areas is formed, which is beneficial for assurance of high operational properties of material.

  11. Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening.

    Science.gov (United States)

    Mills, Anne M; Longacre, Teri A

    2016-06-01

    Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Merrill Lynch kavandab äridelegatsiooni visiiti Eestisse

    Index Scriptorium Estoniae

    2000-01-01

    Investeerimispanga Merrill Lynch eestvedamisel kavandatakse mais ärimeeste visiiti Eestisse, ütles Jüri Mõis, kes viibis New Yorgis toimunud Maailmapanga seminaril "Omavalitsused rahvusvahelistel kapitaliturgudel"

  13. Immunohistochemical Pitfalls: Common Mistakes in the Evaluation of Lynch Syndrome.

    Science.gov (United States)

    Markow, Michael; Chen, Wei; Frankel, Wendy L

    2017-12-01

    At least 15% of colorectal cancers diagnosed in the United States are deficient in mismatch repair mechanisms. Most of these are sporadic, but approximately 3% of colorectal cancers result from germline alterations in mismatch repair genes and represent Lynch syndrome. It is critical to identify patients with Lynch syndrome to institute appropriate screening and surveillance for patients and their families. Exclusion of Lynch syndrome in sporadic cases is equally important because it reduces anxiety for patients and prevents excessive spending on unnecessary surveillance. Immunohistochemistry is one of the most widely used screening tools for identifying patients with Lynch syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Sleep Duration, Mortality, and Heredity-A Prospective Twin Study.

    Science.gov (United States)

    Åkerstedt, Torbjörn; Narusyte, Jurgita; Alexanderson, Kristina; Svedberg, Pia

    2017-10-01

    A number of studies have shown a U-shaped association between sleep duration and mortality. Since sleep duration is partly genetically determined, it seems likely that its association with mortality is also genetically influenced. The purpose of the present study was to investigate the influence on heredity on the association between sleep duration and mortality. We used a cohort of 14267 twins from the Swedish Twin Registry. A Cox proportional hazards regression analysis, adjusted for a number of covariates, confirmed a clear U shape with a hazard ratio (HR) = 1.34 and 95% confidence interval (CI) = 1.15-1.57 for a sleep duration of ≤6.5 hours and HR = 1.18 (CI = 1.07-1.30) for sleep of ≥9.5 hours. Reference value was 7.0 hours. A co-twin analysis of 1942 twins discordant on mortality showed a HR = 2.66 (CI = 1.17-6.04) for long (≥9.5 hours) sleep in monzygotic twins and an HR = 0.66 (CI = 0.20-2.14) for short (sleep. In dizygotic twins, no association was significant. The heritability for mortality was 28% for the whole group, while it was 86% for short sleepers and 42% for long sleepers. Thus, the link with mortality for long sleep appears to be more due to environmental factors than to heredity, while heritability dominates among short sleepers. We found that both long and short sleep were associated with higher total mortality, that the difference in mortality within twin pairs is associated with long sleep, and that short sleep has a higher heritability for mortality, while long sleep is associated with more environmental influences on mortality. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  15. Genetic anticipation in Swedish Lynch syndrome families

    OpenAIRE

    von Salomé, Jenny; Boonstra, Philip S.; Karimi, Masoud; Silander, Gustav; Stenmark-Askmalm, Marie; Gebre-Medhin, Samuel; Aravidis, Christos; Nilbert, Mef; Lindblom, Annika; Lagerstedt-Robinson, Kristina

    2017-01-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, ha...

  16. Theodor and Marcella Boveri: chromosomes and cytoplasm in heredity and development.

    Science.gov (United States)

    Satzinger, Helga

    2008-03-01

    The chromosome theory of heredity, developed in 1902-1904, became one of the foundation stones of twentieth-century genetics. It is usually referred to as the Sutton-Boveri theory after Walter Sutton and Theodor Boveri. However, the contributions of Theodor Boveri and his co-worker, Marcella O'Grady Boveri (also his wife), to the understanding of heredity and development go beyond the localization of the Mendelian hereditary factors onto the chromosomes. They investigated the interaction of cytoplasm and chromosomes, and demonstrated its relevance in heredity and development.

  17. Lynch Syndrome: A Primer for Urologists and Panel Recommendations.

    Science.gov (United States)

    Mork, Maureen; Hubosky, Scott G; Rouprêt, Morgan; Margulis, Vitaly; Raman, Jay; Lotan, Yair; O'Brien, Timothy; You, Nancy; Shariat, Shahrokh F; Matin, Surena F

    2015-07-01

    Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement we reviewed the available published literature and guidelines from 1998 to 2014 on Lynch syndrome and its association with upper tract urothelial carcinoma. Recommendations based on the literature and the consensus of expert opinion are provided. No randomized or prospective study has been done to evaluate Lynch syndrome in the setting of urological cancer. All data were based on retrospective studies. Lynch syndrome is an autosomal dominant genetic disease caused by germline mutations in 4 mismatch repair genes, leading to the accumulation of DNA errors in microsatellite regions. Upper tract urothelial carcinoma develops in up to 28% of patients with known Lynch syndrome. The diagnosis of Lynch syndrome is established by clinical criteria, tumor tissue testing and genetic evaluation. Urologists should suspect Lynch syndrome when a patient with upper tract urothelial carcinoma presents before age 60 years or meets the 3-2-1 rule. Screening patients with Lynch syndrome for upper tract urothelial carcinoma presents a particular challenge. While no ideal screening test exists, at a minimum routine urinalysis is recommended using the American Urological Association guideline of 3 or more red

  18. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2018-07-01

    Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

  19. PMS2 Involvement in Patients Suspected of Lynch Syndrome

    NARCIS (Netherlands)

    Niessen, Renee C.; Kleibeuker, Jan H.; Westers, Helga; Jager, Paul O. J.; Rozeveld, Dennie; Bos, Krista K.; Boersma-van Ek, Wytske; Hollema, Harry; Sijmons, Rolf H.; Hofstra, Robert M. W.

    It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene,

  20. Recurrence and Variability of Germline EPCAM Deletions in Lynch Syndrome

    NARCIS (Netherlands)

    Kuiper, Roland P.; Vissers, Lisenka E. L. M.; Venkatachalam, Ramprasath; Bodmer, Danielle; Hoenselaar, Eveline; Goossens, Monique; Haufe, Aline; Kamping, Eveline; Niessen, Renee C.; Hogervorst, Frans B. L.; Gille, Johan J. P.; Redeker, Bert; Tops, Carli M. J.; van Gijn, Marielle E.; van den Ouweland, Ans M. W.; Rahner, Nils; Steinke, Verena; Kahl, Philip; Holinski-Feder, Elke; Morak, Monika; Kloor, Matthias; Stemmler, Susanne; Betz, Beate; Hutter, Pierre; Bunyan, David J.; Syngal, Sapna; Culver, Julie O.; Graham, Tracy; Chan, Tsun L.; Nagtegaal, Iris D.; van Krieken, J. Han J. M.; Schackert, Hans K.; Hoogerbrugge, Nicoline; van Kessel, Ad Geurts; Ligtenberg, Marjolijn J. L.

    Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like

  1. Management of extracolonic tumours in patients with Lynch syndrome

    NARCIS (Netherlands)

    Koornstra, Jan J; Mourits, Marian Je; Sijmons, Rolf H; Leliveld-Kors, Anna; Hollema, Harry; Kleibeuker, Jan H

    Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2-3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin

  2. Advances in the study of Lynch syndrome in China.

    Science.gov (United States)

    Lu, Jun-Yu; Sheng, Jian-Qiu

    2015-06-14

    Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers due to inherited mutations in mismatch repair (MMR) genes. During the last decades, there have been great advances in research on Chinese Lynch syndrome. This review mainly focuses on the genetic basis, clinicopathologic features, diagnosis, intervention, chemoprevention, and surveillance of Lynch syndrome in China. In addition to frequently altered MMR genes, such as MLH1, MSH2, MSH6, and MLH3, other MMR-associated genes, such as those encoding human exonuclease 1, transforming growth factor β receptor 2, and alanine aminopeptidase, metastasis-associated protein 2, adenomatosis polyposis coli down-regulated 1, and hepatic and glial cell adhesion molecule have also been implicated in Chinese Lynch syndrome. Most Chinese researchers focused on the clinicopathologic features of Lynch syndrome, and it is noticeable that the most frequent extracolonic tumor in northeast China is lung cancer, which is different from other areas in China. The Chinese diagnostic criteria for Lynch syndrome have been established to identify gene mutation or methylation. With regard to chemoprevention, celecoxib may be effective to prevent polyps relapse in Lynch syndrome carriers. Additionally, a colonoscopy-based surveillance strategy for the prevention and early detection of neoplasms in Lynch-syndrome carriers has been proposed.

  3. Features of ovarian cancer in Lynch syndrome (Review).

    Science.gov (United States)

    Nakamura, Kanako; Banno, Kouji; Yanokura, Megumi; Iida, Miho; Adachi, Masataka; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Nomura, Hiroyuki; Hirasawa, Akira; Tominaga, Eiichiro; Aoki, Daisuke

    2014-11-01

    Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.

  4. Mutation spectrum in South American Lynch syndrome families

    DEFF Research Database (Denmark)

    Dominguez-Valentin, Mev; Nilbert, Mef; Wernhoff, Patrik

    2013-01-01

    Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system.......Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system....

  5. Further study on heredity of liquid aluminum modified by electric pulse

    Directory of Open Access Journals (Sweden)

    Qi Jingang

    2011-08-01

    Full Text Available The remarkable heredity of liquid aluminum modified by electric pulse (EP, EPM has been uncovered. For better understanding from all aspects on the hereditary properties, the present research deals with the heredity destruction and the secondary EPM procedure. It is shown that the secondary EPM is capable of preventing the heredity reduction of EP-modified liquid aluminum, and that the final refining effect has a close relationship with technique parameters of the secondary EPM. Furthermore, at a certain superheated temperature depending on the initial EPM technique parameters, the heredity relationship of EP-modified liquid aluminum can be cut off during remelting. High temperature X-ray diffraction combining with the DSC tests also indicates that the EP-induced structure changes have almost disappeared at an elevated remelting temperature.

  6. Molecular subtype classification of urothelial carcinoma in Lynch syndrome

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias

    2018-01-01

    Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome......-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial...... carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed...

  7. Recent discoveries in the molecular genetics of Lynch syndrome.

    Science.gov (United States)

    Boland, C Richard

    2016-07-01

    Lynch syndrome is the inherited predisposition to cancer caused by a germline mutation in a DNA mismatch repair gene. The consequent tumors have a characteristic microsatellite instability (MSI) phenotype. Genomic sequencing of Lynch syndrome-associated colorectal cancers (CRCs) has demonstrated that these tumors have a substantially greater number of mutations than non-MSI CRCs, and that the target mutations driving tumor behavior are also different from what occurs in sporadic tumors. There are multiple non-Lynch syndrome entities that can create clinical confusion with that disease, including the acquired methylation of MLH1, Lynch-like syndrome, and Familial CRC-Type X. Patients with Lynch syndrome-associated CRCs have a substantially better prognosis, and there is growing evidence that this is due to the generation of immunogenic frameshift peptides as a consequence of defective DNA mismatch repair, and an effective immune response to the tumor.

  8. Henrys Fork near Ashton, ID (YHEN)

    Data.gov (United States)

    Department of the Interior — Henrys Fork near Ashton, Idaho (YHEN) Sample Collection: Samples were collected near the USGS stream gage 13046000 (Latitude 44°04'11", Longitude 111°30'38" NAD83)....

  9. Obituary: Henry Emil Kandrup, 1955-2003

    Science.gov (United States)

    Merritt, David; Gottesman, Stephen T.

    2004-12-01

    Henry Emil Kandrup died on 18 October 2003 at his home in Gainesville Florida. Henry was a theoretical astrophysicist specializing in the application of chaotic dynamics to stellar systems. At the time of his death, Henry was a Professor at the University of Florida where he had taught for 13 years. Henry was born in Manhasset, New York on July 24, 1955 and spent most of his childhood in Great Neck. His parents, Jytte and Fred, were immigrants from Denmark where his father had worked as a silver smith. Henry was a precocious child, skipping both third and fifth grades. With the help of Sidney Spivack, a professor of sociology at Columbia University, his parents enrolled Henry in the Brooks Preparatory School in Andover, Massachusetts. After graduating at age 16, Henry enrolled at Cornell, transferring to Princeton the following year. Henry's parents adored their only child and worked hard to provide him with intellectual opportunities. Henry became an accomplished musician (organ, piano, French horn) and linguist (English, Danish, German) and was a passionate devotee of opera and ballet. Henry received his PhD in 1980 from the University of Chicago, where his thesis advisor was James Ipser. He taught at Oakland University in Michigan and Syracuse University in New York before coming to the University of Florida in 1990. Henry was sui generis. He shunned conventionality in his personal appearance and in his public demeanor, and always chose forthrightness and candor over polite silence. But to those of us who knew Henry well, his bluntness was a reflection of his intellectual consistency. Henry always said exactly what he thought, both in his published work and his public presentations, and never compromised himself for the sake of appearances. Nothing that he said or wrote was less than fully thought out. Henry's PhD thesis was entitled "Stochastic Problems in Stellar Dynamics," and most of his subsequent research was in this field. Motion in stellar systems can be

  10. Scaffolding as an effort for thinking process optimization on heredity

    Science.gov (United States)

    Azizah, N. R.; Masykuri, M.; Prayitno, B. A.

    2018-04-01

    Thinking is an activity and process of manipulating and transforming data or information into memory. Thinking process is different between one and other person. Thinking process can be developed by interaction between student and their environment, such as scaffolding. Given scaffolding is based on each student necessity. There are 2 level on scaffolding such as explaining, reviewing, and restructuring; and developing conceptual thinking. This research is aimed to describe student’s thinking process on heredity especially on inheritance that is before and after scaffolding. This research used descriptive qualitative method. There were three kinds of subject degree such as the students with high, middle, and low achieving students. The result showed that subjects had some difficulty in dihybrid inheritance question in different place. Most difficulty was on determining the number of different characteristic, parental genotype, gamete, and ratio of genotype and phenotype F2. Based on discussed during scaffolding showed that the subjects have some misunderstanding terms and difficulty to determine parental, gamete, genotype, and phenotype. Final result in this research showed that the subjects develop thinking process higher after scaffolding. Therefore the subjects can solve question properly.

  11. Molecular subtype classification of urothelial carcinoma in Lynch syndrome.

    Science.gov (United States)

    Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias; Jönsson, Mats; Sjödahl, Gottfrid; Nilbert, Mef; Liedberg, Fredrik

    2018-05-23

    Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome-associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated UC as Urothelial-like tumors with only 20% being Genomically Unstable, Basal/SCC-like or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger data sets revealed that Lynch syndrome-associated UC share molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the Urothelial-like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset. This article is protected by copyright. All rights reserved. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  12. Joseph Henry's Conception of Scientific Knowledge

    Science.gov (United States)

    Theerman, Paul

    1997-04-01

    Joseph Henry, America's premier physicist and physics teacher in the mid-nineteenth century, had decided views of scientific knowledge. These were expressed in two ways. First of all, scientific knowledge led to moral betterment. Thus the study of science was a morally good thing. This was not only because it led to the contemplation of God's creation, which was a standard reason justifying the study of science dating from the Scientific Revolution and even earlier. More importantly, the study of science itself was a moral discipline, imparting to scientists the habits and virtues of truthfulness, respect for others, care and diligence, and the discernment of meaningful patterns from experience. The moral ideals of science were expressed most strongly in Henry's upholding the international "Republic of Science"; conversely, cheapening science was a sign of moral failure. Second, for Henry and his generation, science provided a path to sure truth, separate from falsehood of both the politics and the quackery that characterized mid-century public life. Henry promoted this in his championing of the Smithsonian Institution a scientific establishment, against the ideas of others who wanted to make it a literary establishment or a training school for teachers. For Henry, the Smithsonian's scientific reputation would be established by relying on careful peer review in its publications, and supporting established scientists to write authoritative popular works. The purpose of both these activities was to raise the profile of science in the United States and further establish science and the scientific method as a guide to public life.

  13. Indsigter og udfordringer i danske Lynch-syndrom-familier

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Timshel, Susanne; Nilbert, Mef

    2008-01-01

    identified 88 unique mutations in 164 Danish families delineated as Lynch syndrome families. Predictive genetic diagnostics enables the identification of high risk individuals, who are offered participation in surveillance programmes that effectively reduce morbidity and mortality in colorectal cancer....

  14. Quality colonoscopy and risk of interval cancer in Lynch syndrome

    NARCIS (Netherlands)

    Haanstra, J. F.; Vasen, H. F. A.; Sanduleanu, S.; van der Wouden, E. J.; Koornstra, J. J.; Kleibeuker, J. H.; Cappel, W. H. de Vos Tot Nederveen

    2013-01-01

    Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological

  15. [A Case of Ascending Colon Cancer with Lynch Syndrome Who Underwent XELOX Adjuvant Chemotherapy].

    Science.gov (United States)

    Takase, Koki; Murata, Kohei; Kagawa, Yoshinori; Nose, Yohei; Kawai, Kenji; Sakamoto, Takuya; Naito, Atsushi; Murakami, Kohei; Katsura, Yoshiteru; Omura, Yoshiaki; Takeno, Atsushi; Nakatsuka, Shinichi; Takeda, Yutaka; Kato, Takeshi; Tamura, Shigeyuki

    2018-01-01

    Lynch syndrome is an inherited syndrome with the development of the colorectal and various other cancers. Lynch syndrome is caused by mutations in the mismatch repair genes. A 33 year-old male underwent XELOX adjuvant chemotherapy for ascending colon cancer with Lynch syndrome. Although efficacy of 5-FU is not demonstrated in Lynch syndrome, MOSAIC trial had suggested a benefit from FOLFOX compared with 5-FU in patients who have colorectal cancer with Lynch syndrome. Oxaliplatin-based adjuvant chemotherapy can be a therapeutic option for colorectal cancer in lynch syndrome patients.

  16. Upper urinary tract carcinoma in Lynch syndrome cases.

    Science.gov (United States)

    Crockett, David G; Wagner, David G; Holmäng, Sten; Johansson, Sonny L; Lynch, Henry T

    2011-05-01

    Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. While the risk has been quantified, to our knowledge there is no description of how this population of patients with Lynch syndrome and upper urinary tract cancer differs from the general population with upper urinary tract cancer. We obtained retrospective data on a cohort of patients with Lynch syndrome from the Hereditary Cancer Center in Omaha, Nebraska and compared the data to those on a control general population from western Sweden. These data were supplemented by a new survey about exposure to known risk factors. Of the patients with Lynch syndrome 91% had mutations in MSH2 rather than in MSH1 and 79% showed upper tract urothelial carcinoma a mean of 15.85 years after prior Lynch syndrome-type cancer. Median age at diagnosis was 62 years vs 70 in the general population (p Lynch syndrome 51% had urothelial carcinoma in the ureter while it occurred in the renal pelvis in 65% of the general population (p = 0.0013). Similar numbers of high grade tumors were found in the Lynch syndrome and general populations (88% and 74%, respectively, p = 0.1108). Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome. It has high grade potential similar to that in the general population. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  17. Kolmanda maailma raudteekunn / Henry Posner ; interv. Krister Kivi

    Index Scriptorium Estoniae

    Posner, Henry

    2005-01-01

    Raudteeärimees Henry Posner III, kes kuulub ka Eesti Raudtee omanikeringi, oma äritegevusest, sealhulgas investeeringutest Eestisse. Suhtumisest raudteeturu avamisse. Lisa: Henry Posner mängib rongidega maailma hämarates nurkades

  18. PMS2 involvement in patients suspected of Lynch syndrome.

    Science.gov (United States)

    Niessen, Renée C; Kleibeuker, Jan H; Westers, Helga; Jager, Paul O J; Rozeveld, Dennie; Bos, Krista K; Boersma-van Ek, Wytske; Hollema, Harry; Sijmons, Rolf H; Hofstra, Robert M W

    2009-04-01

    It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected.

  19. Genetic anticipation in Swedish Lynch syndrome families

    DEFF Research Database (Denmark)

    von Salomé, Jenny; Boonstra, Philip S; Karimi, Masoud

    2017-01-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have......-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2...... families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age...

  20. Role for Genetic Anticipation in Lynch Syndrome

    DEFF Research Database (Denmark)

    Nilbert, Mef; Timshel, Susanne; Bernstein, Inge

    2009-01-01

    PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA...... parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. RESULTS: Both methods revealed anticipation with children developing cancer mean 9.8 years (P ... parents using the paired t-test and 5.5 years (P anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years...

  1. Haematuria in association with Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Marwan Ma'ayeh

    2012-04-01

    Full Text Available A 40-year-old Caucasian male presented to the Emergency Department complaining of intermittent painless frank haematuria. Past medical history was significant for Hereditary Non-Polyposis Colon Cancer (HNPCC and a prophylactic total colectomy. Computed tomography urogram showed thickening in the posterior wall of the bladder. Cystoscopy showed a small bladder mass. Histology showed a papillary urothelial neoplasm of low malignant potential. HNPCC, also known as Lynch Syndrome, is an autosomal dominant disorder responsible for 3-5% of colorectal cancers. There are certain cancers known to be associated with HNPCC; colorectal cancer, endometrial, ovarian, stomach, pancreas, biliary tract, small bowel, brain, renal pelvic and ureteric tumours, sebaceous gland adenomas and keratocanthomas. An association with bladder tumours is not well established.

  2. Robert Henry Thurston: Professionalism and Engineering Education

    Science.gov (United States)

    Nienkamp, Paul

    2016-01-01

    Robert Henry Thurston is presented in this article. He provides one the most significant examples of professionalizing engineering through innovative education and promoting scientific education practices in the late nineteenth century. The son of a draftsmen and steam engine mechanic, Thurston spent his early years in Providence, Rhode Island.…

  3. Antoine-Henri Jomini: A Bibliographical Survey.

    Science.gov (United States)

    Alger, John I.

    Although the writings of Antoine-Henri Jomini influenced military thought during the 19th and 20th centuries, the obscurity of their publishing history has led to misunderstandings of the development and substance of Jomini's thought. This review attempts to (1) point out the continuity of his thought on the conduct of war, and (2) provide an…

  4. Translating China : Henri Borel (1869-1933)

    NARCIS (Netherlands)

    Heijns, A.J.

    2016-01-01

    This thesis investigates how Dutch sinologist Henri Borel ‘translated’ China, by examining his renditions of Chinese literature and the writings about China that he produced over a period of forty years. Borel studied Hokkien Chinese at Leiden University and in Xiamen toward a career as Chinese

  5. Transcendentalism and Henry Barnard's "School Architecture"

    Science.gov (United States)

    Rothfork, John

    1977-01-01

    Sketches the intellectual and sociological climate that led Henry Barnard to advocate Greek Revival architecture for school buildings, takes a look at why this style and its implicit values were popular in the era between 1820-1860, and examines a few of the plans in Barnard's "School Architecture" (1838-48). (Author/RK)

  6. The Ideas of Henry Jenkins and Libraries

    Science.gov (United States)

    Anderson, Byron

    2008-01-01

    Henry Jenkins, director of the Comparative Media Studies Program at the Massachusetts Institute of Technology and keynote speaker at the 2007 American Library Association's "Gaming, Learning and Libraries Symposium" in Chicago is a visionary leader in the areas of new media and media convergence. In a white paper on digital media and learning…

  7. Contaminant Monitoring Strategy for Henrys Lake, Idaho

    Energy Technology Data Exchange (ETDEWEB)

    John S. Irving; R. P. Breckenridge

    1992-12-01

    Henrys Lake, located in southeastern Idaho, is a large, shallow lake (6,600 acres, {approx} 17.1 feet maximum depth) located at 6,472 feet elevation in Fremont Co., Idaho at the headwaters of the Henrys Fork of the Snake River. The upper watershed is comprised of high mountains of the Targhee National Forest and the lakeshore is surrounded by extensive flats and wetlands, which are mostly privately owned. The lake has been dammed since 1922, and the upper 12 feet of the lake waters are allocated for downriver use. Henrys Lake is a naturally productive lake supporting a nationally recognized ''Blue Ribbon'' trout fishery. There is concern that increasing housing development and cattle grazing may accelerate eutrophication and result in winter and early spring fish kills. There has not been a recent thorough assessment of lake water quality. However, the Department of Environmental Quality (DEQ) is currently conducting a study of water quality on Henrys Lake and tributary streams. Septic systems and lawn runoff from housing developments on the north, west, and southwest shores could potentially contribute to the nutrient enrichment of the lake. Many houses are on steep hillsides where runoff from lawns, driveways, etc. drain into wetland flats along the lake or directly into the lake. In addition, seepage from septic systems (drainfields) drain directly into the wetlands enter groundwater areas that seep into the lake. Cattle grazing along the lake margin, riparian areas, and uplands is likely accelerating erosion and nutrient enrichment. Also, cattle grazing along riparian areas likely adds to nutrient enrichment of the lake through subsurface flow and direct runoff. Stream bank and lakeshore erosion may also accelerate eutrophication by increasing the sedimentation of the lake. Approximately nine streams feed the lake (see map), but flows are often severely reduced or completely eliminated due to irrigation diversion. In addition, subsurface

  8. Mismatch repair genes in Lynch syndrome: a review

    Directory of Open Access Journals (Sweden)

    Felipe Cavalcanti Carneiro da Silva

    Full Text Available Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2; mutL homolog 1 (MLH1; mutS homolog 6 (MSH6; postmeiotic segregation increased 2 (PMS2; and postmeiotic segregation increased 1 (PMS1. It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3, also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors, approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50% and MSH2 (40%, while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

  9. Henri Fayol and Zero Tolerance Policies

    OpenAIRE

    Lee SCHIMMOELLER

    2012-01-01

    Zero tolerance policies have been increasingly popular in both education and business. Henri Fayol was the one of the earliest and influential thinkers in modern management theory. He defined management as a body of knowledge and defined his 14 administrative principles. It is an interesting exercise to apply Fayol’s teachings to the theory of zero tolerance and attempt to determine what Fayol would think of this new management technique.

  10. Henry P. McKean Jr. selecta

    CERN Document Server

    Moerbeke, Pierre; Moll, Victor

    2015-01-01

    This volume presents a selection of papers by Henry P. McKean, which illustrate the various areas in mathematics in which he has made seminal contributions. Topics covered include probability theory, integrable systems, geometry and financial mathematics. Each paper represents a contribution by Prof. McKean, either alone or together with other researchers, that has had a profound influence in the respective area.

  11. Women with double primary cancers of the colorectum and endometrium: do they have Lynch syndrome?

    Science.gov (United States)

    Song, Taejong; Kim, Min Kyu; Lee, Yoo-Young; Choi, Chel Hun; Kim, Tae-Joong; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

    2016-04-01

    The aim of this study was to determine the clinical characteristics of women with double primary cancers of the colorectum and endometrium and assess the probability of Lynch syndrome. We identified 15 women with paraffin-embedded blocks available who were diagnosed, treated and followed for double primary colorectal and endometrial cancers at in a single institution between 1994 and 2014. If there was a family history that met the revised Amsterdam criteria for Lynch syndrome, the woman was considered to have 'clinically defined Lynch syndrome'. If immunohistochemical (IHC) loss of expression of mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or high microsatellite instability (MSI) was demonstrated in molecular testing, the case was considered 'suspected Lynch syndrome'. The incidence of clinically defined Lynch syndrome according to the revised Amsterdam criteria was 66% (8 of 15). All 8 of the women clinically diagnosed with Lynch syndrome had either abnormal IHC loss or MSI-high, indicating a suspected Lynch syndrome. Furthermore, 27% (4 of 15) experienced second primary colorectal cancer or other Lynch syndrome-related cancers. Overall, 66% (10 of 15) met the criteria for clinically defined Lynch syndrome or suspected Lynch syndrome. Based on our findings, a large percentage (66%) of women with double primary cancers of the colorectum and endometrium are likely to be diagnosed with Lynch syndrome. Copyright © 2015. Published by Elsevier Ireland Ltd.

  12. Diagnosing lynch syndrome in absence of colorectal cancer.

    Science.gov (United States)

    Lynch, Henry T; Knezetic, Joseph; Lanspa, Stephen

    2012-11-01

    There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.

  13. How-to-Do-It: Hands-on Activity for Mitosis, Meiosis and the Fundamentals of Heredity.

    Science.gov (United States)

    Taylor, Mark F.

    1988-01-01

    Described is an exercise which uses inexpensive and easy-to-make materials to demonstrate the basic fundamentals of heredity. Discusses two approaches using a hypothetical insert to demonstrate inheritance, mitosis, meiosis, and genotypic and phenotypic frequencies. (CW)

  14. The history of genetics in Mexico in the light of A Cultural History of Heredity.

    Science.gov (United States)

    Barahona, Ana

    2013-01-01

    In this paper I analyze the conditions for scientific research and the social relationships that allowed the establishment of genetics in Mexico, in the laboratory, the clinic and in agronomy. I give three examples to illustrate how the cultural history of heredity has enlightened this work: the introduction and institutionalization of Mendelism in Mexico, the hereditarian ideas of medical doctors in the late nineteenth century, and the introduction of medical genetics in Mexico.

  15. Henri Tamm : algul küsiti mult kogu aeg autogrammi / Henri Tamm ; interv. Ada Kallam

    Index Scriptorium Estoniae

    Tamm, Henri

    2005-01-01

    Draamaseriaali "Kodu keset linna" lapsnäitleja. Lisaks kolleegid Henrist : M. Veinmann "Tekst on tal esimesena peas", K. Maibaum "Võrdväärne partner suurtele". Artikkel pealkirjaga "Henri Tamm : nüüd saan veidi puhkust" : Linnaleht nr. 22, 3. juuni 2005, A2-A3

  16. HENRY C. WALLICH: A THIRD GENERATION BANKER

    Directory of Open Access Journals (Sweden)

    Saul Engelbourg

    2001-01-01

    Full Text Available Born in Germany and descendant of a wealthy banking family, Henry C. Wallich emigrated to the United States like others of Jewish ancestry who fled during the 1930s. A professor of money and banking at Yale for two decades, Wallich capped his career as a Governor of the Federal Reserve. During the stagflation of the late 1960s, Wallich, a dissenter, tirelessly advocated tighter monetary policy to stem inflation. Always a scholar, Wallich published extensively; he also served as the Fed’s public spokesman. Owing to his Harvard doctorate and his eminence as an economist, Wallich knew everyone worth knowing in the economics profession.

  17. Henri Becquerel: the discovery of radioactivity

    International Nuclear Information System (INIS)

    Allisy, A.

    1996-01-01

    This paper recalls the history of the Becquerel family, the fascinating time of the discovery of radioactivity as well as some important related research published before the radium age. Henri Becquerel was the third in the line of a family of scientists which extended over more than a hundred years. Following in the footsteps of his father and grandfather gave him a thorough grounding in scientific research methods. Science at the turn of the century was very exciting, the discovery of X rays had just been announced and scientists everywhere were hoping to discover new phenomena. (author)

  18. Henry Fuseli’s Alternative Classicism

    Directory of Open Access Journals (Sweden)

    Martin Myrone

    2015-12-01

    Full Text Available The review considers Andrei Pop’s Antiquity, Theatre & The Painting of Henry Fuseli. This argues for the history painter and writer Fuseli as an exemplary ‘Neopagan’, a term coined by Pop to refer to the new sense of cultural pluralism and historical relativism which emerged in Europe after the discovery of the remains of Pompeii and Herculaneum in 1748. While this perspective offers a fresh view of the artist, relating him to the emergence of modernity, and illuminates some important aspects of his work, the reviewer also suggests that the monographic focus risks re-asserting a sense of Fuseli’s exceptionalism.

  19. Revised guidelines for the clinical management of Lynch syndrome (HNPCC)

    DEFF Research Database (Denmark)

    Vasen, Hans F A; Blanco, Ignacio; Aktan-Collan, Katja

    2013-01-01

    Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines...

  20. Colorectal choriocarcinoma in a patient with probable Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Viktor Hendrik Koelzer

    2016-11-01

    Full Text Available Background: Personalized therapy of colorectal cancer (CRC is influenced by morphological, molecular and host-related factors. Here we report the comprehensive clinicopathological and molecular analysis of a pure extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome.Case presentation: A 61 year old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed. Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation, consistent with choriocarcinoma. Disease progression was rapid under oxaliplatin, capecitabine, irinotecan (XELOXIRI and bevacizumab. Molecular phenotyping identified loss of the mismatch-repair (MMR protein PMS2, microsatellite instability, a lack of MLH1 promoter methylation and lack of of BRAF mutation suggestive of Lynch-Syndrome. Targeted next generation sequencing revealed an Ataxia Telangiectasia Mutated (ATM p.P604S missense mutation. A bleomycin, etoposide and cisplatin (BEP treatment protocol targeting germ-cell neoplasia lead to disease remission and prolonged survival of 34 months.Conclusions: Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome. For rare tumors, personalized therapeutic approaches should take both molecular and morphological information into account.Key words: Colorectal cancer, choriocarcinoma, histopathology, prognostic factors, Lynch syndrome, microsatellite instability, ataxia telangiectasia mutated, molecular pathology, next generation sequencing, personalized medicine

  1. Pain evaluation during gynaecological surveillance in women with Lynch syndrome

    NARCIS (Netherlands)

    Helder-Woolderink, Jorien; de Bock, Geertruida; Hollema, Harry; van Oven, Magda; Mourits, Marian

    To evaluate perceived pain during repetitive annual endometrial sampling at gynaecologic surveillance in asymptomatic women with Lynch syndrome (LS) over time and in addition to symptomatic women without LS, undergoing single endometrial sampling. In this prospective study, 52 women with LS or first

  2. Pathological assessment of mismatch repair gene variants in Lynch syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte

    2012-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose...

  3. Sense of coherence and self-concept in Lynch syndrome

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Ladelund, Steen; Carlsson, Christina

    2013-01-01

    Most individuals who learn about hereditary cancer manage well, but identification of subgroups who find this knowledge burdening would allow psychosocial intervention. The objective of the study was to assess sense of coherence (SOC) in individuals with Lynch syndrome with comparison to a general...

  4. Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome

    NARCIS (Netherlands)

    Koornstra, Jan Jacob

    Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of

  5. Surveillance for urinary tract cancer in Lynch syndrome

    DEFF Research Database (Denmark)

    Bernstein, Inge Thomsen; Myrhøj, Torben

    2013-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited multiorgan cancer syndrome, which when caused by a germline mutation in the mismatch repair (MMR) genes is known as Lynch syndrome (LS). Mutation carriers are at risk for developing cancers primarily in the colon, rectum...

  6. Fas Ligand Expression in Lynch Syndrome-Associated Colorectal Tumours

    NARCIS (Netherlands)

    Koornstra, Jan J.; de Jong, Steven; Boersma-van Eck, Wietske; Zwart, Nynke; Hollema, Harry; de Vries, Elisabeth G. E.; Kleibeuker, Jan H.

    Fas Ligand (FasL) expression by cancer cells may contribute to tumour immune escape via the Fas counterattack against tumour-infiltrating lymphocytes (TILs). Whether this plays a role in colorectal carcinogenesis in Lynch syndrome was examined studying FasL expression, tumour cell apoptosis and

  7. Role of new endoscopic techniques in Lynch syndrome

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Kleibeuker, Jan H.; Koornstra, Jan J.

    Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary condition predisposing for colorectal cancer. International guidelines recommend surveillance of the colorectum by colonoscopy every 1-2 years starting at the age of 20-25 years. This has been shown

  8. The identification of Lynch syndrome in Congolese colorectal cancer patients.

    Science.gov (United States)

    Poaty, Henriette; Aba Gandzion, Chandra; Soubeyran, Isabelle; Gassaye, Déby; Peko, Jean Félix; Nkoua Bon, Jean Bernard; Gombé Mbalawa, Charles

    2017-10-01

    We aimed to investigate the prevalence of Lynch syndrome as one of hereditary causes of colorectal cancer (CRC) among young Congolese individuals affected by the CRC, and to define methods for diagnosis in Congo Brazzaville. We conducted a transversal cohort study of 34 patients having a CRC with a family history for a period of eight years. They were selected among 89 CRCs of any type from the Bethesda guidelines criteria combined with pedigrees. Mismatch repair (MMR) genes alterations were researched by immunohistochemistry (IHC). We identified with the Bethesda criteria a total of 38.2% (34/89) patients having familial CRC with a confidence interval (CI) of 95%=[0.34-0.41]. Only 14.7% (5/34) 95% CI=[0.34-2.32] patients showed MMR immunodeficiency involving firstly MLH1 protein then MSH2 protein. These data account for 5.6% (5/89) 95% CI=[0.15-0.33] of patients affected by Lynch syndrome with an earlier median age of 35 years (range 20 to 47 years). The prevalence of Lynch syndrome found in Brazzaville is comparable to that is found in northern countries. The combined Bethesda guidelines, pedigree and IHC is an accessible and good alternative method for the positive diagnosis of Lynch syndrome in current practice in Congo. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  9. Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease.

    Science.gov (United States)

    Derikx, Lauranne A A P; Smits, Lisa J T; van Vliet, Shannon; Dekker, Evelien; Aalfs, Cora M; van Kouwen, Mariëtte C A; Nagengast, Fokko M; Nagtegaal, Iris D; Hoogerbrugge, Nicoline; Hoentjen, Frank

    2017-03-01

    Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by establishing a Lynch syndrome cohort from the Radboud University Medical Center (Nijmegen, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands). Patients with heterozygous germline mutations in MLH1, MSH2 (and EPCAM deletion-mediated MSH2 methylation), MSH6, or PMS2 who were tested and/or treated from 1998 through 2014 were included. Patients who developed IBD were identified by linkage of this cohort to the Dutch nationwide Pathology Registry (PALGA). Subsequently, we compared the risk of CRC between Lynch syndrome patients with IBD and without IBD. Of 1046 patients with Lynch syndrome, 15 developed IBD (1.4%). Patients with Lynch syndrome and IBD were significantly younger (median age, 38.0 y) than patients with Lynch syndrome without IBD (median age, 52.0 y; P = .001). Nevertheless, a similar proportion of patients in each group developed CRC: 4 of the 15 patients (26.7%) with Lynch syndrome and IBD compared with 311 of the 1031 patients (30.2%) with Lynch syndrome without IBD. Patients with Lynch syndrome and IBD developed CRC at a younger age (median age, 36.0 y) than patients with Lynch syndrome without IBD (median age, 46.0 y; P = .045). However, the cumulative incidence of CRC was similar between groups (P = .121). All patients with Lynch syndrome and IBD who developed CRC had ulcerative colitis, producing a higher cumulative incidence of CRC for this IBD subgroup (P Lynch syndrome and IBD develop CRC risk at a younger age than patients without IBD; patients with ulcerative colitis are at especially high risk. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Henry James – Modern Theoretician of Narration

    Directory of Open Access Journals (Sweden)

    Alexandra - Denisa IGNA

    2013-01-01

    Full Text Available Henry James, properly named world writer, was one of the first modern novelists, with an exigent writing conscience. The American writer subverted the prejudgement of the omniscient author in favour of the narration which is centred on the characters’ point of view, thus modernising the novel before V. Woolf, Huxley, Thomas Mann, or in our case Camil Petrescu and G. Călinescu. Some bio-bibliographical information familiarises the reader with the life and work of this writer. The larger part of the article is dedicated to a case study of the novel with the metaphorical title: The Figure in the Carpet, where Henry James tries to illustrate in an artistic manner his conception regarding the profundity and ineffability of the literary creation. The conclusion which the author reaches, alternating the familiar plan of the relationship between a married couple with the esthetical plan, is that the relationship between writer and his work represents an act of fully intimacy, just like a ceremony that takes place in the wedding night

  11. ‘His father’s voice’: Phonographs and Heredity in the Fiction of Samuel Butler

    Directory of Open Access Journals (Sweden)

    Will Abberley

    2014-05-01

    Full Text Available The article explores the interaction between concepts of heredity and technologies of voice recording and reproduction in the late-Victorian imagination through the example of Samuel Butler. Butler’s writing on evolutionary topics frequently conceptualized heredity as a record of ancestral voices echoing through their descendants. His Lamarckian view of evolution caused him to present heredity as analogous to the phonograph, recording the experiences of individuals, storing them in the germ plasm and reproducing them in the offspring. Theorists of hereditary memory such as Ewald Hering described it as a form of vibration and inscription, emphasizing its parallels with phonography. At the same time, language and the physical voice seemed equally haunted for Butler, resonating with the thoughts, feelings, and urges of past generations. I pursue these themes through a close reading of his posthumously published novel The Way of All Flesh' (1903. Butler makes an interesting case study for this subject since his ideas about the inheritance of ancestral voices were inseparable from his complex personal relations with his family. His efforts to escape the influence of his parents were bound up with the notion of escaping the habitual ‘grooves’ in which they lived, thought, and spoke. Such escape sometimes seems impossible in Butler’s vision, with long-term heredity and immediate social convention rendering people echoes of their predecessors. However, the life experience of the individual offered possibilities for breaking with the voices of the past, etching new grooves of habit and redirecting old ones. Further, heredity in Butler’s vision was not a single, commanding voice but a cacophony of competing voices screaming to be heard. In this sense, what seemed like rebellion against the voice of one’s ancestor might turn out to be obedience towards another one. Butler conceived of intellectual influence in the same way, placing thinkers and

  12. Genetic anticipation in Swedish Lynch syndrome families.

    Directory of Open Access Journals (Sweden)

    Jenny von Salomé

    2017-10-01

    Full Text Available Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R estimates a hazard ratio of exp(0.171, or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R and PMS2 (7.3 years/generation and hazard ratio of 1.86. The estimated anticipation effects for MLH1

  13. Genetic anticipation in Swedish Lynch syndrome families.

    Science.gov (United States)

    von Salomé, Jenny; Boonstra, Philip S; Karimi, Masoud; Silander, Gustav; Stenmark-Askmalm, Marie; Gebre-Medhin, Samuel; Aravidis, Christos; Nilbert, Mef; Lindblom, Annika; Lagerstedt-Robinson, Kristina

    2017-10-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are

  14. Henry VIII, McLeod syndrome and Jacquetta's curse.

    Science.gov (United States)

    Stride, P; Lopes Floro, K

    2013-01-01

    The mental decline of King Henry VIII from being a jovial, charismatic and athletic young man into an increasingly paranoid, brutal tyrant in later life, ever more concerned at his lack of one or more male heirs, has attracted many medical diagnostic theories. Previous hypotheses have included diabetes, syphilis and hypothyroidism, among others. However, these inadequately explain Henry's failure to produce a male heir, despite multiple pairings. The latest postulated diagnoses for Henry are the coexistence of both Kell blood group antigenicity (possibly inherited from Jacquetta Woodville, Henry's maternal great grandmother) causing related impaired fertility, and McLeod syndrome, causing psychotic changes. As the mutated McLeod protein of the syndrome significantly reduces the expression, effectively inactivating the Kell antigen, we critically review this theory, examining in detail the pathophysiology of these conditions and assessing the genealogy of Henry VIII and its effect in subsequent generations.

  15. DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome.

    Science.gov (United States)

    Pai, Rish K; Dudley, Beth; Karloski, Eve; Brand, Randall E; O'Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D; Jenkins, Mark A; Thibodeau, Stephen N; French, Amy J; Lindor, Noralane M; Pai, Reetesh K

    2018-06-08

    Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

  16. Obituary: Henry Albers (1925-2009)

    Science.gov (United States)

    Chromey, Fred

    2011-12-01

    Henry Albers, professor of astronomy at Vassar College for over thirty years, died March 29, 2009, in Fairhope, Alabama. For his work at Vassar, where he held the Maria Mitchell Chair, Albers received the first Maria Mitchell Women in Science Award for his inspiration of women astronomers. He said "In the final analysis it is the students who bring the joy into teaching." As a professional astronomer, Albers did observational work on Galactic structure in the southern Milky Way, and on the structure of the Magellanic Clouds. In retirement, Albers published Maria Mitchell - A Life in Journals and Letters, the firsthand account of America's first woman astronomer. Albers's research was on photographic near-infrared spectroscopy of red giant stars in the southern Milky Way, some proper motion studies, and on the structure of the Magellanic Clouds. A series of seven NSF grants supported his six trips to Chile to make spectroscopic observations, as well as his sabbatical collaborations at Minnesota, Leiden, and the Royal Observatory in Edinburgh. Henry Albers arrived at Vassar in 1958, to find an astronomy program that had been recently absorbed by the physics department, and that was suffering neglect after the retirement of Maud Makemson. For the next 31 years, with incredible energy -- he sometimes taught seven courses a year -- he built the astronomy program into one double in size (from one to two tenure lines), whose th century facilities have been replaced with a st century observatory. For a remarkable stretch of 20-some-years, Albers and physicist Bob Stearns, with considerable grace, alternated chairmanship of the joint department of physics and astronomy. Henry Albers was a devoted citizen of Vassar College and an enthusiastic participant in the process of faculty governance at that institution. He would have been the first to concede that his enthusiasm was sometimes excessive, and that his contributions at faculty meetings occasionally failed to move the

  17. Using Leather Puppets as Local Wisdom Based Learning Mediafor Teaching the Material of Heredity of the Natural Sciencessubject for Grade IX Students

    OpenAIRE

    Rakhmawati, Yesi; Apriliani, Putri; Wulansari, Merya

    2013-01-01

    The objectives of this study were (1) to reveal the improvement of students'understanding about heredity by using the media of leather puppets, and (2) to findout the use of leather puppets as learning media for teaching heredity to the grade IXstudents.The method used in this study was quasi experiment post test only. The subjectand object of this study were leather puppets as learning media of heredity at gradeIX and the improvement of the students' understanding about the heredity. About 2...

  18. The genetic basis of Lynch syndrome and its implications for clinical practice and risk management

    Science.gov (United States)

    Cohen, Stephanie A; Leininger, Anna

    2014-01-01

    Lynch syndrome is the most common cause of hereditary colon cancer, and accounts for as much as 3% of all colon and endometrial cancers. The identification and management of individuals with Lynch syndrome have evolved over the past 20 years, yet the syndrome remains vastly underdiagnosed. It is important for clinicians to recognize individuals and families who are at risk in order to be able to manage them appropriately and reduce their morbidity and mortality from this condition. This review will touch on the history of Lynch syndrome, the current knowledge of genotype–phenotype correlations, the cancers associated with Lynch syndrome, and management of individuals who are gene carriers. PMID:25161364

  19. Metachronous Uterine Endometrioid Adenocarcinoma and Peritoneal Mesothelioma in Lynch Syndrome: A Case Report.

    Science.gov (United States)

    Lu, Yuxin; Milchgrub, Sara; Khatri, Gaurav; Gopal, Purva

    2017-05-01

    Lynch syndrome is a hereditary disease with germline mutation in a DNA mismatch repair gene, most often presenting with colorectal and/or endometrial carcinomas; however, the spectrum of Lynch syndrome-associated tumors is expanding. In this article, we report a case of a primary peritoneal epithelioid mesothelioma that developed in a Lynch syndrome patient 10 months after diagnosis of uterine endometrioid adenocarcinoma. To our knowledge, this is the first reported case of a Lynch syndrome patient with metachronous uterine endometrioid adenocarcinoma and primary peritoneal mesothelioma.

  20. Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

    Directory of Open Access Journals (Sweden)

    Kristen M. Drescher

    2010-01-01

    Full Text Available High levels of microsatellite instability (MSI-high are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

  1. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients.

    Science.gov (United States)

    Drescher, Kristen M; Sharma, Poonam; Lynch, Henry T

    2010-01-01

    High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

  2. The Problem of Assessment for Radionuclide and Chemical Hazard to People Heredity and Health

    International Nuclear Information System (INIS)

    Suskov, Igor I.; Glouchtchenko, Alexandre I.

    2003-01-01

    In the 21th century the assessment of the hazard to human heredity and health from the radionuclide and chemical environmental pollution becomes of prime social importance since it is related to the problems of utilization of great amounts of radioactive and chemical wastes, spent nuclear fuel, weapon plutonium, nuclear reactors and emergency discharges of isotopes which in total is higher than 1 billion Ci. Long-term cytogenetic monitoring of nuclear and chemical plant workers, local human populations of radioactive waste areas and radionuclide polluted territories has revealed that the level and spectrum of induced chromosome aberrations in blood lymphocytes correlate with the type, dose and duration of exposure. There is very strong evidence that the yield of chromosome aberrations (Y) is related to the dose (D) by the equation: Y=Ao+aD+bD 2 . Therefore the radiation/radionuclide risk (R(D) ) will correspond to a absorbed dose and its aberrational/mutational consequences ('doubling dose' coefficient). Increased levels of chromosome aberrations in the human body very often precede the development of several syndromes: chronic fatigue, secondary immune deficiency, early aging, reproductive dysfunction, oncological diseases and etc. The increased levels of chromosome aberrations in blood lymphocytes can serve as objective bio indicators of radiation and chemical risk to human heredity and health. Thus, monitoring of chromosome and genome aberrations must be of strategical importance in the system of governmental service for minimization of radionuclide and chemical hazard to human heredity and health the necessity of organization of which has already matured. The above mentioned confirms the necessity of founding a European network for ecological-genetic monitoring with 'Internet' translation of information on radionuclide composition and chromosome aberration levels in people, inhabiting polluted areas

  3. Lynch Syndrome Caused by Germline PMS2 Mutations

    DEFF Research Database (Denmark)

    Ten Broeke, Sanne W; Brohet, Richard M; Tops, Carli M

    2015-01-01

    PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98...... PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks....... Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52...

  4. Ssk or Esw? -- the Bloor-Lynch Debate Revisited

    Science.gov (United States)

    Cheng, Kai-Yuan

    2014-03-01

    Philosophical discussions of rule-following in the later Wittgenstein (1953, 1967) are an important source of inspiration for the development of views on the social nature of scientific knowledge. Two major opposing views in this inquiry -- Bloor's sociology of scientific knowledge (SSK) (1983, 1991, 1992, 1997) and Lynch's (1992, 1993) ethnomethodological studies of work (ESW) -- represent two positions derived from two different readings of Wittgenstein's later writings on rule-following. The aim of this paper is two-fold. One is to re-examine the noted Bloor-Lynch debate by considering Kusch's (2004) recent discussion of this debate. Another is to show that a new semantic framework of rule-following ascriptions based on a cognitive approach to the study of generics can be provided such that SSK and ESW are compatible in it (Leslie, 2009; Cheng, 2011).

  5. Indsigter og udfordringer i danske Lynch-syndrom-familier

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Timshel, Susanne; Nilbert, Mef

    2008-01-01

    The Danish Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Register is a national resource that registers families with hereditary colorectal cancer. HNPCC is the most common type of hereditary colorectal cancer and carries an increased risk of other tumor types. Genetic diagnostics has...... identified 88 unique mutations in 164 Danish families delineated as Lynch syndrome families. Predictive genetic diagnostics enables the identification of high risk individuals, who are offered participation in surveillance programmes that effectively reduce morbidity and mortality in colorectal cancer....

  6. Fertility and apparent genetic anticipation in Lynch syndrome.

    Science.gov (United States)

    Stupart, Douglas; Win, Aung Ko; Jenkins, Mark; Winship, Ingrid M; Goldberg, Paul; Ramesar, Rajkumar

    2014-09-01

    Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent-child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent-child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.

  7. Efficacy of b-lynch brace suture in postpartum haemorrhage

    International Nuclear Information System (INIS)

    Tarique, S.; Wazir, S.; Moeen, G.

    2011-01-01

    Massive uncontrolled haemorrhage after childbirth is the leading cause of maternal death in developing countries. Postpartum haemorrhage is traditionally defined as blood loss of more than 500 ml after vaginal delivery and more than 1000 ml after caesarean section, but intraoperative estimation of blood loss is inaccurate. Uterine atony alone accounts for 75 - 90% of PPH. To estimate the effectiveness and safety of B-Lynch brace Suture in the management of primary postpartum haemorrhage (PPH). (author)

  8. The mutational spectrum of Lynch syndrome in cyprus.

    Directory of Open Access Journals (Sweden)

    Maria A Loizidou

    Full Text Available Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1 and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.

  9. Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients.

    Science.gov (United States)

    Zumstein, Valentin; Vinzens, Fabrizio; Zettl, Andreas; Heinimann, Karl; Koeberle, Dieter; von Flüe, Markus; Bolli, Martin

    2016-01-01

    Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

  10. VoxHenry: FFT-Accelerated Inductance Extraction for Voxelized Geometries

    KAUST Repository

    Yucel, Abdulkadir C.; Georgakis, Ioannis P.; Polimeridis, Athanasios G.; Bagci, Hakan; White, Jacob K.

    2018-01-01

    inductance extractor, FastHenry. Just like FastHenry, VoxHenry solves a combination of the electric volume integral equation and the current continuity equation, but with three distinctions that make VoxHenry suitable and extremely efficient for analyzing

  11. Structural heredity of TiC and its influences on refinement behaviors of AlTiC master alloy

    Institute of Scientific and Technical Information of China (English)

    王振卿; 刘相法; 柳延辉; 张均燕; 于丽娜; 边秀房

    2003-01-01

    Heredity of microstructure in AlTiC master alloy, grain refiners, was analyzed. It is found that, for morphologies and distributions of TiC particles, there are visible heredity which originates from raw materials or processing methods of Al melt, and will ultimately be transferred to the solid state structure through the melt stage, and this phenomenon can cause hereditary influences on refinement: formation of chain-like TiC morphology results in rapid refinement fading behavior; distribution of TiC along grain boundaries greatly reduces refinement efficiency. Controlling of structural heredity through proper selections of raw materials and processing parameters is of great importance in obtaining ideal microstructures and improving refinement behaviors of AlTiC master alloys.

  12. NOAA Ship Henry B. Bigelow Underway Meteorological Data, Quality Controlled

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — NOAA Ship Henry B. Bigelow Underway Meteorological Data (delayed ~10 days for quality control) are from the Shipboard Automated Meteorological and Oceanographic...

  13. Comparison of the acute effects of Tulbaghia violacea William Henry ...

    African Journals Online (AJOL)

    William Henry Harvey (Alliaceae) on blood pressure and heart rate of ... (WKY), and compare the results obtained with those for adult spontaneously hypertensive rats (SHR). Methods: T. ... have similar secondary metabolites and biological ...

  14. Henri Poincaré: Death centenary (1854-1912)

    Science.gov (United States)

    Heinzmann, Gerhard; Villani, Cédric

    2014-08-01

    The year 2012 marked the centenary of the death of Henri Poincaré (Nancy, 1854-Paris, 1912), and through the agency of the Henri-Poincaré Institute in Paris, the Henri-Poincaré Archives in Nancy and The London Mathematical Society, brought with it several exhibitions and meetings commemorating one of the greatest minds in contemporary times. Often referred to as the last polymath, Poincaré embraced multiple branches of mathematics, theoretical physics and celestial mechanics, and made significant contributions to philosophy of science (Heinzmann & Stump, Henri Poincaré, 2013). He wrote 25 textbooks and monographs, 500-plus articles, and was deeply involved in the organization and administration of science at both the national and international levels.1

  15. Study on heredity value in communication skills, for improving individual performance in the workplace

    Directory of Open Access Journals (Sweden)

    Bratu Mihaela Laura

    2017-01-01

    Full Text Available Effective communication is the wish of every intelligent organization. In today’s society, modern communication means saved time, reduced costs, multiplied resources. Communication can be improved early in the development. Heredity of communication can be an excuse, a brake but also a mean of focus personal resources early in child development. To establish the link between communication and heredity was conducted a study at a nursery school in Sibiu. It have been questioned a number of 98 adults and 45 children, using questionnaires for the evaluation of social and communication skills, attention to detail and distributive, and tolerance to change, carried out by researchers from United Kingdom. Adults who have significant problems of communication, have children with communication problems. The results slightly above average obtained by some adults do not always correlate with slightly different results of the children. Another conclusion is that communication ability has a social and cultural coordinated. The correlations have been established between the responses of children and adults, but cannot identify precisely, slightly above average for the cases, which is the incidence of occurrence of communication problems.

  16. How theories became knowledge: Morgan's chromosome theory of heredity in America and Britain.

    Science.gov (United States)

    Brush, Stephen G

    2002-01-01

    T. H. Morgan, A. H. Sturtevant, H. J. Muller and C. B. Bridges published their comprehensive treatise The Mechanism of Mendelian Heredity in 1915. By 1920 Morgan's "Chromosome Theory of Heredity" was generally accepted by geneticists in the United States, and by British geneticists by 1925. By 1930 it had been incorporated into most general biology, botany, and zoology textbooks as established knowledge. In this paper, I examine the reasons why it was accepted as part of a series of comparative studies of theory-acceptance in the sciences. In this context it is of interest to look at the persuasiveness of confirmed novel predictions, a factor often regarded by philosophers of science as the most important way to justify a theory. Here it turns out to play a role in the decision of some geneticists to accept the theory, but is generally less important than the CTH's ability to explain Mendelian inheritance, sex-linked inheritance, non-disjunction, and the connection between linkage groups and the number of chromosome pairs; in other words, to establish a firm connection between genetics and cytology. It is remarkable that geneticists were willing to accept the CTH as applicable to all organisms at a time when it had been confirmed only for Drosophila. The construction of maps showing the location on the chromosomes of genes for specific characters was especially convincing for non-geneticists.

  17. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2.

    Directory of Open Access Journals (Sweden)

    Jafar Kiani

    2013-05-01

    Full Text Available RNA-mediated transmission of phenotypes is an important way to explain non-Mendelian heredity. We have previously shown that small non-coding RNAs can induce hereditary epigenetic variations in mice and act as the transgenerational signalling molecules. Two prominent examples for these paramutations include the epigenetic modulation of the Kit gene, resulting in altered fur coloration, and the modulation of the Sox9 gene, resulting in an overgrowth phenotype. We now report that expression of the Dnmt2 RNA methyltransferase is required for the establishment and hereditary maintenance of both paramutations. Our data show that the Kit paramutant phenotype was not transmitted to the progeny of Dnmt2(-/- mice and that the Sox9 paramutation was also not established in Dnmt2(-/- embryos. Similarly, RNA from Dnmt2-negative Kit heterozygotes did not induce the paramutant phenotype when microinjected into Dnmt2-deficient fertilized eggs and microinjection of the miR-124 microRNA failed to induce the characteristic giant phenotype. In agreement with an RNA-mediated mechanism of inheritance, no change was observed in the DNA methylation profiles of the Kit locus between the wild-type and paramutant mice. RNA bisulfite sequencing confirmed Dnmt2-dependent tRNA methylation in mouse sperm and also indicated Dnmt2-dependent cytosine methylation in Kit RNA in paramutant embryos. Together, these findings uncover a novel function of Dnmt2 in RNA-mediated epigenetic heredity.

  18. [Colorectal Carcinoma with Suspected Lynch Syndrome: A Multidisciplinary Algorithm].

    Science.gov (United States)

    Schneider, R; Schneider, C; Büttner, R; Reinacher-Schick, A; Tannapfel, A; Fürst, A; Rüschoff, J; Jakobeit, C; Royer-Pokora, B; Möslein, G

    2015-12-01

    Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3-5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic - especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and - as recommended in the German S3 guidelines - to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of

  19. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome : a cohort study

    NARCIS (Netherlands)

    Kempers, Marlies J. E.; Kuiper, Roland P.; Ockeloen, Charlotte W.; Chappuis, Pierre O.; Hutter, Pierre; Rahner, Nils; Schackert, Hans K.; Steinke, Verena; Holinski-Feder, Elke; Morak, Monika; Kloor, Matthias; Buettner, Reinhard; Verwiel, Eugene T. P.; van Krieken, J. Han; Nagtegaal, Iris D.; Goossens, Monique; van der Post, Rachel S.; Niessen, Renee C.; Sijmons, Rolf H.; Kluijt, Irma; Hogervorst, Frans B. L.; Leter, Edward M.; Gille, Johan J. P.; Aalfs, Cora M.; Redeker, Egbert J. W.; Hes, Frederik J.; Tops, Carli M. J.; van Nesselrooij, Bernadette P. M.; van Gijn, Marielle E.; Garcia, Encarna B. Gomez; Eccles, Diana M.; Bunyan, David J.; Syngal, Sapna; Stoffel, Elena M.; Culver, Julie O.; Palomares, Melanie R.; Graham, Tracy; Velsher, Lea; Papp, Janos; Olah, Edith; Chan, Tsun L.; Leung, Suet Y.; van Kessel, Ad Geurts; Kiemeney, Lambertus A. L. M.; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.

    Background Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of

  20. Small-bowel cancer in Lynch syndrome : is it time for surveillance?

    NARCIS (Netherlands)

    Koornstra, Jan J.; Kleibeuker, Jan H.; Vasen, Hans F. A.

    Small-bowel cancer is part of the tumour spectrum of Lynch syndrome. Lynch syndrome, or hereditary non-polyposis colorectal cancer, is caused by germline mutations in one of the mismatch repair genes. Mutation carriers have an estimated lifetime risk for the development of small-bowel cancer of

  1. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations

    DEFF Research Database (Denmark)

    Nielsen, Sofie V,; Stein, Amelie; Dinitzen, Alexander B.

    2017-01-01

    selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than...... and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases....

  2. Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease

    NARCIS (Netherlands)

    Derikx, L.A.A.P.; Smits, L.J.T.; Lent-van Vliet, S. van; Dekker, E.; Aalfs, C.M.; Kouwen, M.C.A. van; Nagengast, F.M.; Nagtegaal, I.D.; Hoogerbrugge, N.; Hoentjen, F.

    2017-01-01

    Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by

  3. L'Abbe Henri Breuil: Archaeologist

    Directory of Open Access Journals (Sweden)

    Lawrence Guy Straus

    1992-05-01

    Full Text Available In his otherwise excellent book, A History of Archaeological Thought, Trigger (1989: 156 makes only one passing reference in a half-sentence to the central figure in the development of Paleolithic prehistory in the first half of the 20th century -- and manages to get his name wrong, confusing Henri Breuil with his long-time, close colleague, Hugo Obenrnaie . Thirty years after his death, Breuil's role in the history of Old World prehistory required more serious consideration. He was a seminal figure not only in rock art studies, but also in the archaeology of at least France, Spain, England, Portugal, South Africa, and China. Before I had read Trigger's work or Sackett's (1991 critique of my supposed misinterpretation of Breuil's theoretical stance (e.g., Straus 1986, 1987, I had presented a review of Breuil's contributions in the 1991 Annual Snead-Wertheim Lecture in Anthropology and History at the University of New Mexico (Straus n.d.. The following is a brief summary of some of my conclusions.

  4. Henry Head and the Theatre of Reverie

    Directory of Open Access Journals (Sweden)

    Tiffany Watt-Smith

    2011-04-01

    Full Text Available In 1903, the neurologist Henry Head (1861-1940 embarked on a painful self-experiment, in which he severed the radial nerve of his left arm, and then charted the gradual and faltering return of sensitivity to the limb over the next four and a half years. To directly experience his own sensations, Head entered into a trance-like state of distraction or reverie he called a ‘negative attitude of attention’. This article explores Head’s peculiar technique for looking within, and argues that while introspection was an established strategy in psychological laboratories, Head’s reverie also resonated with techniques associated with actors and theatrical audiences during this period. Viewing psychological self-experimentation through the lens of theatre, this article makes visible aspects of Head’s embodied, affective laboratory encounters, often obscured in accounts of his experiment. At the same time, it proposes that the broader historical and cultural significance of Head’s experiment lies in his attempt to observe himself by producing states of inattention and reverie at will, mental ‘attitudes’ that were themselves the subject of a rapidly evolving debate in scientific and aesthetic circles at the turn of the twentieth century.

  5. Victor Henri: 111 years of his equation.

    Science.gov (United States)

    Cornish-Bowden, Athel; Mazat, Jean-Pierre; Nicolas, Serge

    2014-12-01

    Victor Henri's great contribution to the understanding of enzyme kinetics and mechanism is not always given the credit that it deserves. In addition, his earlier work in experimental psychology is totally unknown to biochemists, and his later work in spectroscopy and photobiology almost equally so. Applying great rigour to his analysis he succeeded in obtaining a model of enzyme action that explained all of the observations available to him, and he showed why the considerable amount of work done in the preceding decade had not led to understanding. His view was that only physical chemistry could explain the behaviour of enzymes, and that models should be judged in accordance with their capacity not only to explain previously known facts but also to predict new observations against which they could be tested. The kinetic equation usually attributed to Michaelis and Menten was in reality due to him. His thesis of 1903 is now available in English. Copyright © 2014 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

  6. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

    Science.gov (United States)

    Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

    2018-01-01

    Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers. PMID:29587389

  7. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

    Directory of Open Access Journals (Sweden)

    Kohei Nakamura

    2018-03-01

    Full Text Available Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1, MutS Homolog 2 (MSH2, MutS Homolog 6 (MSH6, and PMS1 Homolog 2 (PMS2. The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

  8. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report.

    Science.gov (United States)

    Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

    2018-03-25

    Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 ( MLH1 ), MutS Homolog 2 ( MSH2 ), MutS Homolog 6 ( MSH6 ), and PMS1 Homolog 2 ( PMS2 )). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

  9. Early onset of colorectal cancer in a 13-year-old girl with Lynch syndrome.

    Science.gov (United States)

    Ahn, Do Hee; Rho, Jung Hee; Tchah, Hann; Jeon, In-Sang

    2016-01-01

    Lynch syndrome is the most common inherited colon cancer syndrome. Patients with Lynch syndrome develop a range of cancers including colorectal cancer (CRC) and carry a mutation on one of the mismatched repair (MMR) genes. Although CRC usually occurs after the fourth decade in patients with Lynch syndrome harboring a heterozygous MMR gene mutation, it can occur in children with Lynch syndrome who have a compound heterozygous or homozygous MMR gene mutation. We report a case of CRC in a 13-year-old patient with Lynch syndrome and congenital heart disease. This patient had a heterozygous mutation in MLH1 (an MMR gene), but no compound MMR gene defects, and a K-RAS somatic mutation in the cancer cells.

  10. Universal Point of Care Testing for Lynch Syndrome in Patients with Upper Tract Urothelial Carcinoma.

    Science.gov (United States)

    Metcalfe, Michael J; Petros, Firas G; Rao, Priya; Mork, Maureen E; Xiao, Lianchun; Broaddus, Russell R; Matin, Surena F

    2018-01-01

    Patients with Lynch syndrome are at risk for upper tract urothelial carcinoma. We sought to identify the incidence and most reliable means of point of care screening for Lynch syndrome in patients with upper tract urothelial carcinoma. A total of 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch syndrome were universally screened during followup from January 2013 through July 2016. We evaluated patient and family history using AMS (Amsterdam criteria) I and II, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Patients who were positive for AMS I/II, microsatellite instability or immunohistochemistry were classified as potentially having Lynch syndrome and referred for clinical genetic analysis and counseling. Patients with known Lynch syndrome served as positive controls. Of the 115 patients 16 (13.9%) screened positive for potential Lynch syndrome. Of these patients 7.0% met AMS II criteria, 11.3% had loss of at least 1 mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, 9 completed genetic analysis and counseling, and 6 were confirmed to have Lynch syndrome. All 7 patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for AMS II criteria and at least a single mismatch repair protein loss while 5 of 6 had high microsatellite instability. We identified 13.9% of upper tract urothelial carcinoma cases as potential Lynch syndrome and 5.2% as confirmed Lynch syndrome at the point of care. These findings have important implications for universal screening of upper tract urothelial carcinoma, representing one of the highest rates of undiagnosed genetic disease in a urological cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  11. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

    OpenAIRE

    Moller, Pal; Seppala, Toni; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Evans, D. Gareth; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind

    2017-01-01

    Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.\\ud \\ud Design We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle rela...

  12. Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism

    DEFF Research Database (Denmark)

    Rao, Fangwen; Wessel, Jennifer; Wen, Gen

    2007-01-01

    biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine...... hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable......, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention...

  13. An improved sheep flock heredity algorithm for job shop scheduling and flow shop scheduling problems

    Directory of Open Access Journals (Sweden)

    Chandramouli Anandaraman

    2011-10-01

    Full Text Available Job Shop Scheduling Problem (JSSP and Flow Shop Scheduling Problem (FSSP are strong NP-complete combinatorial optimization problems among class of typical production scheduling problems. An improved Sheep Flock Heredity Algorithm (ISFHA is proposed in this paper to find a schedule of operations that can minimize makespan. In ISFHA, the pairwise mutation operation is replaced by a single point mutation process with a probabilistic property which guarantees the feasibility of the solutions in the local search domain. A Robust-Replace (R-R heuristic is introduced in place of chromosomal crossover to enhance the global search and to improve the convergence. The R-R heuristic is found to enhance the exploring potential of the algorithm and enrich the diversity of neighborhoods. Experimental results reveal the effectiveness of the proposed algorithm, whose optimization performance is markedly superior to that of genetic algorithms and is comparable to the best results reported in the literature.

  14. “Not a man from England”: assimilating the exotic ‘other’ through performance, from Henry IV to Henry VI

    OpenAIRE

    Penlington, A.

    2010-01-01

    This essay will consider recent shifts in performance representations of England and the exotic ‘other’ in Shakespeare’s Henry IV, Henry V and Henry VI plays. By tracing the texts’ varied representations of non-English Britons and those for whom English is not their mother tongue (such as Owen Glyndwr in 1 Henry IV and Princess Catherine in Henry V), recent criticism has identified that Shakespeare’s narrative portrays the challenges of assimilating ‘otherness’ within English culture. This es...

  15. Is there a role for prophylactic colectomy in Lynch syndrome patients with inflammatory bowel disease?

    Science.gov (United States)

    McNamara, Kate L; Aronson, Melyssa D; Cohen, Zane

    2016-01-01

    Lynch syndrome and chronic inflammatory bowel disease are two important risk factors for colorectal cancer. It is unclear whether Lynch syndrome patients with inflammatory bowel disease are at sufficiently increased risk for colorectal cancer to warrant prophylactic colectomy. This study aims to identify all cases of Lynch syndrome and concurrent inflammatory bowel disease in a large familial gastrointestinal cancer registry, define incidence of colorectal cancer, and characterize mismatch repair protein gene mutation status and inflammatory bowel disease-associated colorectal cancer risk factors. We retrospectively identified and collected clinical data for all cases with confirmed diagnoses of Lynch syndrome and inflammatory bowel disease in the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital in Toronto, Canada. Twelve cases of confirmed Lynch syndrome, and concurrent inflammatory bowel disease were identified. Four cases developed colorectal cancer. An additional five cases had colectomy; one was performed for severe colitis, and four were performed for low-grade dysplasia. None of these surgical specimens contained malignancy or high-grade dysplasia. The presentation of Lynch syndrome with inflammatory bowel disease is uncommon and not well described in the literature. This small but important series of twelve cases is the largest reported to date. In this series, patients with Lynch syndrome and concurrent inflammatory bowel disease do not appear to have sufficiently increased risk for colorectal cancer to recommend prophylactic surgery. Therefore, the decision to surgery should continue to be guided by surgical indications for each disease. Further evaluation of this important area will require multi-institutional input.

  16. Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

    Science.gov (United States)

    Erten, Mujde Z; Fernandez, Luca P; Ng, Hank K; McKinnon, Wendy C; Heald, Brandie; Koliba, Christopher J; Greenblatt, Marc S

    2016-10-01

    Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain. We compared targeted versus universal screening of CRCs for Lynch syndrome. In 2010-2011, we employed targeted screening (age Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model. Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case. In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

  17. Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

    Science.gov (United States)

    Sekine, Shigeki; Mori, Taisuke; Ogawa, Reiko; Tanaka, Masahiro; Yoshida, Hiroshi; Taniguchi, Hirokazu; Nakajima, Takeshi; Sugano, Kokichi; Yoshida, Teruhiko; Kato, Mamoru; Furukawa, Eisaku; Ochiai, Atsushi; Hiraoka, Nobuyoshi

    2017-08-01

    Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

  18. Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population.

    Science.gov (United States)

    Chika, Noriyasu; Eguchi, Hidetaka; Kumamoto, Kensuke; Suzuki, Okihide; Ishibashi, Keiichiro; Tachikawa, Tetsuhiko; Akagi, Kiwamu; Tamaru, Jun-Ichi; Okazaki, Yasushi; Ishida, Hideyuki

    2017-02-09

    We investigated the prevalence of Lynch syndrome and Lynch-like syndrome among Japanese colorectal cancer patients, as there have been no credible data from Japan. Immunohistochemical analyses for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were carried out in surgically resected, formalin-fixed paraffin-embedded specimens obtained from 1,234 newly diagnosed colorectal cancer patients between March 2005 and April 2014. The presence/absence of the BRAF V600E mutation and hypermethylation of the MLH1 promoter was analyzed where necessary. Genetic testing was finally undertaken in patients suspected as having Lynch syndrome. By the universal screening approach with immunohistochemical analysis for mismatch repair proteins followed by analyses for the BRAF V600E mutation and MLH1 promoter methylation status, 11 (0.9%) of the 1,234 patients were identified as candidates for genetic testing. Out of the 11 patients, 9 (0.7%) were finally diagnosed as having Lynch syndrome; the responsible genes included MLH1 (n = 1), MSH2 (n = 4), EPCAM (n = 1) and MSH6 (n = 3). The remaining two patients (0.2%) were regarded as having Lynch-like syndrome, since biallelic somatic deletion of the relevant mismatch repair genes was detected in the absence of germline mismatch repair alterations. None of the cases was identified as having germline MLH1 epimutation. The prevalence of Lynch syndrome among all newly diagnosed cases of colorectal cancer in Japan is in the same range as that recently reported by studies in Western population. The prevalence of Lynch-like syndrome seems to be extremely low. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  19. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Gruber, Stephen B; Raymond, Victoria M

    2010-01-01

    the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation...... in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review...

  20. SNP association study in PMS2-associated Lynch syndrome.

    Science.gov (United States)

    Ten Broeke, Sanne W; Elsayed, Fadwa A; Pagan, Lisa; Olderode-Berends, Maran J W; Garcia, Encarna Gomez; Gille, Hans J P; van Hest, Liselot P; Letteboer, Tom G W; van der Kolk, Lizet E; Mensenkamp, Arjen R; van Os, Theo A; Spruijt, Liesbeth; Redeker, Bert J W; Suerink, Manon; Vos, Yvonne J; Wagner, Anja; Wijnen, Juul T; Steyerberg, E W; Tops, Carli M J; van Wezel, Tom; Nielsen, Maartje

    2017-11-17

    Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.

  1. History, genetics, and strategies for cancer prevention in Lynch syndrome.

    Science.gov (United States)

    Kastrinos, Fay; Stoffel, Elena M

    2014-05-01

    Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC cases diagnosed annually are due to sporadic events, but up to 6% are attributed to known monogenic disorders that confer a markedly increased risk for the development of CRC and multiple extracolonic malignancies. Lynch syndrome is the most common inherited CRC syndrome and is associated with mutations in DNA mismatch repair genes, mainly MLH1 and MSH2 but also MSH6, PMS2, and EPCAM. Although the risk of CRC and endometrial cancer may approach near 75% and 50%, respectively, in gene mutation carriers, the identification of these individuals and at-risk family members through predictive genetic testing provides opportunities for cancer prevention including specialized cancer screening, intensified surveillance, and/or prophylactic surgeries. This article will provide a review of the major advances in risk assessment, molecular genetics, DNA mutational analyses, and cancer prevention and management made since Lynch syndrome was first described 100 years ago. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  2. “Silencio”: hearing loss in David Lynch's Mulholland Drive

    Directory of Open Access Journals (Sweden)

    Allister Mactaggart

    2014-11-01

    Full Text Available In a filmmaking career replete with extraordinary images and sounds, David Lynch's Mulholland Drive (2001 stands out for attention as a striking and seemingly inexhaustible resource for analysis. In this article, this film is used to examine the specific ways in which Lynch uses pre-existing pop songs to wrap the spectator within the filmic soundscape. Nowhere is the complexity and uncanniness of pop music made more explicit than in Rebekah Del Rio's stunning performance of “Llorando (Crying” in the Club Silencio scene. The split between the singer's powerful performance and her subsequent collapse with the sound of the voice left hanging in the air marks a pivotal point in the film. This scene, coupled with other examples of feminine jouissance, is contrasted with the deadening roar of the master's voice, which solely demands obedience but is deaf to any reply. At the core of this article is an analysis of the status of the voice (and the gaze as examples of the Lacanian object a and its relationship to Marx's concept of surplus value. Mulholland Drive provides a powerful demonstration of how these concepts can be seen, heard, and felt in relation to film, and how sound can reverberate into the spaces and silences beyond the screen.

  3. LYNCHING IN RUSSIAN COUNTRYSIDE (late XIX-early XX

    Directory of Open Access Journals (Sweden)

    Vladimir Borisovich Bezgin

    2013-08-01

    Full Text Available Research actuality is due to the frequent attempts of extrajudicial killings of criminals in the country as a result of the citizens' law enforcement distrust, their doubt of deserved retribution.Such phenomenon of legal life of the Russian countryside as a lynch mob is studied in the article on the basis of a wide range of archival and ethnographic sources. The author analyzes the crimes for which the perpetrators are arbitrarily subjected to massacre in the village. The role of the peasant community in the punishment implementation of criminals was found out. The causes of the stability of this tradition in rural society were set.Lynching played an effective means of suppression of unlawful acts of the peasants. The collective nature of the spontaneously created killings of criminals was the result of mutual responsibility of community members and rural solidarity preservation condition. According to farmers gathering verdict gave legal force to massacre and left no doubt about the justice of the decision.DOI: http://dx.doi.org/10.12731/2218-7405-2013-8-1

  4. Novel Implications in Molecular Diagnosis of Lynch Syndrome

    Directory of Open Access Journals (Sweden)

    Raffaella Liccardo

    2017-01-01

    Full Text Available About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP and Lynch syndrome (LS. In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

  5. Lynch syndrome in South America: past, present and future.

    Science.gov (United States)

    Vaccaro, Carlos A; Sarroca, Carlos; Rossi, Benedito; Lopez-Kostner, Francisco; Dominguez, Mev; Calo, Natalia Causada; Cutait, Raul; Valle, Adriana Della; Nuñez, Lina; Neffa, Florencia; Alvarez, Karin; Gonzalez, Maria Laura; Kalfayan, Pablo; Lynch, Henry T; Church, James

    2016-07-01

    After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.

  6. The Failure of Lehman Brothers and Merril Lynch: A Lesson for the ...

    African Journals Online (AJOL)

    DR Nneka

    the United State America treasury securities market. Ahimie (2008) ... Thus, the above school of thought considered a bank failure as not when it ceases .... Lynch had further confirmed the historical fact that, no bank or financial institution is.

  7. Surveillance colonoscopy practice in Lynch syndrome in the Netherlands : A nationwide survey

    NARCIS (Netherlands)

    Koornstra, Jan J.; Vasen, Hans Fa

    2007-01-01

    Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common genetic disorder predisposing to colorectal cancer. As regular colonoscopic surveillance has been shown to reduce the incidence of colorectal cancer, this strategy is recommended worldwide. Recently, several

  8. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

    DEFF Research Database (Denmark)

    Clendenning, Mark; Senter, Leigha; Hampel, Heather

    2008-01-01

    BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (Lynch syndrome cases...... on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n=61). These individuals all display the rare allele (population...... and Swedish ancestry. We estimate that there are >10,000 carriers of this mutation in the United States alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected...

  9. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic...... ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified...

  10. Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome.

    Science.gov (United States)

    Harper, Holly L; McKenney, Jesse K; Heald, Brandie; Stephenson, Andrew; Campbell, Steven C; Plesec, Thomas; Magi-Galluzzi, Cristina

    2017-01-01

    Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir-Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir-Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial

  11. Common mutations identified in the MLH1 gene in familial Lynch syndrome

    OpenAIRE

    Jisha Elias; Coral Karunakaran; Snigdha Majumder; Malini Manoharan; Rakshit Shah; Yogesh Mistry; Rajesh Ramanuj; Niraj Bhatt; Arati Khanna- Gupta

    2017-01-01

    Lynch syndrome (Hereditary Non Polyposis Colorectal Cancer, HNPCC) is one of the most common hereditary familial colorectal cancers (CRC) with an autosomal dominant pattern of inheritance. It accounts for 2-5% of the total CRCs reported worldwide. Although a lower incidence for CRCs have been observed in India, the last decade has shown a remarkable increase of CRC incidences (2-4 %). Features of Lynch syndrome associated colorectal cancer include early age of cancer onset, accelerated car...

  12. In praise of the literary eponym--Henry V sign.

    LENUS (Irish Health Repository)

    Shanahan, F

    2013-01-01

    The use of eponyms in medicine is often discouraged. However, the literary eponym should be an exception as it is not linked with many of the difficulties associated with conventional eponyms and offers descriptive brevity and accuracy. Here, we illustrate the point with Henry V sign, which will be familiar to many who have cared for patients in the terminal stage of illness.

  13. Henry the Seventh and Italy, an historiographical account

    Directory of Open Access Journals (Sweden)

    Gian Maria Varanini

    2014-06-01

    Full Text Available The article represents an introduction to the contributions published in the monographic section dedicated to the expedition of Henry VII of Luxembourg in Italy (1310-1313. It provides an historiographic overview and some insightful clues.

  14. The Transformative Intellectual: An Examination of Henry Giroux's Ethics

    Science.gov (United States)

    Kashani, Tony

    2012-01-01

    This article explores Henry Giroux's contributions to critical pedagogy. The author demonstrates how Giroux, as a public intellectual, has found his Ethics in the right place. The author further argues that Giroux's Ethics of virtue are present not only in the public person but also in his transformative writing.

  15. Kesknoored tegid visiidi Šveitsi / Henri Kaselo

    Index Scriptorium Estoniae

    Kaselo, Henri

    2005-01-01

    Keskerakonna noorte esindus külastas 20.-25. aprillini 2005 Šveitsi, et osaleda sealsete noorte liberaalide Jungfreisinnige Schweizi kongressil. Delegatsiooni kuulusid esimees Tarmo Lausing, välissekretär Olga Sõtnik, endine pressisekretär Raimond Kaljulaid ja noortekogu esimees Henri Kaselo

  16. The Teaching Approach of Henry Schaefer-Simmern.

    Science.gov (United States)

    Abrahamson, Roy E.

    1980-01-01

    This description of the teaching approach of Henry Schaefer-Simmern emphasizes his use of questioning to evoke student self-evaluation and to develop clarity of vision and interfunctional unity in students' art products and their mental, artistic conceiving. Two case reports of his work with elementary students are included. (Author/SJL)

  17. Principles in Action: The Work of Henri Wallon

    Science.gov (United States)

    Voyat, Gilbert

    1974-01-01

    An examination of the life and philosophy of Henri Wallon, A French psychiatrist, psychologist, and educator, focusing on his views regarding the role of imitation in adaptation and learning, emotional development, syncretic thought, his differences with Piaget, and an assessment of the impact of his work. (EH)

  18. La Vie et L'oeuvre d'Henri Wallon.

    Science.gov (United States)

    Aubrey, Carol

    1987-01-01

    Outlines the life and philosophy of noted French child psychologist, Henri Wallon (1879-1962). Reviews the philosophical origins of the Wallonian Approach including the theory of emotions, the development of representational thought, the role of imitation in the formation of representation, and the role of language in the development of thought…

  19. The Failed Educations of John Stuart Mill and Henry Adams.

    Science.gov (United States)

    Crossley, Robert

    1979-01-01

    Analyzes and contrasts Mill's "Autobiography" and Adams'"The Education of Henry Adams" in order to present two approaches to the nature of education and of failure. Maintains that their perspectives may serve as catalysts and cautions for contemporary theories of education and its utility and relevance. (CAM)

  20. Henri Becquerel and the discovery of natural radioactivity

    International Nuclear Information System (INIS)

    Barquins, M.

    2003-01-01

    This article presents the life and achievements of Henri Becquerel particularly in the domain of natural radioactivity which he discovered. In 1903 H.Becquerel was awarded the Nobel prize of physics (jointly with the Curies). The author highlights the importance of his talent but also the influence of his family background: his grand-father and father were both renowned scientists

  1. Henri Poincaré a biography through the daily papers

    CERN Document Server

    Ginoux, Jean-Marc

    2014-01-01

    On July 17, 2012, the centenary of Henri Poincaré's death was commemorated; his name being associated with so many fields of knowledge that he was considered as the Last Universalist. In Pure and Applied Mathematics, Physics, Astronomy, Engineering and Philosophy, his works have had a great impact all over the world. Poincaré acquired in his lifetime such a reputation that, both nationally and internationally, his life and career were made the object of various articles in the daily papers not only in France, but also in the USA. Some of his philosophical concepts have even caused sharp controversies in the Press (as we will discover in this book).This work presents an original portrait of Henri Poincaré based on various press cuttings from The New York Times, The San Francisco Sunday Call, The Times, The Sun, The Washington Post that chronicled unknown anecdotes of his life (for example, his first name was actually not Henri, but Henry; he obtained his high school diploma in sciences with a zero in mathem...

  2. 2. Robin Attfield Henry Odera Oruka, Ecophilosophy and Climate ...

    African Journals Online (AJOL)

    Attfield

    Henry Odera Oruka, ecophilosophy, climate change ethics, impacts of climate ... One of the fields of environmental philosophy which he would almost ... engineering, and on “Humanity's Carbon Budget”, followed by Conclusions about ... countries that are largely responsible for these emissions must take the lion's share of.

  3. Comparison of the acute effects of Tulbaghia violacea William Henry ...

    African Journals Online (AJOL)

    Purpose: To assess the effect of the crude methanol leaf extracts of Tulbaghia violacea William Henry Harvey (Alliaceae) on blood pressure (BP) and heart rate in ageing normotensive Wistar Kyoto rats (WKY), and compare the results obtained with those for adult spontaneously hypertensive rats (SHR). Methods: T.

  4. Potential Beneficial Effects of Tulbaghia violacea William Henry ...

    African Journals Online (AJOL)

    Tulbaghia violacea William Henry Harvey (Harv. Alliaceae) is a small bulbous herb belonging to the family Alliaceae. It is used in South Africa to treat fever, colds, asthma, paralysis, and hypertension. Meanwhile, cardiovascular disease accounts for about 30 % of total global death, with most of these deaths occurring in low ...

  5. Clinicopathological Features and Management of Cancers in Lynch Syndrome

    Directory of Open Access Journals (Sweden)

    Markku Aarnio

    2012-01-01

    Full Text Available Lynch syndrome (LS is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

  6. Thomas Henry Huxley et la Bible Thomas Henry Huxley and the Bible

    Directory of Open Access Journals (Sweden)

    Christophe Duvey

    2009-10-01

    Full Text Available Thomas Henry Huxley devoted several essays to the study of the Bible. This interest can only be accounted for if his ideas on history, religion as well as epistemology are examined. According to him, a struggle between free thought and supernaturalism was culminating during the Victorian era, hence the need for a “New Reformation” which was heir to the ideals of freedom defended by the humanists of the Renaissance. This movement opposed the principles of the supporters of what he called “ecclesiasticism”. The advocates of the “New Reformation” could rely on the progress of modern science, and agnosticism, which Huxley identified with scientific method, became its epistemological foundation. As a result, Huxley thought that the authority of physical science was in conflict with the infallibility of the Scriptures and with the theological arguments which rested on it, and this notably led him to the conclusion that the biblical narrative of the Flood was unhistorical. The naturalisation of the Scriptures seems then logically to follow his philosophical views based on the limits of human knowledge.It appears that it was the question of authority which underlay Huxley’s interest in the Bible. He thought that the authority of the Scriptures must be replaced by that of science.

  7. Obituary: Roy Henry Garstang (1925-2009)

    Science.gov (United States)

    Malville, J.

    2011-12-01

    Roy Henry Garstang 84 passed away on November 1, 2009 in Boulder Colorado. He was born in Southport, England in September of 1925 to Percy Brocklehurst and Eunice (Gledhill) Garstang. He won a scholarship to Caius College in Cambridge University. Because it was wartime, he could spend only two years at his studies. However, he managed to complete three years of required work during that time, and then spent 1945-46 as a Junior Scientific Officer at the Royal Aircraft Establishment at Farnborough. He received his BA in 1946 from Cambridge, his MA in 1950, and his PhD in Mathematics in 1954, with a thesis: "Atomic Transitions in Astrophysics," working under D. R. Hartree. He also received a ScD from Cambridge in Physics and Chemistry in 1983. He married Ann in August 1959. She and two daughters, Jennifer and Susan, survive him. While still pursuing his PhD, Roy Garstang served as a Research Associate at the Yerkes Observatory, from 1951-1952, working under Subrahmanyan Chandrasekhar. During that time he continued with his own calculations of atomic structure and transition probabilities, although these were not part of Chandra's research interests. After earning his PhD, he went to teach at the University of London, where he also served as the Assistant Director of the University of London Observatory (1959-1964). He was editor of "The Observatory" Magazine form 1953-1960. The continuing theme of this research was to help meet the needs of astrophysicists for atomic data. In 1964, he left England for the United States, where he joined the faculty at the University of Colorado, Boulder, where he would remain for the rest of his professional career. It was entirely fitting, considering his interest in performing calculations of interest to astrophysicists, that soon after arriving in Boulder he was appointed Chairman of JILA - Joint Institute for Laboratory Astrophysics (1966-1967). He was Director of the Division of Physics and AstroGeophysics (1979-80), acting

  8. Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: The heredity survey.

    Science.gov (United States)

    Faggiano, Pompilio; Pirillo, Angela; Griffo, Raffaele; Ambrosetti, Marco; Pedretti, Roberto; Scorcu, Giampaolo; Werren, Marika; Febo, Oreste; Malfatto, Gabriella; Favretto, Giuseppe; Sarullo, Filippo; Antonini-Canterin, Francesco; Zobbi, Gianni; Temporelli, Pierluigi; Catapano, Alberico L

    2018-02-01

    Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low density lipoprotein cholesterol (LDL-C) predisposing to premature cardiovascular disease. Its prevalence varies and has been estimated around 1 in 200-500. The Heredity survey evaluated the prevalence of potential FH and the therapeutic approaches among patients with established coronary artery disease (CAD) or peripheral artery disease (PAD) in which it is less well documented. Data were collected in patients admitted to programs of rehabilitation and secondary prevention in Italy. Potential FH was estimated using Dutch Lipid Clinic Network (DLCN) criteria. Potential FH was defined as having a total score≥6. Among the 1438 consecutive patients evaluated, the prevalence of potential FH was 3.7%. The prevalence was inversely related to age, with a putative prevalence of 1:10 in those with Definite FH (DLCN score>8) had the highest percentages of patients after an ACS (75% vs 52.5% in the whole study population). At discharge, most patients were on high intensity statin therapy, but despite this, potential FH group still had a higher percentage of patients with LDL-C levels not at target and having a distance from the target higher than 50%. Among patients with established coronary heart disease, the prevalence of potential FH is higher than in the general population; the results suggest that a correct identification of potential FH, especially in younger patients, may help to better manage their high cardiovascular risk. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  9. The Contributions - and Collapse - of Lamarckian Heredity in Pasteurian Molecular Biology: 1. Lysogeny, 1900-1960.

    Science.gov (United States)

    Loison, Laurent; Gayon, Jean; Burian, Richard M

    2017-02-01

    This article shows how Lamarckism was essential in the birth of the French school of molecular biology. We argue that the concept of inheritance of acquired characters positively shaped debates surrounding bacteriophagy and lysogeny in the Pasteurian tradition during the interwar period. During this period the typical Lamarckian account of heredity treated it as the continuation of protoplasmic physiology in daughter cells. Félix d'Hérelle applied this conception to argue that there was only one species of bacteriophage and Jules Bordet applied it to develop an account of bacteriophagy as a transmissible form of autolysis and to analyze the new phenomenon of lysogeny. In a long-standing controversy with Bordet, Eugène Wollman deployed a more morphological understanding of the inheritance of acquired characters, yielding a particulate, but still Lamarckian, account of lysogeny. We then turn to André Lwoff who, with several colleagues, completed Wollman's research program from 1949 to 1953. We examine how he gradually set aside the Lamarckian background, finally removing inheritance of acquired characters from the resulting account of bacteriophagy and lysogeny. In the conclusion, we emphasize the complex dual role of Lamarckism as it moved from an assumed explanatory framework to a challenge that the nascent molecular biology had to overcome.

  10. Thyroid cancer in a patient with Lynch syndrome - case report and literature review.

    Science.gov (United States)

    Fazekas-Lavu, Monika; Parker, Andrew; Spigelman, Allan D; Scott, Rodney J; Epstein, Richard J; Jensen, Michael; Samaras, Katherine

    2017-01-01

    Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, MLH1 , MSH2 , MSH6 , and PMS2 and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the MSH2 gene) with a synchronous papillary thyroid cancer. Six years later, she developed metachronous breast cancer. Metastatic bone disease developed after 3 years, and the disease burden was due to both breast and thyroid diseases. Despite multiple interventions for both metastatic breast and thyroid diseases, the patient's metastatic burden progressed and she died of leptomeningeal metastatic disease. Two prior case reports suggested thyroid cancer may be an extraintestinal malignancy of the Lynch syndrome cancer group. Hence, this study examined the genetic relationship between the patient's known Lynch syndrome and her thyroid cancer. The thyroid cancer tissue showed normal expression of MSH2 , suggesting that the tumor was not due to the oncogenic mutation of Lynch syndrome, and molecular analysis confirmed BRAF V600E mutation. Although in this case the thyroid cancer was sporadic, it raises the importance of considering cancer genetics in familial cancer syndromes when other cancers do not fit the criteria of the syndrome. Careful documentation of other malignancies in patients with thyroid cancer and their families would assist in better understanding of any potential association. Appropriate genetic testing will clarify whether a common pathogenic mechanism links seemingly unrelated cancers.

  11. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance : first report from the prospective Lynch syndrome database

    NARCIS (Netherlands)

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

    Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. Design We undertook a multicentre

  12. INOVATION AND ANTREPRENEURIAL CREATIVITY BUSINESS DURING HENRY FORD

    Directory of Open Access Journals (Sweden)

    GHICAJANU MIHAELA

    2015-03-01

    Full Text Available In this paper I presented the innovation and entrepeneurial creativity as a basis in the process of business redesign. I chose as a case study the the Ford brand products, because it is considered that Henry Ford is one of the greatest innovators and entrepreneurs of all time and I decided to present and to analyze these things. The first part of the paper will include theoretical approaches on the innovation and creativity business concepts and premises, and then I showed the ways in which four types of economic innovation under the leadership of Henry Ford (innovation in product, in process, market and organizational were achieved, with the purpose to recognize them in other companies, nowadays .

  13. Iraagi olukorral on poliitiline lahendus / Henry A. Kissinger

    Index Scriptorium Estoniae

    Kissinger, Henry, 1923-

    2007-01-01

    USA endine riigisekretär Henry Kissinger kirjutab, et Ameerika Ühendriikide eesmärgiks peaks olema riikidevaheline kokkulepe, mis tunnistaks Iraagi rahvusvahelist staatust. See oleks vägivalla lõpetamiseks hea alus ja eeltingimuseks vägede väljaviimisele. Vt. samas: Ameerika Ühendriikide vahekokkuvõte Iraagi sõja kohta oli suhteliselt pessimistlik

  14. Should bulk cloudwater or fogwater samples obey Henry's law?

    Science.gov (United States)

    Pandis, Spyros N.; Seinfeld, John H.

    1991-06-01

    Mixing of droplets with different pH that are individually in Henry's law equilibrium with the surrounding atmosphere always results in a bulk mixture that is supersaturated with weak acids like S(IV) and HCOOH, and bases like NH3 with respect to the original atmosphere. High supersaturations result only when the pH of the bulk droplet mixture exceeds the pKa of the species, in which pH range large pH differences among droplets of different sizes lead to large deviations from Henry's law for the bulk mixture. The deviation is shown to depend on the ratio of the arithmetic mean to the harmonic mean of the hydrogen ion concentrations of the droplets with the liquid water content used as weighting factor in the calculation of the means. The theory developed can explain observed discrepancies from Henry's law in atmospheric samples and also other observed phenomena like the reported increase of pH values of bulk aqueous samples during storage.

  15. TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

    Science.gov (United States)

    Gray, Phillip N; Tsai, Pei; Chen, Daniel; Wu, Sitao; Hoo, Jayne; Mu, Wenbo; Li, Bing; Vuong, Huy; Lu, Hsiao-Mei; Batth, Navanjot; Willett, Sara; Uyeda, Lisa; Shah, Swati; Gau, Chia-Ling; Umali, Monalyn; Espenschied, Carin; Janicek, Mike; Brown, Sandra; Margileth, David; Dobrea, Lavinia; Wagman, Lawrence; Rana, Huma; Hall, Michael J; Ross, Theodora; Terdiman, Jonathan; Cullinane, Carey; Ries, Savita; Totten, Ellen; Elliott, Aaron M

    2018-04-17

    The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2 , MSH6 , MLH1 , PMS2 and EPCAM . Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.

  16. The Course of Law: State Intervention in Southern Lynch Mob Violence 1882–1930

    Directory of Open Access Journals (Sweden)

    Kinga Makovi

    2016-09-01

    Full Text Available Collective violence when framed by its perpetrators as "citizen" justice is inherently a challenge to state legitimacy. To properly account for such violence, it is necessary to consider an opportunity structure incorporating the actions of both vigilantes and agents of the state. The motivation and lethality of lynch mobs in the South cannot be understood without considering how the state reacted to the legitimacy challenges posed by lynching. We trace the shifting orientation of state agents to lynching attempts between the end of Reconstruction and the start of the Great Depression. Analyzing an inventory of more than 1,000 averted and completed lynching events in three Southern states, we model geographic and temporal patterns in the determinants of mob formation, state intervention, and intervention success. Opponents of lynching often pled with mobs to "let the law take its course." This article examines the course followed by the law itself, as state actors moved between encouraging, accommodating, and in many instances averting mob violence.

  17. How does genetic risk information for Lynch syndrome translate to risk management behaviours?

    Science.gov (United States)

    Steel, Emma; Robbins, Andrew; Jenkins, Mark; Flander, Louisa; Gaff, Clara; Keogh, Louise

    2017-01-01

    There is limited research on why some individuals who have undergone predictive genetic testing for Lynch syndrome do not adhere to screening recommendations. This study aimed to explore qualitatively how Lynch syndrome non-carriers and carriers translate genetic risk information and advice to decisions about risk managment behaviours in the Australian healthcare system. Participants of the Australasian Colorectal Cancer Family Registry who had undergone predictive genetic testing for Lynch syndrome were interviewed on their risk management behaviours. Transcripts were analysed thematically using a comparative coding analysis. Thirty-three people were interviewed. Of the non-carriers ( n  = 16), 2 reported having apparently unnecessary colonoscopies, and 6 were unsure about what population-based colorectal cancer screening entails. Of the carriers ( n  = 17), 2 reported they had not had regular colonoscopies, and spoke about their discomfort with the screening process and a lack of faith in the procedure's ability to reduce their risk of developing colorectal cancer. Of the female carriers ( n  = 9), 2 could not recall being informed about the associated risk of gynaecological cancers. Non-carriers and female carriers of Lynch syndrome could benefit from further clarity and advice about appropriate risk management options. For those carriers who did not adhere to colonoscopy screening, a lack of faith in both genetic test results and screening were evident. It is essential that consistent advice is offered to both carriers and non-carriers of Lynch syndrome.

  18. Targeted Screening With Combined Age- and Morphology-Based Criteria Enriches Detection of Lynch Syndrome in Endometrial Cancer.

    Science.gov (United States)

    Lin, Douglas I; Hecht, Jonathan L

    2016-06-01

    Endometrial cancer is associated with Lynch syndrome in 2% to 6% of cases. Adequate screening may prevent of a second cancer and incident cancers in family members via risk-reducing strategies. The goal of the study was to evaluate the detection rate of Lynch syndrome via a targeted screening approach. In 2009, we incorporated targeted Lynch syndrome screening via immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, followed by MLH1 promoter hypermethylation, in select cases of endometrial carcinoma. Criteria for patient selection included (1) all patients Lynch syndrome. Therefore, targeted screening with combined age and morphology based criteria enriches detection of Lynch syndrome in endometrial cancer. However, the detection rate is lower than the rates from published series that offer universal screening. © The Author(s) 2016.

  19. Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Jönsson, Göran; Dominguez-Valentin, Mev

    2013-01-01

    Lynch syndrome and familial colorectal cancer type X, FCCTX, represent the two predominant colorectal cancer syndromes. Whereas Lynch syndrome is clinically and genetically well defined, the genetic cause of FCCTX is unknown and genomic differences between Lynch syndrome and FCCTX tumours...... are largely unknown. We applied array-based comparative genomic hybridisation to 23 colorectal cancers from FCCTX with comparison to 23 Lynch syndrome tumours and to 45 sporadic colorectal cancers. FCCTX tumours showed genomic complexity with frequent gains on chromosomes 20q, 19 and 17 and losses of 18, 8p...... and 15. Gain of genetic material in two separate regions encompassing, 20q12-13.12 and 20q13.2-13.32, was identified in 65% of the FCCTX tumours. Gain of material on chromosome 20q and loss on chromosome 18 significantly discriminated colorectal cancers associated with FCCTX from Lynch syndrome, which...

  20. Some aspects of molecular diagnostics in Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Kurzawski Grzegorz

    2006-12-01

    Full Text Available Abstract This manuscript is composed of five parts which summarize five publications in succession. Essentially, they are concerned with molecular diagnostics of Lynch syndrome and are based on studies in 238 families. The finding that young age at diagnosis is the key feature in patients with MSH2 and MLH1 mutations (Part 1 has helped to define simple criteria for the preliminary diagnosis of this syndrome. A cheaper method for the detection of mutations has been developed (Part 2 and applied to study the types of mutations and their prevalence in Poland (Part 3 and the Baltic States (Part 4. A specific feature of these mutations, i.e. presence of recurrent mutations in the majority of affected families with mutations, has suggested the feasibility of effective diagnostics with a single test disclosing all of them. An attempt to reveal other causes of familial aggregation of colorectal cancer has ruled out any association with C insertion in the NOD2 gene (Part 5.

  1. Lynch syndrome in the 21st century: clinical perspectives.

    Science.gov (United States)

    Tiwari, A K; Roy, H K; Lynch, H T

    2016-03-01

    Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes- MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI). Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Floral pipe: length in Petunia x hybrida heredability, number of genes and the interaction of the date with the character

    OpenAIRE

    Fatta, N.; Vazquez, M.; García, N.; Mascarini, A.; Grigioni, G.

    2007-01-01

    Petunia x hybrida, a floral summer of a economical importance in Buenos Aires, is nowadays produced with imported seed. The research presented is focused on the study of the feasibility to obtain locally competitive seed. The length of the floral pipe is a relevant character so the assay was designed in order to estimate the heredability, the number of genes intervener and the interactions with the date. The assay began with a F1 purchased from United States. In 2003, the F1 and F2 were sowed...

  3. Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

    Science.gov (United States)

    Liccardo, Raffaella; De Rosa, Marina; Duraturo, Francesca

    2018-01-01

    Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair ( MMR ) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.

  4. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

    DEFF Research Database (Denmark)

    Clendenning, Mark; Senter, Leigha; Hampel, Heather

    2008-01-01

    BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (Lynch syndrome cases...... on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n=61). These individuals all display the rare allele (population...... are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. METHODS: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  6. Neuroendocrine-type prostatic adenocarcinoma with microsatellite instability in a patient with lynch syndrome.

    Science.gov (United States)

    Wagner, David G; Gatalica, Zoran; Lynch, Henry T; Kohl, Shane; Johansson, Sonny L; Lele, Subodh M

    2010-12-01

    Lynch syndrome is an autosomal-dominant cancer syndrome that can be identified with microsatellite instability molecular tests or immunohistochemical stains on pathologic material from patients who meet the Amsterdam Criteria II. The development of prostatic carcinoma in situ or invasive small cell carcinoma (SCC) of the prostate has not been previously reported in a patient with this syndrome. In this report, an 87-year-old White man with the Lynch syndrome had a prostate biopsy that revealed a mixed high-grade conventional adenocarcinoma and SCC of the prostate with high-grade prostatic intraepithelial neoplasia of the small cell neuroendocrine-type (HGPIN-NE), all showing MSH2 microsatellite instability and loss of MSH2 expression, a finding not previously published. These findings suggest that HGPIN-NE is a precursor of invasive SCC and also that prostatic SCC can develop in a patient with the Lynch syndrome.

  7. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated....... Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model...

  8. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome

    DEFF Research Database (Denmark)

    Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka

    2008-01-01

    BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect...... on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome...... on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)...

  9. Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

    Science.gov (United States)

    Kravochuck, Sara E; Church, James M

    2017-12-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance. © 2016 Royal Australasian College of Surgeons.

  10. Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

    Science.gov (United States)

    Takeda, Takashi; Tsuji, Kosuke; Banno, Kouji; Yanokura, Megumi; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

    2018-05-01

    Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM₅ were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM₅, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

  11. General practitioner attitudes towards prescribing aspirin to carriers of Lynch Syndrome: findings from a national survey.

    Science.gov (United States)

    Smith, Samuel G; Foy, Robbie; McGowan, Jennifer; Kobayashi, Lindsay C; Burn, John; Brown, Karen; Side, Lucy; Cuzick, Jack

    2017-10-01

    A dose non-inferiority study comparing 100 mg, 300 mg and 600 mg of aspirin for cancer prevention among Lynch Syndrome carriers is underway (Colorectal Adenoma/Carcinoma Prevention Programme trial 3, CaPP3). To guide implementation of the findings, we investigated general practitioner (GP) attitudes towards aspirin prescribing for Lynch Syndrome carriers. We surveyed 1007 UK GPs (9.6% response rate). Using a within-subjects design, GPs read a statement on harms and benefits of aspirin and indicated their willingness to prescribe aspirin at three doses (100 mg, 300 mg, 600 mg). Approximately two-thirds (70.8%) of GPs had heard of Lynch Syndrome or its associated names, and among those 46.7% were aware of the cancer preventive effects of aspirin among carriers. Two-thirds (68.1%) of GPs reported feeling comfortable discussing harms and benefits of aspirin with a Lynch Syndrome patient. Willingness to prescribe was 91.3% at 100 mg, and declined to 81.8% at 300 mg and 62.3% at 600 mg (p Lynch Syndrome patient in practice (OR 1.44, 95% CI 1.01-2.05, p = 0.045). GPs report limited awareness of Lynch Syndrome and the preventive effects of aspirin among carriers. To ensure the optimal dose identified in the CaPP3 trial is readily available to patients, prescribing guidance and strategies to educate GPs should be developed.

  12. Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma.

    Science.gov (United States)

    Djordjevic, Bojana; Broaddus, Russell R

    2016-06-01

    This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

    Science.gov (United States)

    Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R; Bowles, Karla R; Judkins, Thaddeus; Kaushik, Praveen; Roa, Benjamin B; Wenstrup, Richard J; Hartman, Anne-Renee; Syngal, Sapna

    2015-09-01

    Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many

  14. An overview of a multifactor-system theory of personality and individual differences: III. Life span development and the heredity-environment issue.

    Science.gov (United States)

    Powell, A; Royce, J R

    1981-12-01

    In Part III of this three-part series on multifactor-system theory, multivariate, life-span development is approached from the standpoint of a quantitative and qualitative analysis of the ontogenesis of factors in each of the six systems. The pattern of quantitative development (described via the Gompertz equation and three developmental parameters) involves growth, stability, and decline, and qualitative development involves changes in the organization of factors (e.g., factor differentiation and convergence). Hereditary and environmental sources of variation are analyzed via the factor gene model and the concept of heredity-dominant factors, and the factor-learning model and environment-dominant factors. It is hypothesized that the sensory and motor systems are heredity dominant, that the style and value systems are environment dominant, and that the cognitive and affective systems are partially heredity dominant.

  15. Rahvaliit : Henri Kaselo süüdistus on idiootsus / Jüri Saar

    Index Scriptorium Estoniae

    Saar, Jüri, 1946-

    2008-01-01

    Keskerakonna Tartumaa piirkonna esimeheks valitud Tartu linnavolinik Henri Kaselo kritiseeris teravalt Rahvaliitu kuuluvaid Tartumaa vallajuhte, kelle juhtimisstiil ja korruptiivne poliitika polevat nõukogude ajast muutunud

  16. [From apprenticeship to Nobel Prize: Henri Moissan's fabulous destiny].

    Science.gov (United States)

    Lafont, O

    2008-01-01

    Born in Paris on September 28, 1852, son of an eastern railways' employee and of a dressmaker, Henri Moissan's secondary schooling in Meaux did not allow him to get access to the sesame diploma "baccalauréat" (GCE). In 1869, he did obtain a special certificate of secondary schooling so that he could become an apprentice in watch making. That could have been the end of the story, but dreadful event for France appeared to have beneficial effects for Moissan. Under the threat of the Prussian army, Moissan's family took refuge near Paris. This gave the young Henri the opportunity to register as a student for the second-class pharmacy diploma, which did not need, at the time, the GCE. Moissan became then a trainee in pharmacy in 1871. Meanwhile, he followed the special schooling of "Ecole de chimie" founded by E. Frémy, and then joined the laboratory of Dehérain at the Museum, where he worked in plant physiology. He finally obtained the famous "baccalauréat" (GCE) and could register as a student in first-class pharmacy. He became a pharmacist as well as a doctor in sciences. In 1883, Moissan was named professor at the school of pharmacy in Paris. In 1886, he isolated fluorine by electrolysis of fluorhydric acid, in the presence of potassium fluoride, at a low temperature. He then studied diamond synthesis and gave a start to high temperature chemistry, designing his famous furnace. These findings and many others allowed Moissan to rise to membership in many learned academies around the world. Crowning achievement, Moissan won the Nobel Prize in 1906. A man of culture, collector of autographs and paintings, he died in 1907. Nothing of that would have been possible if there had not been a second-class pharmacist diploma. The history of Henri Moissan is one of a rise from apprenticeship to the Nobel Prize.

  17. O pensamento crítico de Henri Lefebvre

    Directory of Open Access Journals (Sweden)

    William Gómez Soto

    2012-12-01

    Full Text Available Este trabalho é uma análise da presença de Henri Lefebvre na sociologia brasileira. Lefebvre faz uma leitura crítica de Marx, recuperando o método dialético e propondo uma teoria da vida cotidiana. José de Souza Martins influenciado por Lefebvre e utilizando o método dialético, analisa o processo histórico da constituição do capitalismo brasileiro. Apesar de que há certa presença de Lefebvre na sociologia brasileira, ainda a riqueza de sua obra está para ser descoberta.

  18. Henry Duméry and the sacredness of history

    OpenAIRE

    Labèque, Marcelo Horacio; Pontificia Universidad Católica Argentina

    2014-01-01

    Following the steps of the French phenomenologist HenryDuméry, It is pursued to identify the particularities of what have been called before the «historical sacred», in the most general frame of a «morphology of sacred». In that sense it is intended to demonstrate that the originality of the experience and configuration of the sacred, in both Jewish and Christian religion, comes out from a transformation of cosmic archaic experiences and points of view, leading into a new way of sacred that g...

  19. Edward Henry Sieveking and the demise of essential epilepsy.

    Science.gov (United States)

    Bladin, Peter F

    2008-04-01

    Edward Henry Sieveking, eminent London physician of Victorian times, is best known as the speaker at the historic meeting at which the chairman, Sir Charles Locock, seem to overshadow him in announcing the introduction of bromide--the first effective anti-convulsant. But in fact Sieveking had announced a most important conceptual advance in epileptology--the demise of "essential epilepsy". In addition his book, published soon after and based upon his lecture, is an important historical resumé of Victorian era concepts and management of epilepsy. His important contributions to the understanding and management of this condition are discussed herein.

  20. Henri Ey's neojacksonism and the psychopathology of disintegrated mind.

    Science.gov (United States)

    Farina, Benedetto; Ceccarelli, Maurizio; Di Giannantonio, Massimo

    2005-01-01

    The French psychiatrist Henri Ey developed his organo-dynamic theory of the mind function and consciousness 50 years ago incorporating Hughling Jackson's thinking, along with psychiatric and philosophical theorizations by Janet and Bergson. This model has not received the attention it deserved, but recent advances in neuroscience rekindled interest for Ey's theory. By overcoming the Cartesian mind-body dualism and treating the mind-body unit as an inseparable whole, this model opens the way for the integrated treatment of mental disorders. Ey's conceptualization of consciousness as being simultaneously both synchronous and diachronic anticipates current theories of consciousness (Damasio, Edelman, Mesulam).

  1. Pain evaluation during gynaecological surveillance in women with Lynch syndrome.

    Science.gov (United States)

    Helder-Woolderink, Jorien; de Bock, Geertruida; Hollema, Harry; van Oven, Magda; Mourits, Marian

    2017-04-01

    To evaluate perceived pain during repetitive annual endometrial sampling at gynaecologic surveillance in asymptomatic women with Lynch syndrome (LS) over time and in addition to symptomatic women without LS, undergoing single endometrial sampling. In this prospective study, 52 women with LS or first degree relatives who underwent repetitive annual gynaecological surveillance including endometrial sampling of which 33 were evaluated twice or more and 50 symptomatic women without LS who had single endometrial sampling, were included. Pain intensity was registered with VAS scores. Differences in pain intensities between subsequent visits (in LS) and between the two groups were evaluated. The use of painkillers before endometrial sampling was registered. If women with LS decided for preventive surgery, the reason was recorded. The LS group reported a median VAS score of 5.0 (range 0-10) at the first surveillance (n = 52) and at the second visit (n = 24). Women who repeatedly underwent endometrial sampling more often used painkillers for this procedure. During the study period 7/52 (13 %) women with LS choose for preventive surgery, another 4/52 (8 %) refused further endometrial sampling. Painful endometrial sampling was mentioned as main reason to quit screening. The median VAS score of the 50 symptomatic women was 5.0 (range 1-9). Endometrial sampling, irrespective of indication, is a painful procedure, with a median VAS score of 5.0. During subsequent procedures in women with LS, the median pain score does not aggravate although one in five women chose an alternative for endometrial sampling.

  2. Elisa Alicia Lynch: a Dama de Aço do Paraguai * Elisa Alicia Lynch: the Steel ‘S Lady of Paraguay

    OpenAIRE

    Frota, Luciara Silveira de Aragão e

    2015-01-01

    Este trabalho mostra uma nova visão da irlandesa Elisa Alicia Lynch, longe da figura de prostituta manipuladora que incitou o Marechal Solano López no começo da Guerra do Paraguai. Dentro de uma corrente revisionista histórica, apoiada em Marc Bloch, propõe uma nova análise de seu papel na vida de Solano López e do Paraguai, comentando a literatura sobre o assunto.

  3. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2016-10-01

    The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5 %) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50 %) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4 %) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p = 0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non-polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials.

  4. Evaluating Henry's law constant of N-nitrosodimethylamine (NDMA).

    Science.gov (United States)

    Haruta, Shinsuke; Jiao, Wentao; Chen, Weiping; Chang, Andrew C; Gan, Jay

    2011-01-01

    N-Nitrosodimethylamine (NDMA), a potential carcinogen, may contaminate the groundwater when the reclaimed wastewater is used for irrigation and groundwater recharge. Henry's law constant is a critical parameter to assess the fate and transport of reclaimed wastewater-borne NDMA in the soil profile. We conducted a laboratory experiment in which the change of NDMA concentration in water exposed to the atmosphere was measured with respect to time and, based on the data, obtained the dimensionless Henry's law constant (K(H)') of NDMA, at 1.0 x 10(-4). The K(H)' suggests that NDMA has a relatively high potential to volatilize in the field where NDMA-containing wastewater is used for irrigation and the volatilization loss may be a significant pathway of NDMA transport. The experiment was based on the two boundary-layer approach of mass transfer at the atmosphere-water interface. It is an expedient method to delineate K(H)' for volatile or semi-volatile compounds present in water at low concentrations.

  5. Lynch, Urry and city marketing: Taking advantage of the city as a built and graphic image

    NARCIS (Netherlands)

    Hospers, G-J.

    2009-01-01

    City marketing is usually addressed from the perspective of marketing theory. This article follows an alternative approach by exploring city marketing from the viewpoint of urban planning and the sociology of tourism. In his classic ‘The Image of the City’ (1960), planner Kevin Lynch found that

  6. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, F.J.B. van; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  7. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome: The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, van F.J.B.; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  8. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, Akke; Vasen, Hans F. A.; van Duijnhoven, Franzel J. B.; Kleibeuker, Jan H.; Nagengast, Fokko M.; Kampman, Ellen

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  9. Inflammatory potential of the diet and colorectal tumor risk in persons with Lynch syndrome

    NARCIS (Netherlands)

    Brouwer, Jesca G.M.; Makama, Maureen; Woudenbergh, Van Geertruida J.; Vasen, Hans F.A.; Nagengast, Fokko M.; Kleibeuker, Jan H.; Kampman, Ellen; Duijnhoven, Van Fränzel J.B.

    2017-01-01

    Background: Persons with Lynch syndrome (LS) have high lifetime risk of developing colorectal tumors (CRTs) because of a germline mutation in one of their mismatch repair (MMR) genes. An important process in the development of CRTs is inflammation, which has been shown to be modulated by diet.

  10. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

    DEFF Research Database (Denmark)

    Lagerstedt-Robinson, Kristina; Rohlin, Anna; Aravidis, Christos

    2016-01-01

    Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2...... Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large...... deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder...

  11. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk

    NARCIS (Netherlands)

    Broeke, S.W. ten; Brohet, R.M.; Tops, C.M.; Klift, H.M. van der; Velthuizen, M.E.; Bernstein, I.; Capella Munar, G.; Garcia, E.; Hoogerbrugge, N.; Letteboer, T.G.; Menko, F.H.; Lindblom, A.; Mensenkamp, A.R.; Moller, P.; Os, T.A. van; Rahner, N.; Redeker, B.J.; Sijmons, R.H.; Spruijt, L.; Suerink, M.; Vos, Y.J.; Wagner, A.; Hes, F.J.; Vasen, H.F.A.; Nielsen, M.; Wijnen, J.T.

    2015-01-01

    PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98

  12. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Al-Toma, Abdul; Dekker, Evelien; Vanhoutvin, Steven A. L. W.; Nagengast, Fokko M.; Mathus-Vliegen, Elisabeth M.; van Leerdam, Monique E.; de Vos tot Nederveen Cappel, Wouter H.; Sanduleanu, Silvia; Veenendaal, Roeland A.; Cats, Annemieke; Vasen, Hans F. A.; Kleibeuker, Jan H.; Koornstra, Jan J.

    2015-01-01

    The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE). After obtaining informed consent, asymptomatic proven gene mutation carriers aged 35-70 years were included in this prospective multicentre study in

  13. Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

    NARCIS (Netherlands)

    ten Broeke, Sanne W.; Brohet, Richard M.; Tops, Carli M.; van der Klift, Heleen M.; Velthuizen, Mary E.; Bernstein, Inge; Capellá Munar, Gabriel; Gomez Garcia, Encarna; Hoogerbrugge, Nicoline; Letteboer, Tom G. W.; Menko, Fred H.; Lindblom, Annika; Mensenkamp, Arjen R.; Moller, Pal; van Os, Theo A.; Rahner, Nils; Redeker, Bert J. W.; Sijmons, Rolf H.; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J.; Wagner, Anja; Hes, Frederik J.; Vasen, Hans F.; Nielsen, Maartje; Wijnen, Juul T.

    2015-01-01

    Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2

  14. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Al-Toma, Abdul; Dekker, Evelien; Vanhoutvin, Steven A. L. W.; Nagengast, Fokko M.; Mathus-Vliegen, Elisabeth M.; van Leerdam, Monique E.; Cappel, Wouter H. de Vos tot Nederveen; Sanduleanu, Silvia; Veenendaal, Roeland A.; Cats, Annemieke; Vasen, Hans F. A.; Kleibeuker, Jan H.; Koornstra, Jan J.

    2015-01-01

    Objective The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE). Design After obtaining informed consent, asymptomatic proven gene mutation carriers aged 3570 years were included in this prospective

  15. Lynch Syndrome Caused by Germline PMS2 Mutations : Delineating the Cancer Risk

    NARCIS (Netherlands)

    ten Broeke, Sanne W.; Brohet, Richard M.; Tops, Carli M.; van der Klift, Heleen M.; Velthuizen, Mary E.; Bernstein, Inge; Capella Munar, Gabriel; Garcia, Encarna Gomez; Hoogerbrugge, Nicoline; Letteboer, Tom G. W.; Menko, Fred H.; Lindblom, Annika; Mensenkamp, Arjen R.; Moller, Pal; Van Os, Theo A.; Rahner, Nils; Redeker, Bert J. W.; Sijmons, Rolf H.; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J.; Wagner, Anja; Hes, Frederik J.; Vasen, Hans F.; Nielsen, Maartje; Wijnen, Juul T.

    2015-01-01

    Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2

  16. Diagnostic Strategies for Early Lynch Syndrome Detection: From Molecular Testing to Economic Evaluation

    NARCIS (Netherlands)

    C.H.M. Leenen (Celine)

    2015-01-01

    markdownabstract__Abstract__ Lynch syndrome (LS) is an autosomal dominant inherited syndrome that predisposes to multiple malignancies, in particular colorectal cancer (CRC) and endometrial cancer (EC). The lifetime risk of developing CRC for a LS mutation carrier is 25 to 70%, while women

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  19. Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.

    Science.gov (United States)

    Hesson, Luke B; Packham, Deborah; Kwok, Chau-To; Nunez, Andrea C; Ng, Benedict; Schmidt, Christa; Fields, Michael; Wong, Jason W H; Sloane, Mathew A; Ward, Robyn L

    2015-06-01

    Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

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

    DEFF Research Database (Denmark)

    Hinrichsen, Inga; Brieger, Angela; Trojan, Jörg

    2013-01-01

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

  1. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

    NARCIS (Netherlands)

    Sijmons, Rolf H.; Greenblatt, Marc S.; Genuardi, Maurizio

    Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance

  2. Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers : A qualitative exploration

    NARCIS (Netherlands)

    Visser, Annemiek; Vrieling, Alina; Murugesu, Laxsini; Hoogerbrugge, Nicoline; Kampman, Ellen; Hoedjes, Meeke

    2017-01-01

    Background: Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower this risk. To promote adherence to these recommendations, knowledge on determinants of

  3. Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers

    NARCIS (Netherlands)

    Vrieling, A.; Visser, A.; Hoedjes, Meeke; Hurks, H.M.H.; Gómez García, E.; Hoogerbrugge, N.; Kampman, E.

    2018-01-01

    Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and

  4. Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers: a qualitative exploration.

    NARCIS (Netherlands)

    Visser, A.; Vrieling, A.; Murugesu, L.; Hoogerbrugge, N.; Kampman, E.; Hoedjes, M.

    2017-01-01

    Background: Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower this risk. To promote adherence to these recommendations, knowledge on determinants of

  5. Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists

    NARCIS (Netherlands)

    Menko, Fred H.; Aalfs, Cora M.; Henneman, Lidewij; Stol, Yrrah; Wijdenes, Miranda; Otten, Ellen; Ploegmakers, Marleen M. J.; Legemaate, Johan; Smets, Ellen M. A.; de Wert, Guido M. W. R.; Tibben, Aad

    2013-01-01

    The diagnosis of Lynch syndrome can lead to the prevention of colorectal cancer through periodic colonoscopies and removal of premalignant lesions in susceptible individuals. Therefore, predisposed individuals identified by mutation analysis are advised to inform their at-risk relatives about the

  6. What the physician needs to know about Lynch syndrome: an update.

    Science.gov (United States)

    Lynch, Henry T; Lynch, Jane F

    2005-04-01

    The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene--most commonly MSH2, MLHI, or, to a lesser degree, MSH6--is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.

  7. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....

  8. Assessing Genetic Variants of Uncertain Significance: The Example of Lynch Syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D.

    2014-01-01

    cancer syndrome, Lynch syndrome, is used as an example. This challenge is addressed by illustrating the importance of combining genetic and functional data in future strategies to assess VUS. The proposed strategies combine clinical genetic, analytical, functional and in silico approaches....

  9. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome

    DEFF Research Database (Denmark)

    Watson, Patrice; Vasen, Hans F A; Mecklin, Jukka-Pekka

    2008-01-01

    Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention...

  10. Informing family members of individuals with Lynch syndrome : a guideline for clinical geneticists

    NARCIS (Netherlands)

    Menko, Fred H.; Aalfs, Cora M.; Henneman, Lidewij; Stol, Yrrah; Wijdenes, Miranda; Otten, Ellen; Ploegmakers, Marleen M. J.; Legemaate, Johan; Smets, Ellen M. A.; de Wert, Guido M. W. R.; Tibben, Aad

    The diagnosis of Lynch syndrome can lead to the prevention of colorectal cancer through periodic colonoscopies and removal of premalignant lesions in susceptible individuals. Therefore, predisposed individuals identified by mutation analysis are advised to inform their at-risk relatives about the

  11. Thyroid cancer in a patient with Lynch syndrome – case report and literature review

    Directory of Open Access Journals (Sweden)

    Fazekas-Lavu M

    2017-07-01

    Full Text Available Monika Fazekas-Lavu,1 Andrew Parker,2 Allan D Spigelman,3,4 Rodney J Scott,5 Richard J Epstein,6 Michael Jensen,7 Katherine Samaras1,8 1Department of Endocrinology, 2Department of Pathology, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 3Hereditary Cancer Clinic, St Vincent’s Cancer Genetics Service, Darlinghurst, NSW, Australia; 4University of NSW, St Vincent’s Clinical School, Darlinghurst, NSW, Australia; 5Division of Molecular Medicine, Pathology North, John Hunter Hospital and The Hunter Medical Research Institute, Newcastle, NSW, Australia; 6Department of Oncology, 7Department of Oncological Surgery/General Surgery, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 8Diabetes and Metabolism Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia Abstract: Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6, and PMS2 and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the MSH2 gene with a synchronous papillary thyroid cancer. Six years later, she developed metachronous breast cancer. Metastatic bone disease developed after 3 years, and the disease burden was due to both breast and thyroid diseases. Despite multiple interventions for both metastatic breast and thyroid diseases, the patient’s metastatic burden progressed and she died of leptomeningeal metastatic disease. Two prior case reports suggested thyroid cancer may be an extraintestinal malignancy of the Lynch syndrome cancer group. Hence, this study examined the genetic relationship between the patient’s known Lynch syndrome and her

  12. HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (LYNCH SYNDROME PADA WANITA UMUR 16 TAHUN

    Directory of Open Access Journals (Sweden)

    Asril Zahari

    2011-09-01

    Full Text Available AbstrakKanker kolorektal menduduki peringkat ketiga jenis kanker yang paling sering terjadi di dunia. Sekitar 3% kasus kanker kolorektal merupakan jenis hereditary non polyposis colorectal cancer (HNPCC/Lynch syndrome, yang sering muncul pada usia muda. Dilaporkan satu kasus di rumah sakit Dr. M. Djamil Padang, wanita berumur 16 tahun dengan keluhan nyeri perut kanan bawah. Didapatkan riwayat penyakit serupa pada kakek, bibi pasien dan enam anggota keluarga yang lain. Pada pemeriksaan fisik abdomen teraba massa dengan konsistensi keras dan terfiksir. Pada kolonoskopi dan biopsi ditemukan tumor jenis adenocarcinoma colon moderatly differentiated di fleksura hepatika dan polip di kolon sigmoid. Berdasarkan kriteria Amsterdam pasien didiagnosa Lynch syndrome. Pada Pasien dilakukan subtotal kolektomi, anastomose ileorectal dan kemoterapi ajuvan. Identifikasi genetik sedang dikerjakan untuk melihat adanya kelainan genetik pada pasien. Pasien melakukan skrining berkala untuk mencegah kanker HNPCC jenis yang lain.Kata kunci : Hereditary non polyposis colorectal cancer, Lynch syndrome, Microsatellite instability, skrining.AbstractCarcinoma colorectal is the third most common type of cancer that occurs in the world. About 2% -3% of cases of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome, which often appear at a young age. Amsterdam and Bethesda criteria have been used to identify patients with Lynch syndrome.one case was reported at the Dr. M. Djamil Padang hospital, a 16-year-old girl with right lower abdominal pain. Obtained a history of similar disease in grandparents, aunts and six other family members. On physical examination found palpable fixed abdominal mass with hard consistency in the lower right abdomen. At colonoscopy and biopsy found a moderatly differentiated adenocarcinoma colon type at the hepatic flexure and the sigmoid colon polyp. Based on the Amsterdam criteria, patients diagnosed with HNPCC/Lynch

  13. VoxHenry: FFT-Accelerated Inductance Extraction for Voxelized Geometries

    KAUST Repository

    Yucel, Abdulkadir C.

    2018-01-18

    VoxHenry, a fast Fourier transform (FFT)-accelerated integral-equation-based simulator for extracting frequency-dependent inductances and resistances of structures discretized by voxels, is presented. VoxHenry shares many features with the popular inductance extractor, FastHenry. Just like FastHenry, VoxHenry solves a combination of the electric volume integral equation and the current continuity equation, but with three distinctions that make VoxHenry suitable and extremely efficient for analyzing voxelized geometries: 1) it leverages a carefully selected set of piecewise-constant and piecewise-linear basis functions; 2) it exploits FFTs to accelerate the matrix-vector multiplications during the iterative solution of system of equations; and 3) it employs a sparse preconditioner to ensure the rapid convergence of iterative solution. VoxHenry is capable of accurately computing frequency-dependent inductances and resistances of arbitrarily shaped and large-scale structures on a desktop computer. The accuracy, efficiency, and applicability of VoxHenry are demonstrated through inductance analysis of various structures, including square and circular coils as well as arrays of RF inductors (situated over ground planes).

  14. 1787 and 1776: Patrick Henry, James Madison, and the Revolutionary Legitimacy of the Constitution.

    Science.gov (United States)

    Banning, Lance

    1988-01-01

    Discusses Patrick Henry's and James Madison's opinions on how the U.S. Constitution should be constructed. Describes how Henry introduced a set of substantive objections which were shared by Antifederalists throughout the country and persuaded many Revolutionaries that the Constitution was essentially at odds with the principles of 1776. (BSR)

  15. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N.; Lindor, Noralane M.; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert

    2009-01-01

    Background and Aims Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods We performed PMS2 mutation analysis using long range PCR and MLPA for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results Germline PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2 fold higher and the incidence of endometrial cancer was 7.5 fold higher. In North America, this translates to a cumulative cancer risk to age 70 of 15–20% for colorectal cancer, 15% for endometrial cancer, and 25–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions PMS2 mutations contribute significantly to Lynch syndrome but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. PMID:18602922

  16. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N; Lindor, Noralane M; Young, Joanne; Winship, Ingrid; Dowty, James G; White, Darren M; Hopper, John L; Baglietto, Laura; Jenkins, Mark A; de la Chapelle, Albert

    2008-08-01

    Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

  17. Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome.

    Science.gov (United States)

    Chang, Kyle; Taggart, Melissa W; Reyes-Uribe, Laura; Borras, Ester; Riquelme, Erick; Barnett, Reagan M; Leoni, Guido; San Lucas, F Anthony; Catanese, Maria T; Mori, Federica; Diodoro, Maria G; You, Y Nancy; Hawk, Ernest T; Roszik, Jason; Scheet, Paul; Kopetz, Scott; Nicosia, Alfredo; Scarselli, Elisa; Lynch, Patrick M; McAllister, Florencia; Vilar, Eduardo

    2018-04-16

    Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. To characterize the immune profile of premalignant lesions from a cohort of patients with LS. Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells

  18. Henri Pirenne: Historian and Man of the World

    Directory of Open Access Journals (Sweden)

    Sarah Keymeulen

    2016-12-01

    Full Text Available Henri Pirenne (1862-1935 is generally recognised as one of the most influential European historians of the late nineteenth- and early twentieth-century. The combination of his scholarly activity with the social mission that he set himself earned him an extraordinarily successful career and a double reputation: at least in Belgium, he was regarded not only as a ‘father of history’, but also as great citizen. Although his influence was unmistakably large, there is no consensus about the existence or the nature of a ‘Pirennian persona’. He combined the ideal collection of skills, values and standards required of historians with very specific personal characteristics. At the same time he was inextricably linked to a certain era and a certain Belgium that died with him. Pirenne therefore, did not so much represent a new type of scientific persona as the prestige of an idealised, long-vanished Belgium and its corresponding academic culture. Henri Pirenne. Historicus en man van de wereldHenri Pirenne (1862-1935 wordt beschouwd als één van de meest invloedrijke Europese geschiedschrijvers van de laatnegentiende en vroegtwintigste eeuw. Het verband tussen zijn wetenschappelijke activiteit en de maatschappelijke taak die hij voor zichzelf zag weggelegd, leverde hem een uitzonderlijk succesvolle carrière en een dubbele reputatie op. Pirenne staat, althans in België, immers niet alleen geboekstaafd als een ‘vader van de geschiedenis’, maar ook als een groot staatsburger. Hoewel de invloed van Pirenne onmiskenbaar groot is geweest, is er geen consensus over het bestaan of de aard van een ‘pirenniaanse persona’. Hij combineerde het ideaalpakket van vaardigheden, normen en waarden die historici werden geacht te bezitten met zeer specifieke karaktereigenschappen. Tegelijk was hij onlosmakelijk verknoopt met een zeker tijdsgewricht en een zeker België, dat samen met hem ter ziele ging. Pirenne stond dan ook niet zozeer model voor een nieuw

  19. Henri Pirenne: Historian and Man of the World.

    Directory of Open Access Journals (Sweden)

    S. Keymeulen

    2016-12-01

    Full Text Available Henri Pirenne (1862-1935 is generally recognised as one of the most influential European historians of the late nineteenth- and early twentieth-century. The combination of his scholarly activity with the social mission that he set himself earned him an extraordinarily successful career and a double reputation: at least in Belgium, he was regarded not only as a ‘father of history’, but also as great citizen. Although his influence was unmistakably large, there is no consensus about the existence or the nature of a ‘Pirennian persona’. He combined the ideal collection of skills, values and standards required of historians with very specific personal characteristics. At the same time he was inextricably linked to a certain era and a certain Belgium that died with him. Pirenne therefore, did not so much represent a new type of scientific persona as the prestige of an idealised, long-vanished Belgium and its corresponding academic culture. Henri Pirenne. Historicus en man van de wereld. Henri Pirenne (1862-1935 wordt beschouwd als één van de meest invloedrijke Europese geschiedschrijvers van de laatnegentiende en vroegtwintigste eeuw. Het verband tussen zijn wetenschappelijke activiteit en de maatschappelijke taak die hij voor zichzelf zag weggelegd, leverde hem een uitzonderlijk succesvolle carrière en een dubbele reputatie op. Pirenne staat, althans in België, immers niet alleen geboekstaafd als een ‘vader van de geschiedenis’, maar ook als een groot staatsburger. Hoewel de invloed van Pirenne onmiskenbaar groot is geweest, is er geen consensus over het bestaan of de aard van een ‘pirenniaanse persona’. Hij combineerde het ideaalpakket van vaardigheden, normen en waarden die historici werden geacht te bezitten met zeer specifieke karaktereigenschappen. Tegelijk was hij onlosmakelijk verknoopt met een zeker tijdsgewricht en een zeker België, dat samen met hem ter ziele ging. Pirenne stond dan ook niet zozeer model voor een nieuw

  20. Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Esplen, Mary Jane; Ladelund, Steen

    2011-01-01

    An increasing number of individuals seek genetic counseling and hereby learn about hereditary cancer in the family. Lynch syndrome is associated with an inherited high risk for colorectal and gynecological cancer, but knowledge about how family members at risk perceive their situation is limited....... We used the national Danish HNPCC register to collect data on self-concept from 413 individuals with Lynch syndrome. The recently developed Lynch syndrome self-concept scale contains 20 items within two subscales related to stigma-vulnerability and bowel symptom-related anxiety. Significantly higher...... more often reported by women (odds ratio 1.8) and by individuals with less education (OR 1.8). This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about...

  1. The B-Lynch uterine brace suture, and a bit of this and a bit of that...

    Science.gov (United States)

    Karoshi, Mahantesh

    2010-03-01

    The widespread application of the B-Lynch brace suture to control postpartum hemorrhage has sparked interest in a variety of adjunctive methods, used alone or in combination, to control uterine bleeding. Although the B-Lynch brace suture has been used with good results throughout the world, failures can and do occur in rare instances, especially when the suture is incorrectly placed for use for an inappropriate indication. Four reports of additional methods to control postpartum hemorrhage are published in this issue of IJGO. Three use the B-Lynch brace suture combined with other techniques. The need for additional techniques reminds the reader of the importance of proper suture application for proper indication. Potential reasons for failure of the B-Lynch suture are provided.

  2. Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.

    Directory of Open Access Journals (Sweden)

    Maria A Johansson

    Full Text Available BACKGROUND: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age. METHODS AND FINDINGS: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B. adolescentis, B. breve, B. bifidum, Clostridium (C. difficile, a group of Lactobacilli (Lactobacillus (L. casei, L. paracasei and L. rhamnosus as well as Staphylococcus (S. aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014. However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028. Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038. Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048. CONCLUSION: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that early Lactobacilli (L. casei, L. paracasei, L. rhamnosus colonization seems to decrease the risk for allergy at five years of age despite allergic heredity.

  3. História e psicologia em Henri Berr

    OpenAIRE

    Waeny, Maria Fernanda Costa

    2017-01-01

    O artigo aborda algumas das idéias de Henri Berr; trata de sua proposta em história, especialmente no que ela se opõe à filosofia da história e à história alemãs; e examina como esta concepção de história à la francesa introduz a psicologia nas pesquisas em história e inaugura a psicologia histórica.Palavras-chave: História da Psicologia; Psicologia Histórica; História das Ciências Humanas; História das Idéias; Annales

  4. Henri de Régnier portraitiste du Parnasse

    OpenAIRE

    Mortelette, Yann

    2016-01-01

    Henri de Régnier disait de José-Maria de Heredia qu’il avait fait le lien entre le Parnasse et le symbolisme. Lui-même fit le lien entre le symbolisme et le Parnasse. En 1895, il notait dans son journal intime : « J’ai subi de grandes influences. Aux premiers jours, Mallarmé m’a […] nettoyé l’esprit ; j’en ai été affiné et ankylosé. Puis j’ai subi les contacts plus vivants d’Heredia. » Cette seconde influence contrebalança la première. Régnier fréquenta les samedis de la rue Balzac avec autan...

  5. Thinking in time an introduction to Henri Bergson

    CERN Document Server

    Guerlac, Suzanne

    2006-01-01

    "In recent years, we have grown accustomed to philosophical language that is intensely self-conscious and rhetorically thick, often tragic in tone. It is enlivening to read Bergson, who exerts so little rhetorical pressure while exacting such a substantial effort of thought. . . . Bergson's texts teach the reader to let go of entrenched intellectual habits and to begin to think differently—to think in time. . . . Too much and too little have been said about Bergson. Too much, because of the various appropriations of his thought. Too little, because the work itself has not been carefully studied in recent decades."—from Thinking in TimeHenri Bergson (1859–1941), whose philosophical works emphasized motion, time, and change, won the Nobel Prize for Literature in 1927. His work remains influential, particularly in the realms of philosophy, cultural studies, and new media studies. In Thinking in Time, Suzanne Guerlac provides readers with the conceptual and contextual tools necessary for informed appreciati...

  6. Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome.

    Science.gov (United States)

    Mork, Maureen E; Rodriguez, Andrea; Taggart, Melissa W; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; Bannon, Sarah A; You, Y Nancy; Vilar, Eduardo

    2017-07-01

    Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

  7. W.E. Henry Symposium compendium: The importance of magnetism in physics and material science

    Energy Technology Data Exchange (ETDEWEB)

    Carwell, H.

    1997-09-19

    This compendium contains papers presented at the W. E. Henry Symposium, The Importance of Magnetism in Physics and Material Science. The one-day symposium was conducted to recognize the achievements of Dr. Warren Elliot Henry as educator, scientist, and inventor in a career spanning almost 70 years. Dr. Henry, who is 88 years old, attended the symposium. Nobel Laureate, Dr. Glenn Seaborg, a friend and colleague for over 40 years, attended the event and shared his personal reminiscences. Dr. Seaborg is Associate Director-At-Large at the Lawrence Berkeley National Laboratory. The Compendium begins with three papers which demonstrate the ongoing importance of magnetism in physics and material science. Other contributions cover the highlights of Dr. Henry`s career as a researcher, educator, and inventor. Colleagues and former students share insights on the impact of Dr. Henry`s research in the field of magnetism, low temperature physics, and solid state physics; his influence on students as an educator; and his character, intellect and ingenuity, and passion for learning and teaching. They share a glimpse of the environment and times that molded him as a man, and the circumstances under which he made his great achievements despite the many challenges he faced.

  8. Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X

    DEFF Research Database (Denmark)

    Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef

    2017-01-01

    BACKGROUND: Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other...... than MMR proteins. METHODS: We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. RESULTS: Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch...... syndrome (p Lynch syndrome tumors compared with FCCTX tumors (p = 0.001,

  9. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance

    DEFF Research Database (Denmark)

    Møller, Pål; Seppälä, Toni; Bernstein, Inge

    2017-01-01

    study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous...... carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24......%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite...

  10. Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

    OpenAIRE

    Umar, Asad; Boland, C. Richard; Terdiman, Jonathan P.; Syngal, Sapna; de la Chapelle, Albert; Rüschoff, Josef; Fishel, Richard; Lindor, Noralane M.; Burgart, Lawrence J.; Hamelin, Richard; Hamilton, Stanley R.; Hiatt, Robert A.; Jass, Jeremy; Lindblom, Annika; Lynch, Henry T.

    2004-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to...

  11. »Just cut them up like regular children.« : Eraserhead (USA 1977, David Lynch)

    OpenAIRE

    Höltgen, Stefan

    2010-01-01

    Zwischen 1970 und 1977 entsteht in fünfjähriger Dreharbeit mit Unterbrechungen und unter extrem schwierigen Produktionsbedingungen David Lynchs erster Spielfilm "Eraserhead". Vorbereitet wurde er in mehrfacher Hinsicht durch das Frühwerk des noch jungen Regisseurs. Seine kinetische Skulptur "Six Men getting sick", sowie seine Kurzfilme "The Alphabet" und "The Grandmother" verhalfen ihm nicht nur zu Stipendien (etwa der AFI für "The Grandmother"), sondern etablierten auch ein Motivinventar, au...

  12. Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome

    OpenAIRE

    Serracant Barrera, Anna; Serra Pla, Sheila; Blázquez Maña, Carmen María; Salas, Rubén Carrera; García Monforte, Neus; Bejarano González, Natalia; Romaguera Monzonis, Andreu; Andreu Navarro, Francisco Javier; Bella Cueto, Maria Rosa; Borobia, Francisco G.

    2017-01-01

    Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and seboma...

  13. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    OpenAIRE

    Campos, Sara; Amaro, Pedro; Cunha, Inês; Fraga, João; Cipriano, Maria Augusta; Tomé, Luís

    2017-01-01

    Introduction: Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. Case: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections d...

  14. Field performance of timber bridges. 8, Lynches Woods Park stress-laminated deck bridge

    Science.gov (United States)

    J. P. Wacker; M. A. Ritter; D. Conger

    The Lynches Woods Park bridge was constructed during the summer of 1990 in Newberry, South Carolina. It is a single-span, single-lane, stress-laminated deck superstructure that measures approximately 30 ft long, 16 ft wide, and 14 in. deep. The bridge is unique in that is one of the first known stress-laminated deck bridges to be constructed of Southern Pine lumber...

  15. Lynch syndrome: barriers to and facilitators of screening and disease management.

    Science.gov (United States)

    Watkins, Kathy E; Way, Christine Y; Fiander, Jacqueline J; Meadus, Robert J; Esplen, Mary Jane; Green, Jane S; Ludlow, Valerie C; Etchegary, Holly A; Parfrey, Patrick S

    2011-09-07

    Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC) and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23) were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health.

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

    Hitchins, Megan P

    2016-07-01

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

  18. Lynch syndrome: barriers to and facilitators of screening and disease management

    Directory of Open Access Journals (Sweden)

    Watkins Kathy E

    2011-09-01

    Full Text Available Abstract Background Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. Methods The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23 were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Results Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Conclusions Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health.

  19. Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

    Science.gov (United States)

    Lynch, Henry T; Lanspa, Stephen; Shaw, Trudy; Casey, Murray Joseph; Rendell, Marc; Stacey, Mark; Townley, Theresa; Snyder, Carrie; Hitchins, Megan; Bailey-Wilson, Joan

    2018-07-01

    Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

  20. A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification

    OpenAIRE

    Tognetto, Alessia; Michelazzo, Maria Benedetta; Calabró, Giovanna Elisa; Unim, Brigid; Di Marco, Marco; Ricciardi, Walter; Pastorino, Roberta; Boccia, Stefania

    2017-01-01

    Background Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3–5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for ...

  1. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome.

    Science.gov (United States)

    Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; von Knebel Doeberitz, Magnus

    2010-06-01

    High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.

  2. Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome

    OpenAIRE

    Özcan, Mine

    2017-01-01

    Microsatellite-unstable (MSI) cancers occurring in the context of the hereditary Lynch syndrome or as sporadic cancers elicit pronounced tumor-specific immune responses. The pronounced immune response was shown to be closely associated with frameshift peptides (FSP) that are generated as a result of deficiency in DNA mismatch repair system leading to insertion/deletion mutations in coding microsatellites (cMS). FSP neoantigens are long antigenic amino acid stretches that bear m...

  3. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome

    Science.gov (United States)

    Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; Doeberitz, Magnus von Knebel

    2014-01-01

    High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer (HNPCC) or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites (cMS) and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n=69), healthy Lynch syndrome mutation carriers (n=31) and healthy controls (n=52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (p=0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients. PMID:19957108

  4. Using Social Media Data to Understand the Impact of Promotional Information on Laypeople's Discussions: A Case Study of Lynch Syndrome.

    Science.gov (United States)

    Bian, Jiang; Zhao, Yunpeng; Salloum, Ramzi G; Guo, Yi; Wang, Mo; Prosperi, Mattia; Zhang, Hansi; Du, Xinsong; Ramirez-Diaz, Laura J; He, Zhe; Sun, Yuan

    2017-12-13

    Social media is being used by various stakeholders among pharmaceutical companies, government agencies, health care organizations, professionals, and news media as a way of engaging audiences to raise disease awareness and ultimately to improve public health. Nevertheless, it is unclear what effects this health information has on laypeople. This study aimed to provide a detailed examination of how promotional health information related to Lynch syndrome impacts laypeople's discussions on a social media platform (Twitter) in terms of topic awareness and attitudes. We used topic modeling and sentiment analysis techniques on Lynch syndrome-related tweets to answer the following research questions (RQs): (1) what are the most discussed topics in Lynch syndrome-related tweets?; (2) how promotional Lynch syndrome-related information on Twitter affects laypeople's discussions?; and (3) what impact do the Lynch syndrome awareness activities in the Colon Cancer Awareness Month and Lynch Syndrome Awareness Day have on laypeople's discussions and their attitudes? In particular, we used a set of keywords to collect Lynch syndrome-related tweets from October 26, 2016 to August 11, 2017 (289 days) through the Twitter public search application programming interface (API). We experimented with two different classification methods to categorize tweets into the following three classes: (1) irrelevant, (2) promotional health information, and (3) laypeople's discussions. We applied a topic modeling method to discover the themes in these Lynch syndrome-related tweets and conducted sentiment analysis on each layperson's tweet to gauge the writer's attitude (ie, positive, negative, and neutral) toward Lynch syndrome. The topic modeling and sentiment analysis results were elaborated to answer the three RQs. Of all tweets (N=16,667), 87.38% (14,564/16,667) were related to Lynch syndrome. Of the Lynch syndrome-related tweets, 81.43% (11,860/14,564) were classified as promotional and 18

  5. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.

    Science.gov (United States)

    Clendenning, M; Senter, L; Hampel, H; Robinson, K Lagerstedt; Sun, S; Buchanan, D; Walsh, M D; Nilbert, M; Green, J; Potter, J; Lindblom, A; de la Chapelle, A

    2008-06-01

    When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency 10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.

  6. Lynch syndrome patients' views of and preferences for return of results following whole exome sequencing.

    Science.gov (United States)

    Hitch, Kelly; Joseph, Galen; Guiltinan, Jenna; Kianmahd, Jessica; Youngblom, Janey; Blanco, Amie

    2014-08-01

    Whole exome sequencing (WES) uses next generation sequencing technology to provide information on nearly all functional, protein-coding regions in an individual's genome. Due to the vast amount of information and incidental findings that can be generated from this technology, patient preferences must be investigated to help clinicians consent and return results to patients. Patients (n = 19) who were previously clinically diagnosed with Lynch syndrome, but received uninformative negative Lynch syndrome genetic results through traditional molecular testing methods participated in semi-structured interviews after WES testing but before return of results to explore their views of WES and preferences for return of results. Analyses of interview results found that nearly all participants believed that the benefits of receiving all possible results generated from WES outweighed the undesirable effects. The majority of participants conveyed that relative to coping with a cancer diagnosis, information generated from WES would be manageable. Importantly, participants' experience with Lynch syndrome influenced their notions of genetic determinism, tolerance for uncertain results, and family communication plans. Participants would prefer to receive WES results in person from a genetic counselor or medical geneticist so that an expert could help explain the meaning and implications of the potentially large quantity and range of complicated results. These results underscore the need to study various populations with regard to the clinical use of WES in order to effectively and empathetically communicate the possible implications of this new technology and return results.

  7. Physical activity and the risk of colorectal cancer in Lynch syndrome.

    Science.gov (United States)

    Dashti, S Ghazaleh; Win, Aung Ko; Hardikar, Sheetal S; Glombicki, Stephen E; Mallenahalli, Sheila; Thirumurthi, Selvi; Peterson, Susan K; You, Y Nancy; Buchanan, Daniel D; Figueiredo, Jane C; Campbell, Peter T; Gallinger, Steven; Newcomb, Polly A; Potter, John D; Lindor, Noralane M; Le Marchand, Loic; Haile, Robert W; Hopper, John L; Jenkins, Mark A; Basen-Engquist, Karen M; Lynch, Patrick M; Pande, Mala

    2018-06-14

    Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk for people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n=807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49, and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-h/week) during the age-period of cancer diagnosis or censoring (near-term exposure), and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. Lynch syndrome, however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk for people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk. This article is protected by copyright. All rights reserved. © 2018 UICC.

  8. Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.

    Science.gov (United States)

    Medina-Arana, V; Delgado, L; González, L; Bravo, A; Díaz, H; Salido, E; Riverol, D; González-Aguilera, J J; Fernández-Peralta, A M

    2011-06-01

    Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

  9. Restauration de la statue de Henri IV

    Directory of Open Access Journals (Sweden)

    Stéphanie Celle

    2012-04-01

    Full Text Available Cette intervention de conservation du bronze de la statue de Henri IV était la première depuis sa création en 1818 : on héritait de la surface originale de l’œuvre altérée par les vicissitudes du temps et les événements historiques traversés. Le protocole de conservation se voulait respectueux de cette authenticité de la patine et a cherché à en laisser les marques tout en apportant une réponse pour contrer la corrosion active de l’alliage. C’est en conformité aux principes de conservation établis par Cesare Brandi, qu’ont été définis le nettoyage sélectif des surfaces et l’application de couches protectives sur le bronze. Par ailleurs, le moment du chantier est un moment privilégié pour observer un monument et mieux connaître son histoire particulière. Ce chantier nous a permis de redécouvrir deux ensembles de boîtes déposées dans l’antre du cheval dans des situations parfois surprenantes.This conservation treatment for the bronze statue of Henri IV is the first since its creation in 1818. While the original surface of the work remains, it has been altered by natural and human forces; including the weathering of the material from exposure to the elements and damage caused by historic events. The conservation protocol is respectful of this authenticity of the surface patina and the marks of damage due to historical events, while developing a treatment plan to counter the active corrosion of the alloy. In keeping with the principles of conservation established by Cesare Brandi, the treatment program defines the selective cleaning of the surface and the application of several layers of a protective coating on the bronze. In addition, the conservation project is an opportunity to carefully study a monument to better understand its unique history. This project allowed us to rediscover two sets of boxes placed inside the cavity of the horse; an unxpected discovery.

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

    Science.gov (United States)

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

    2014-01-01

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

  11. Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers.

    Science.gov (United States)

    Hunter, Jessica Ezzell; Zepp, Jamilyn M; Gilmore, Mari J; Davis, James V; Esterberg, Elizabeth J; Muessig, Kristin R; Peterson, Susan K; Syngal, Sapna; Acheson, Louise S; Wiesner, Georgia L; Reiss, Jacob A; Goddard, Katrina A B

    2015-09-15

    Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer-specific factors and survey responses were analyzed. The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  12. Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium.

    Science.gov (United States)

    Pan, Jennifer Y; Haile, Robert W; Templeton, Allyson; Macrae, Finlay; Qin, FeiFei; Sundaram, Vandana; Ladabaum, Uri

    2018-04-24

    Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts. We collected data from the International Mismatch Repair Consortium (IMRC), which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns. Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome-associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multigene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases in which suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying on passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied-nearly all programs (98%) recommended colonoscopy every 1 to 2 years, but only 35% recommended chemoprevention with aspirin. There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state-of-the-art Lynch syndrome management. Copyright © 2018 AGA Institute. Published by

  13. The personality of Henry Cavendish a great scientist with extraordinary peculiarities

    CERN Document Server

    McCormmach, Russell

    2014-01-01

    This book explores the 18th century natural philosopher Henry Cavendish, best known for his work in chemistry and physics. It traces aspects of his personality, views and interpretations of him, and explores notions of eccentricity and autism.

  14. NOAA Ship Henry B. Bigelow Underway Meteorological Data, Near Real Time

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — NOAA Ship Henry B. Bigelow Underway Meteorological Data (Near Real Time, updated daily) are from the Shipboard Automated Meteorological and Oceanographic System...

  15. Hiina kompartei pole NLKP-ga võrreldav / Henri Kaselo

    Index Scriptorium Estoniae

    Kaselo, Henri

    2005-01-01

    20.-26. novembril Hiinas Pekingis ja sadamalinnas Tianjinis peetud Euroopa ja Aasia noorte kohtumisest, kus Eestit esindasid Keskerakonna noortekogu esimees Henri Kaselo ja Euroopa Noorte Sotsiaaldemokraatide aseesimees ning Toomas Hendrik Ilvese nõunik Rander Läntsi

  16. Strelku vsjo ravno perevedut. No v kakuju storonu? / Henry Posner ; interv. Eteri Kekelidze

    Index Scriptorium Estoniae

    Posner, Henry

    2006-01-01

    Eesti Raudtee üks erastajaist, RDC juht Henry Posner III meenutab ER erastamist 2001. a., investeeringutest, reeglite muutmisest, Eesti Raudtee müümise põhjustest, Eesti transiidi tulevikust. Diagramm: Eesti Raudtee kasum 1998-2004

  17. 2008 USGS Lidar: Twelve County, Illinois (Grundy, Kane, McHenry only)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This LiDAR data is within Illinois Department of Transportation districts 1 and 3 covering Grundy, Kane and McHenry counties. The data is updated from its original...

  18. Why it was natural for Henri Becquerel to discover natural radioactivity

    International Nuclear Information System (INIS)

    Barquins, M.

    2002-01-01

    This article presents the scientific saga of the Becquerel family. 4 generations of Becquerel Antoine-Cesar (1788-1878), Edmond (1820-1891), Henri (1852-1906) and Jean (1878-1953) were involved in scientific activities at the highest level. Henri was awarded the Nobel prize of physics (shared with Pierre and Marie Curie) in 1903 for the discovery of radioactivity. The author shows that the discovery of radioactivity was due to talent, family emulation, genetics and chance. (A.C.)

  19. 46 CFR 7.55 - Cape Henry, VA to Cape Fear, NC.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Cape Henry, VA to Cape Fear, NC. 7.55 Section 7.55 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY PROCEDURES APPLICABLE TO THE PUBLIC BOUNDARY LINES Atlantic Coast § 7.55 Cape Henry, VA to Cape Fear, NC. (a) A line drawn from Rudee Inlet Jetty Light “2” to...

  20. The advantage of using the henry straight line in {gamma} spectrometry (1963); Interet de l'utilisation de la droite de henry en spectrometrie {gamma} (1963)

    Energy Technology Data Exchange (ETDEWEB)

    Jockey, [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

    1963-07-01

    The Henry construction is a convenient way to interpret the total absorption peaks in gamma spectrometry by exploiting their statistical significance. It is so possible to determine graphically, and accurately, such values as: - position of the peak - resolution, etc. The main practical applications are considered. (author) [French] La construction de la droite de Henry fournit un moyen commode d'interpreter les pics d'absorption totale en spectrometrie gamma en exploitant leur signification statistique, il est ainsi possible de determiner graphiquement, avec precision, des notions telles que: - position du pic - resolution, etc. Les principales applications pratiques sont envisagees. (auteur)

  1. Henry Beecher's Contributions to the Ethics of Clinical Research.

    Science.gov (United States)

    Veatch, Robert M

    2016-01-01

    In the 1950s and '60s, Henry Beecher pioneered the discussion of the ethics of clinical research, leading eventually to the publication of the famous New England Journal of Medicine article summarizing 22 research studies that Beecher suggests were unethical. Those studies generally showed a pattern of posing serious risks to subjects without anticipated proportional benefit. Beecher famously claimed that the problem was not that researchers were malicious or evil; rather, he claimed the problem was they manifested thoughtlessness or carelessness. He called for more rigorous self-scrutiny rather than public review.This article argues that Beecher's reliance on conscientious investigators is problematic. In particular, it focuses on benefits and harms to the exclusion of other moral criteria. However, both research subjects and public regulators are also concerned about autonomy and the consent requirement, confidentiality, and fairness in subject selection and research design. The movement in the 1970s toward more public scrutiny was critical, even though Beecher was right in holding that it was not "vicious disregard for subject welfare" that explained unethical protocols.

  2. The enigmatic figure of Dr Henry Maudsley (1835-1918).

    Science.gov (United States)

    Pantelidou, Maria; Demetriades, Andreas K

    2014-08-01

    In spite of his contribution to psychiatry in 19th century Britain, Henry Maudsley remains a mysterious figure, a man mostly known for his donation to the London County Council for the building of the Maudsley Hospital and for The Maudsley Annual Lecture created in honour of his benevolence. Besides Sir Aubrey Lewis' article in 1951 and Michael Collie's attempt in 1988 to construct a biographical study on Maudsley, there does not seem to be any current endeavour to tell the story of his life, whereas Trevor Turner's contribution to the 2004 Oxford Dictionary of National Biography gives a somewhat scathing but unattributed account of Maudsley's personality. This essay attempts to explore his contributions to the Medico-Psychological Association (MPA), the current Royal College of Psychiatrists, his editorship of the Journal of Mental Health (currently named the British Journal of Psychiatry), his literary contributions and his vision for a psychiatric hospital. This essay is an attempt to demystify his figure and to explore some of the rumours and criticisms surrounding his name and the reasons why so little has been written about him. It is also a venture to unravel his complex personality and his intricate philosophy. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  3. RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.

    Science.gov (United States)

    Fennell, Lochlan J; Clendenning, Mark; McKeone, Diane M; Jamieson, Saara H; Balachandran, Samanthy; Borowsky, Jennifer; Liu, John; Kawamata, Futoshi; Bond, Catherine E; Rosty, Christophe; Burge, Matthew E; Buchanan, Daniel D; Leggett, Barbara A; Whitehall, Vicki L J

    2018-01-01

    The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers

  4. Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer

    Science.gov (United States)

    Ladabaum, Uri; Wang, Grace; Terdiman, Jonathan; Blanco, Amie; Kuppermann, Miriam; Boland, C. Richard; Ford, James; Elkin, Elena; Phillips, Kathryn A.

    2013-01-01

    Background Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. Objective To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. Design Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. Data Sources Published literature. Target Population All persons with newly diagnosed colorectal cancer and their relatives. Time Horizon Lifetime. Perspective Third-party payer. Intervention Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. Outcome Measures Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. Results of Base-Case Analysis The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36 200 per life-year gained. Results of Sensitivity Analysis The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50 000 per life-year gained. Immunohistochemistry

  5. H3ABioNet, a sustainable pan-African bioinformatics network for human heredity and health in Africa

    Science.gov (United States)

    Mulder, Nicola J.; Adebiyi, Ezekiel; Alami, Raouf; Benkahla, Alia; Brandful, James; Doumbia, Seydou; Everett, Dean; Fadlelmola, Faisal M.; Gaboun, Fatima; Gaseitsiwe, Simani; Ghazal, Hassan; Hazelhurst, Scott; Hide, Winston; Ibrahimi, Azeddine; Jaufeerally Fakim, Yasmina; Jongeneel, C. Victor; Joubert, Fourie; Kassim, Samar; Kayondo, Jonathan; Kumuthini, Judit; Lyantagaye, Sylvester; Makani, Julie; Mansour Alzohairy, Ahmed; Masiga, Daniel; Moussa, Ahmed; Nash, Oyekanmi; Ouwe Missi Oukem-Boyer, Odile; Owusu-Dabo, Ellis; Panji, Sumir; Patterton, Hugh; Radouani, Fouzia; Sadki, Khalid; Seghrouchni, Fouad; Tastan Bishop, Özlem; Tiffin, Nicki; Ulenga, Nzovu

    2016-01-01

    The application of genomics technologies to medicine and biomedical research is increasing in popularity, made possible by new high-throughput genotyping and sequencing technologies and improved data analysis capabilities. Some of the greatest genetic diversity among humans, animals, plants, and microbiota occurs in Africa, yet genomic research outputs from the continent are limited. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive the development of genomic research for human health in Africa, and through recognition of the critical role of bioinformatics in this process, spurred the establishment of H3ABioNet, a pan-African bioinformatics network for H3Africa. The limitations in bioinformatics capacity on the continent have been a major contributory factor to the lack of notable outputs in high-throughput biology research. Although pockets of high-quality bioinformatics teams have existed previously, the majority of research institutions lack experienced faculty who can train and supervise bioinformatics students. H3ABioNet aims to address this dire need, specifically in the area of human genetics and genomics, but knock-on effects are ensuring this extends to other areas of bioinformatics. Here, we describe the emergence of genomics research and the development of bioinformatics in Africa through H3ABioNet. PMID:26627985

  6. At issue: siblings of patients with schizophrenia: sibling bond, coping patterns, and fear of possible schizophrenia heredity.

    Science.gov (United States)

    Stålberg, Gabriella; Ekerwald, Hedvig; Hultman, Christina M

    2004-01-01

    Siblings of schizophrenia patients are from the patient's perspective important support providers, but most studies on family burden have focused on the parental role. This study aims to develop a detailed analysis of the psychological aspects of having a sibling with schizophrenia. We did a qualitative study with audiotaped semistructured interviews of 16 siblings. The reliability of the inductive categorization of data was high. A unifying theme appeared to be an emotional sibling bond characterized by feelings of love, sorrow, anger, envy, guilt, and shame. The major categories linked to coping with the situation were avoidance, isolation, normalization, caregiving, and grieving. A third major theme consisted of a fear of possible schizophrenia heredity. The siblings described concerns about the impact of a family history of psychiatric illness, a fear of becoming mentally ill, and reflections about "bad genes." Our findings support earlier findings of coping patterns but complement them by providing a model that includes awareness of genetic vulnerability as an important part of siblings' subjective burden.

  7. Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum.

    Science.gov (United States)

    Yamaguchi, Tatsuro; Furukawa, Yoichi; Nakamura, Yusuke; Matsubara, Nagahide; Ishikawa, Hideki; Arai, Masami; Tomita, Naohiro; Tamura, Kazuo; Sugano, Kokichi; Ishioka, Chikashi; Yoshida, Teruhiko; Moriya, Yoshihiro; Ishida, Hideyuki; Watanabe, Toshiaki; Sugihara, Kenichi

    2015-02-01

    The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients. We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch repair gene mutations were diagnosed with suspected familial colorectal cancer type X. We identified 69 patients with Lynch syndrome and 25 with suspected familial colorectal cancer type X. The frequencies of gastric and extracolonic Lynch syndrome-associated cancers were lower with suspected familial colorectal cancer type X than with Lynch syndrome. The number of organs with Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. The cumulative incidence of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. We estimated that the median cancer risk in 60-year-old patients with Lynch syndrome was 89, 36 and 24% for colorectal, endometrial and gastric cancers, respectively. Analyses of family members, including probands, revealed that the median age at diagnosis of extracolonic Lynch syndrome-associated cancer was significantly older with suspected familial colorectal cancer type X than with Lynch syndrome. The frequency of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. A significant difference in extracolonic Lynch syndrome-associated cancer was evident between suspected familial colorectal cancer type X and Lynch syndrome. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X.

    Science.gov (United States)

    Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef; Bernstein, Inge; Bonde, Jesper; Holck, Susanne

    2017-01-01

    Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other than MMR proteins. We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch syndrome ( p  Lynch syndrome tumors compared with FCCTX tumors ( p  = 0.001, Lynch syndrome with a more sporadic-like profile in the former group and a more distinct profile with frequent MUC6 positivity in the latter group.

  9. The Works of Henry Moseley, 1887-1915

    Science.gov (United States)

    Scerri, Eric

    2013-04-01

    In 1913 Henry Moseley, an unknown young English physicist published an article in the Philosophical Magazine under the title of ``The High Frequency Spectra of the Elements.'' The 10-page article was to have far reaching implications in both chemistry and physics and helped to resolve a major conundrum in the periodic table of the elements. The talk will briefly examine the life and work of Moseley who died tragically while fighting in the trenches of World War I in 1915. The build-up to the discovery of atomic number took several different avenues including contributions from Rutherford and Barkla. However the more direct motivation for Moseley's work, as he readily acknowledged, were the articles of an unknown Dutch econometrician Anton Van den Broek who attempted to improve on Mendeleev's periodic table. Moseley began as a student of Rutherford at Manchester and took a keen interest in the development of research using X-rays following the work of Roentgen, von Laue and Bragg. Although Rutherford was at first reluctant to enter this new field he soon yielded to young Moseley's request and sent him to Leeds for brief training with Bragg. On returning to Manchester, Moseley devised an ingenious apparatus in which a set of metal samples could be rotated so as to become the target for a beam of electrons in order to measure the frequencies of the emitted K X-rays. The first set of such experiments used nine successive elements in the periodic table, from titanium to zinc. Moseley's now immense fame rests with the results of this study as well as a subsequent one which extended the study into a further 30 elements, in addition to the use that his method was put to by himself as well as subsequent chemists and physicists.

  10. Freshwater and Saline Loads of Dissolved Inorganic Nitrogen to Hood Canal and Lynch Cove, Western Washington

    Science.gov (United States)

    Paulson, Anthony J.; Konrad, Christopher P.; Frans, Lonna M.; Noble, Marlene; Kendall, Carol; Josberger, Edward G.; Huffman, Raegan L.; Olsen, Theresa D.

    2006-01-01

    Hood Canal is a long (110 kilometers), deep (175 meters) and narrow (2 to 4 kilometers wide) fjord of Puget Sound in western Washington. The stratification of a less dense, fresh upper layer of the water column causes the cold, saltier lower layer of the water column to be isolated from the atmosphere in the late summer and autumn, which limits reaeration of the lower layer. In the upper layer of Hood Canal, the production of organic matter that settles and consumes dissolved oxygen in the lower layer appears to be limited by the load of dissolved inorganic nitrogen (DIN): nitrate, nitrite, and ammonia. Freshwater and saline loads of DIN to Hood Canal were estimated from available historical data. The freshwater load of DIN to the upper layer of Hood Canal, which could be taken up by phytoplankton, came mostly from surface and ground water from subbasins, which accounts for 92 percent of total load of DIN to the upper layer of Hood Canal. Although DIN in rain falling on land surfaces amounts to about one-half of the DIN entering Hood Canal from subbasins, rain falling directly on the surface of marine waters contributed only 4 percent of the load to the upper layer. Point-source discharges and subsurface flow from shallow shoreline septic systems contributed less than 4 percent of the DIN load to the upper layer. DIN in saline water flowing over the sill into Hood Canal from Admiralty Inlet was at least 17 times the total load to the upper layer of Hood Canal. In September and October 2004, field data were collected to estimate DIN loads to Lynch Cove - the most inland marine waters of Hood Canal that routinely contain low dissolved-oxygen waters. Based on measured streamflow and DIN concentrations, surface discharge was estimated to have contributed about one-fourth of DIN loads to the upper layer of Lynch Cove. Ground-water flow from subbasins was estimated to have contributed about one-half of total DIN loads to the upper layer. In autumn 2004, the relative

  11. [Hypospadia and infertility of Henry II of France (1519-1559)].

    Science.gov (United States)

    Hatzinger, M; Al-Shajlawi, S; Sohn, M

    2014-03-01

    Henry II (1519-1559) of France was the second son of Francis I (1494-1547) and Claude de France (1498-1524) born in 1519 in St. Germain-en-Laye. After his older brother's and his father's death in 1547, he was anointed the French king in Reims. In 1533 already, as a 14-year-old boy, for reasons of state, he was married to the same aged Catherine de Medici (1519-1589), as her uncle was Pope Clement VII (1478-1534). The marriage remained childless for 11 years since Henry, due to a distinct hypospadia and a completely sexually inexperienced wife was unable to conceive children with her. His existing liaison to Diane de Poitiers (1499-1566) - a 19-year-older maid of honor of his father Francis I from 1537 until his death - influenced his sexual life immensely.The blame for the childless marriage was placed primarily on his wife, as Henry had become father of an illegitimate daughter with a mistress. Catherine then underwent all possible medical and alchemical procedures to finally give birth to the hoped Dauphin. Ironically, her rival for the favor of her husband, Diane de Poitiers was one of her greatest allies. She made clear that the cause lay with Henry and not with his wife. This was confirmed by the added solid physician Jean Fernel (1497-1558). His treatment of Henry and the simultaneous training of the unexperienced Catherine by Diane de Poitiers led to success.The result was the birth of Francis II (1544-1560) in 1544, the first of 10 children in 12 years. Thus, the dynasty was saved. After the death of Henry in a tragic tournament accident in 1559, three of his sons became kings of France. But the line of Valois remained without further descendants and was continued by Henry IV, the first Bourbon king in 1589.

  12. Sessile serrated polyps of the colorectum are rare in patients with Lynch syndrome and in familial colorectal cancer families

    DEFF Research Database (Denmark)

    Andersen, S H; Lykke, E; Folker, M B

    2008-01-01

    Whereas the generally accepted carcinogenesis pathway of the microsatellite instabile high (MSI-H) colorectal carcinoma (CRC) involves the traditional adenoma in patients with Lynch syndrome, a serrate pathway involving serrate adenomas (SA) and sessile serrate polyps (SSP) characterize...... the sporadic MSI-H counterpart. Recent studies have, however, challenged such simple one-pathway models, inviting the consideration of alternative, unexpected pathways. Here, the issue as to the possible role of SSP, primarily in the context of Lynch syndrome, but also in subjects from familial CRC families...... (FCF) is addressed. Polyps coded as hyperplastic polyps (HP) from subjects with Lynch syndrome and FCF enrolled in the HNPCC-register at the Hvidovre University Hospital as well as adenomas from this population were retrieved and reviewed for features of SSP. Ninety-eight polyps coded as HP and 41...

  13. Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Esplen, Mary Jane; Ladelund, Steen

    2011-01-01

    . We used the national Danish HNPCC register to collect data on self-concept from 413 individuals with Lynch syndrome. The recently developed Lynch syndrome self-concept scale contains 20 items within two subscales related to stigma-vulnerability and bowel symptom-related anxiety. Significantly higher...... total scores, indicating a greater impact on self-concept, were reported by females and by individuals with experience from cancer in close relatives, whereas individuals with less formal education scored significantly higher on the stigma and vulnerability subscale. Scores in the upper quartile were...... more often reported by women (odds ratio 1.8) and by individuals with less education (OR 1.8). This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about...

  14. Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry.

    Science.gov (United States)

    Pande, Mala; Wei, Chongjuan; Chen, Jinyun; Amos, Christopher I; Lynch, Patrick M; Lu, Karen H; Lucio, Laura A; Boyd-Rogers, Stephanie G; Bannon, Sarah A; Mork, Maureen E; Frazier, Marsha L

    2012-09-01

    The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P ≤ 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.

  15. Molecular changes preceding endometrial and ovarian cancer: a study of consecutive endometrial specimens from Lynch syndrome surveillance.

    Science.gov (United States)

    Niskakoski, Anni; Pasanen, Annukka; Lassus, Heini; Renkonen-Sinisalo, Laura; Kaur, Sippy; Mecklin, Jukka-Pekka; Bützow, Ralf; Peltomäki, Päivi

    2018-03-27

    Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are

  16. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Buchanan DD

    2014-10-01

    Full Text Available Daniel D Buchanan,1,2 Christophe Rosty,1,3,4 Mark Clendenning,1 Amanda B Spurdle,5 Aung Ko Win2 1Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia; 2Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; 3Envoi Specialist Pathologists, Herston, QLD, Australia; 4School of Medicine, University of Queensland, Herston, QLD, Australia; 5Molecular Cancer Epidemiology Laboratory, Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Herston, QLD, AustraliaAbstract: Carriers of a germline mutation in one of the DNA mismatch repair (MMR genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome. MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the

  17. Achieving behaviour change for detection of Lynch syndrome using the Theoretical Domains Framework Implementation (TDFI) approach: a study protocol.

    Science.gov (United States)

    Taylor, Natalie; Long, Janet C; Debono, Deborah; Williams, Rachel; Salisbury, Elizabeth; O'Neill, Sharron; Eykman, Elizabeth; Braithwaite, Jeffrey; Chin, Melvin

    2016-03-12

    Lynch syndrome is an inherited disorder associated with a range of cancers, and found in 2-5 % of colorectal cancers. Lynch syndrome is diagnosed through a combination of significant family and clinical history and pathology. The definitive diagnostic germline test requires formal patient consent after genetic counselling. If diagnosed early, carriers of Lynch syndrome can undergo increased surveillance for cancers, which in turn can prevent late stage cancers, optimise treatment and decrease mortality for themselves and their relatives. However, over the past decade, international studies have reported that only a small proportion of individuals with suspected Lynch syndrome were referred for genetic consultation and possible genetic testing. The aim of this project is to use behaviour change theory and implementation science approaches to increase the number and speed of healthcare professional referrals of colorectal cancer patients with a high-likelihood risk of Lynch syndrome to appropriate genetic counselling services. The six-step Theoretical Domains Framework Implementation (TDFI) approach will be used at two large, metropolitan hospitals treating colorectal cancer patients. Steps are: 1) form local multidisciplinary teams to map current referral processes; 2) identify target behaviours that may lead to increased referrals using discussion supported by a retrospective audit; 3) identify barriers to those behaviours using the validated Influences on Patient Safety Behaviours Questionnaire and TDFI guided focus groups; 4) co-design interventions to address barriers using focus groups; 5) co-implement interventions; and 6) evaluate intervention impact. Chi square analysis will be used to test the difference in the proportion of high-likelihood risk Lynch syndrome patients being referred for genetic testing before and after intervention implementation. A paired t-test will be used to assess the mean time from the pathology test results to referral for high

  18. Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome.

    Science.gov (United States)

    Dillon, Jessica L; Gonzalez, Jorge L; DeMars, Leslie; Bloch, Katarzyna J; Tafe, Laura J

    2017-12-01

    Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

    Science.gov (United States)

    Johnatty, Sharon E; Tan, Yen Y; Buchanan, Daniel D; Bowman, Michael; Walters, Rhiannon J; Obermair, Andreas; Quinn, Michael A; Blomfield, Penelope B; Brand, Alison; Leung, Yee; Oehler, Martin K; Kirk, Judy A; O'Mara, Tracy A; Webb, Penelope M; Spurdle, Amanda B

    2017-11-01

    To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10 -7 ), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (P Trend =4.43×10 -6 ), and with increasing numbers of Lynch cancers in relatives (P Trend ≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Subtotal Colectomy for Colon Cancer Reduces the Need for Subsequent Surgery in Lynch Syndrome.

    Science.gov (United States)

    Renkonen-Sinisalo, Laura; Seppälä, Toni T; Järvinen, Heikki J; Mecklin, Jukka-Pekka

    2017-08-01

    The risk of metachronous colorectal cancer is high after surgical resection for first colon cancer in Lynch syndrome. This study aimed to examine whether extended surgery decreases the risk of subsequent colorectal cancer and improves long-term survival. This was a retrospective study. Data were collected from a nationwide registry. Two hundred forty-two Lynch syndrome pathogenic variant carriers who underwent surgery for a first colon cancer from 1984 to 2009 were included. Patients underwent standard segmental colectomy (n = 144) or extended colectomy (n = 98) for colon cancer. Patients were followed a median of 14.6 up to 25 years. Risk of subsequent colorectal cancer in either group, overall and disease-specific survival, and operative mortality were the primary outcomes measured. Subtotal colectomy decreased the risk of subsequent colorectal cancer (HR, 0.20; 95% CI, 0.08-0.52; p = 0.001), compared with segmental resection. Subsequent colorectal cancer decreased in MLH1 carriers. The MSH2 carriers showed no statistical difference, possibly because of their small number. Disease-specific and overall survival within 25 years did not differ between the standard and extended surgeries (82.7% vs 87.2%, p = 0.76 and 47.2% vs 41.4%, p = 0.83). The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. The cumulative risk of metachronous colorectal cancer was 7% within 25 years after subtotal colectomy with ileosigmoidal anastomosis. One patient died of postoperative septicemia within 30 days after segmental colectomy. Data on surgical procedures were primarily collected retrospectively. Lynch syndrome pathogenic variant carriers may undergo subtotal colectomy to manage first colon cancer and avoid repetitive abdominal surgery and to reduce the remaining bowel to facilitate easier endoscopic surveillance. It provides no survival benefit, compared with segmental colon

  1. Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  2. Validation of a Self-Concept Scale for Lynch Syndrome in Different Nationalities

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Domanska, Katarina; Bendahl, Pär-Ola

    2011-01-01

    syndrome. We compared the performance of this scale in 591 mutation carriers from Denmark, Sweden and Canada. Principal component analysis identified two sets of linked statements-the first related to feeling different, isolated and labeled, and the second to concern and worry about bowel changes....... The scale performed consistently in the three countries. Minor differences were identified, with guilt about passing on a defective gene and feelings of losing one's privacy being more pronounced among Canadians, whereas Danes more often expressed worries about cancer. Validation of the Lynch syndrome self...

  3. Henry constants in polymer solutions with the van der Waals equation of state

    DEFF Research Database (Denmark)

    Bithas, Sotiris; Kalospiros, Nikolaos; Kontogeorgis, Georgios

    1996-01-01

    parameter is satisfactory, with typical errors within the experimental uncertainty and comparable to those with the more complex Perturbed Hard Chain Theory-based equations of state with the same number of adjustable parameters. A predictive scheme for calculating Henry constants is also presented, which...... is a corresponding-states correlation for a dimensionless Henry constant defined based on the van der Waals equation of state. Satisfactory results-often close to the ones from the one-parameter correlation-are obtained for all systems investigated in this work. Compared with literature models that have been applied...

  4. Copper-Mediated Reactions of Nitriles with Nitromethanes: Aza-Henry Reactions and Nitrile Hydrations.

    Science.gov (United States)

    Kuwabara, Jun; Sawada, Yoshiharu; Yoshimatsu, Mitsuhiro

    2018-02-16

    In this study, the first aza-Henry reaction of nitriles with nitromethane in a CuI/Cs 2 CO 3 /DBU system is described. The process was conveniently and directly used for the synthesis of β-aminonitroalkenes 2a-x and tolerated aryl-, alkyl-, hetaryl-, alkenyl-, and alkynylnitriles. The resulting aminonitroalkenes 2 could be successfully transformed to the corresponding 2-nitroacetophenones, 2-amino-1-halonitroalkenes, 2-alkylaminonitroalkenes, or 3-nitropyridines. In the presence of H 2 O, the aza-Henry reaction turned the reaction path to the nitrile hydration to exclusively yield the amides 3a-s.

  5. Taxing junk food: applying the logic of the Henry tax review to food.

    Science.gov (United States)

    Bond, Molly E; Williams, Michael J; Crammond, Brad; Loff, Bebe

    2010-10-18

    The recent review of taxation in Australia - the Henry tax review - has recommended that the federal government increase the taxes already levied on tobacco and alcohol. Tobacco and alcohol taxes are put forward as the best way of reducing the social harms caused by the use and misuse of these substances. Junk foods have the same pattern of misuse and the same social costs as tobacco and alcohol. The Henry tax review rejects the idea of taxing fatty foods, and to date the government has not implemented a tax on junk food. We propose that a tax on junk food be implemented as a tool to reduce consumption and address the obesity epidemic.

  6. M. Pirgerou on D. Izzo and C. Martinez’s Revisionary Interventions into Henry James

    Directory of Open Access Journals (Sweden)

    2009-07-01

    Full Text Available Donatella Izzo and Carlo Martinez. Revisionary Interventions Into Henry James. Eds. Napoli, 2008. Revisionary Interventions into Henry James is a compilation of a series of papers presented at a colloquium which took place at Università Orientale in Naples, Italy, on October 27, 2006. In her introduction to the volume, Donatella Izzo acknowledges the “rather blatant plagiarism” (7 which lent the book its title.  The borrowing, of course, refers to Donald Pease’s landmark Revisionary Interve...

  7. A model-based assessment of the cost–utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients

    International Nuclear Information System (INIS)

    Snowsill, Tristan; Huxley, Nicola; Hoyle, Martin; Jones-Hughes, Tracey; Coelho, Helen; Cooper, Chris; Frayling, Ian; Hyde, Chris

    2015-01-01

    Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost–utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could

  8. A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients.

    Science.gov (United States)

    Snowsill, Tristan; Huxley, Nicola; Hoyle, Martin; Jones-Hughes, Tracey; Coelho, Helen; Cooper, Chris; Frayling, Ian; Hyde, Chris

    2015-04-25

    Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh

  9. An {sup 57}Fe Mössbauer study of the ordinary chondrite meteorite Lynch 001

    Energy Technology Data Exchange (ETDEWEB)

    Elewa, Nancy N., E-mail: nancy.elewa@student.unsw.edu.au; Cadogan, J. M. [The University of New South Wales at the Australian Defence Force Academy, School of Physical, Environmental and Mathematical Sciences (Australia)

    2017-11-15

    The Lynch 001 meteorite was found in the Nullarbor Plain region of Western Australia in 1977. This meteorite is classified as an ordinary chondrite of the petrologic group L5/6 that has undergone ‘minor to moderate’ terrestrial weathering. Here, we characterize the Fe-bearing phases in this chondrite using {sup 57}Fe Mössbauer spectroscopy carried out over the temperature range 13 K to room temperature (295 K). The paramagnetic doublets of olivine, pyroxene and a superparamagnetic ferric phase dominate the room temperature Mössbauer spectrum. On the basis of the room temperature quadrupole splitting of the olivine component, we estimate its composition to be Fa {sub 30(5)}. Besides the paramagnetic ferric component, accounting for ∼15 % of the spectral area at room temperature, magnetically ordered ferric phases were also detected. The total relative proportion of the Fe {sup 3+} components allows us to estimate the terrestrial age of Lynch 001 to be 6,500 ± 1,500 yr, consistent with the value of 6,700 ± 1,300 yr determined by {sup 14}C dating.

  10. Locating inputs of freshwater to Lynch Cove, Hood Canal, Washington, using aerial infrared photography

    Science.gov (United States)

    Sheibley, Rich W.; Josberger, Edward G.; Chickadel, Chris

    2010-01-01

    The input of freshwater and associated nutrients into Lynch Cove and lower Hood Canal (fig. 1) from sources such as groundwater seeps, small streams, and ephemeral creeks may play a major role in the nutrient loading and hydrodynamics of this low dissolved-oxygen (hypoxic) system. These disbursed sources exhibit a high degree of spatial variability. However, few in-situ measurements of groundwater seepage rates and nutrient concentrations are available and thus may not represent adequately the large spatial variability of groundwater discharge in the area. As a result, our understanding of these processes and their effect on hypoxic conditions in Hood Canal is limited. To determine the spatial variability and relative intensity of these sources, the U.S. Geological Survey Washington Water Science Center collaborated with the University of Washington Applied Physics Laboratory to obtain thermal infrared (TIR) images of the nearshore and intertidal regions of Lynch Cove at or near low tide. In the summer, cool freshwater discharges from seeps and streams, flows across the exposed, sun-warmed beach, and out on the warm surface of the marine water. These temperature differences are readily apparent in aerial thermal infrared imagery that we acquired during the summers of 2008 and 2009. When combined with co-incident video camera images, these temperature differences allow identification of the location, the type, and the relative intensity of the sources.

  11. Common mutations identified in the MLH1 gene in familial Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Jisha Elias

    2017-12-01

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

  12. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

    Science.gov (United States)

    ten Broeke, Sanne W; Brohet, Richard M; Tops, Carli M; van der Klift, Heleen M; Velthuizen, Mary E; Bernstein, Inge; Capellá Munar, Gabriel; Gomez Garcia, Encarna; Hoogerbrugge, Nicoline; Letteboer, Tom G W; Menko, Fred H; Lindblom, Annika; Mensenkamp, Arjen R; Moller, Pal; van Os, Theo A; Rahner, Nils; Redeker, Bert J W; Sijmons, Rolf H; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J; Wagner, Anja; Hes, Frederik J; Vasen, Hans F; Nielsen, Maartje; Wijnen, Juul T

    2015-02-01

    The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks. © 2014 by American Society of Clinical Oncology.

  13. [Management and Nursing care for a patient with Lynch syndrome: A case report].

    Science.gov (United States)

    Pacheco-Pérez, Luis Arturo; Guevara Valtier, Milton Carlos

    2016-01-01

    Colorectal cancer is one of the leading causes of death from cancer worldwide. Main interventions to reduce the impact are aimed to enhance prevention and early detection. Results of several studies show that tests such as the fecal occult blood test and colonoscopy are effective for early diagnosis. There are hereditary syndromes such as Lynch Syndrome that can lead to certain types of cancers, including bowel neoplasms, therefore early detection needs to be included as part of the treatment. In these cases, family genetic testing is recommended if the bowel cancer is diagnosed before 50 years old. A care plan including the NANDA (North American Nursing Diagnosis Association), NOC (Nursing Outcomes Classification) and NIC (Nursing Interventions Classification) was developed for a patient with suspected Lynch Syndrome. Nurses should be qualified to identify potential cases of cancer associated with this syndrome, and thus, reduce the likelihood that family members develop the disease, through genetic counseling and education of environmental risk factors. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  14. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

    Directory of Open Access Journals (Sweden)

    Sofie V Nielsen

    2017-04-01

    Full Text Available Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

  15. Comparison of extended colectomy and limited resection in patients with Lynch syndrome.

    Science.gov (United States)

    Natarajan, Nagendra; Watson, Patrice; Silva-Lopez, Edibaldo; Lynch, Henry T

    2010-01-01

    The purpose of the study was to determine the advantages and disadvantages of prophylactic/extended colectomy (subtotal colectomy) in patients with Lynch syndrome who manifest colorectal cancer. A retrospective cohort using Creighton University's hereditary cancer database was used to identify cases and controls. Cases are patients who underwent subtotal colectomy, either with no colorectal cancer diagnosis (prophylactic) or at diagnosis of first colorectal cancer; controls for these 2 types of cases were, respectively, patients who underwent no colon surgery or those having limited resection at time of diagnosis of first colorectal cancer. The Kaplan-Meier and proportional hazard regression models from the Statistical Analysis Software program was used to calculate the difference in survival, time to subsequent colorectal cancer, and subsequent abdominal surgery between cases and controls. The event-free survival of our study did not reach 50%, so we used the event-free survival at 5 years as our parameter to compare the 2 groups. The event-free survival for subsequent colorectal cancer, subsequent abdominal surgery, and death was 94%, 84%, and 93%, respectively, for cases and 74%, 63%, and 88%, respectively, for controls. Times to subsequent colorectal cancer and subsequent abdominal surgery were significantly shorter in the control group (P Lynch syndrome.

  16. Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome.

    Science.gov (United States)

    Katz, L H; Burton-Chase, A M; Advani, S; Fellman, B; Polivka, K M; Yuan, Y; Lynch, P M; Peterson, S K

    2016-03-01

    Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. 78 FR 34428 - Missouri Central Railroad Company-Abandonment Exemption-in Cass, Henry, Johnson, and Pettis...

    Science.gov (United States)

    2013-06-07

    ... No. AB 1070; (Sub-No. 1X)] Missouri Central Railroad Company--Abandonment Exemption--in Cass, Henry, Johnson, and Pettis Counties, MO; Central Midland Railway Company--Discontinuance of Service Exemption--in Cass, Henry, Johnson, and Pettis Counties, MO Missouri Central Railroad Company (MCRR) and Central...

  18. Henri Fayol’un Yönetim Düşüncesi Üzerine Notlar(Notes on Managerial Thought of Henry Fayol)

    OpenAIRE

    Ramazan ŞENGÜL

    2007-01-01

    Henri Fayol, developed a managerial approach which is a perfect guide for both private and public sectors through focusing systematically upon managerial process. A major advantage of Fayol in creating a general managerial doctrine was his pratician side. His managerial thought which was developed in the early 20th century lasted up to our times. The distinguished characteristic of Fayol’s thought was studying the administrative reality through separating it into its functions, in that it hel...

  19. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

    Science.gov (United States)

    Haraldsdottir, Sigurdis; Rafnar, Thorunn; Frankel, Wendy L.; Einarsdottir, Sylvia; Sigurdsson, Asgeir; Hampel, Heather; Snaebjornsson, Petur; Masson, Gisli; Weng, Daniel; Arngrimsson, Reynir; Kehr, Birte; Yilmaz, Ahmet; Haraldsson, Stefan; Sulem, Patrick; Stefansson, Tryggvi; Shields, Peter G.; Sigurdsson, Fridbjorn; Bekaii-Saab, Tanios; Moller, Pall H.; Steinarsdottir, Margret; Alexiusdottir, Kristin; Hitchins, Megan; Pritchard, Colin C.; de la Chapelle, Albert; Jonasson, Jon G.; Goldberg, Richard M.; Stefansson, Kari

    2017-01-01

    Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations. PMID:28466842

  20. Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion

    NARCIS (Netherlands)

    Lynch, H.T.; Riegert-Johnson, D.L.; Snyder, C.; Lynch, J.F.; Hagenkord, J.; Boland, C.R.; Rhees, J.; Thibodeau, S.N.; Boardman, L.A.; Davies, J.; Kuiper, R.P.; Hoogerbrugge, N.; Ligtenberg, M.J.L.

    2011-01-01

    OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some

  1. Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

    NARCIS (Netherlands)

    A. Goverde (Anne); M.C.W. Spaander (Manon); D. Nieboer (Daan); A.M.W. van den Ouweland (Ans); W.N.M. Dinjens (Winand); H.J. Dubbink (Erik Jan); C. Tops (Cmj); S.W. Ten Broeke (Sanne W.); M.J. Bruno (Marco); R.M.W. Hofstra (Robert); E.W. Steyerberg (Ewout); A. Wagner (Anja)

    2017-01-01

    textabstractUntil recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for

  2. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

    Science.gov (United States)

    Haraldsdottir, Sigurdis; Rafnar, Thorunn; Frankel, Wendy L; Einarsdottir, Sylvia; Sigurdsson, Asgeir; Hampel, Heather; Snaebjornsson, Petur; Masson, Gisli; Weng, Daniel; Arngrimsson, Reynir; Kehr, Birte; Yilmaz, Ahmet; Haraldsson, Stefan; Sulem, Patrick; Stefansson, Tryggvi; Shields, Peter G; Sigurdsson, Fridbjorn; Bekaii-Saab, Tanios; Moller, Pall H; Steinarsdottir, Margret; Alexiusdottir, Kristin; Hitchins, Megan; Pritchard, Colin C; de la Chapelle, Albert; Jonasson, Jon G; Goldberg, Richard M; Stefansson, Kari

    2017-05-03

    Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

  3. Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors

    DEFF Research Database (Denmark)

    Ketabi, Zohreh; Bartuma, Katarina; Bernstein, Inge

    2011-01-01

    . The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed. CONCLUSION: The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch...

  4. Barriers and Motivators for Referral of Patients with Suspected Lynch Syndrome to Cancer Genetic Services: A Qualitative Study

    Science.gov (United States)

    Tan, Yen Y.; Fitzgerald, Lisa J.

    2014-01-01

    This article explores the views of general practitioners and specialists on their referral of patients with suspected Lynch syndrome to cancer genetic services. Using a purposive maximum variation sampling strategy, we conducted semi-structured interviews face-to-face with 28 general practitioners and specialists in public or private hospitals and specialist clinics between March and August 2011. General practitioners and specialists were recruited in a major metropolitan area in Australia. Interview transcripts were reviewed by two independent researchers, and thematic analysis was performed using NVivo10 software. The main barriers and motivators identified were: (1) clinician-related (e.g., familiarity with Lynch syndrome and family history knowledge); (2) patient-related (e.g., patients’ interests and personal experience with cancer); and (3) organizational-related (e.g., access to services, guidelines and referral pathway). Referral of patients with suspected Lynch syndrome to cancer genetic services is motivated and hindered by a range of individual, interpersonal and organizational factors. In order to improve the care and quality of life of patients and family with suspected Lynch syndrome, further research is needed to develop supportive tools for clinicians. PMID:25562140

  5. A rare case of choroid plexus carcinoma that led to the diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer).

    Science.gov (United States)

    Zhu, Viola W; Hinduja, Sanjay; Knezevich, Stevan R; Silveira, William R; DeLozier, Celia D

    2017-07-01

    Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder characterized by a significant risk of colorectal and endometrial cancers. A variety of other epithelial cancers may be associated with this syndrome. Brian tumors are infrequent, but have been reported in series. Here, we report a case of a 34-year-old Caucasian woman with WHO grade III choroid plexus carcinoma (CPC). Comprehensive genomic profiling of the patient's resected brain tumor revealed mutations in six genes: PTEN, VHL, MSH6, NOTCH1, RB1, and TP53. Family history is significant for endometrial cancer in her mother and sister as well as colon cancer in her maternal grandfather suggestive of Lynch syndrome. Site-specific mutational analysis showed the MSH6 mutation (p.R482*) in peripheral lymphocytes. Subsequently we performed immunohistochemical staining of the tumor tissue which demonstrated widespread loss of MSH6 with intact MSH2, MLH1, and PMS2. The diagnosis of Lynch syndrome due to a mutation in MSH6 was therefore established. Our patient elected to have adjuvant radiation to the surgical bed only followed by prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy and is doing very well. To our knowledge, this is the first case report of CPC in an adult patient with a germline MSH6 mutation. We believe our data have provided molecular evidence to suggest that CPC could potentially be part of the Lynch syndrome spectrum. Published by Elsevier B.V.

  6. Barriers and Motivators for Referral of Patients with Suspected Lynch Syndrome to Cancer Genetic Services: A Qualitative Study

    Directory of Open Access Journals (Sweden)

    Yen Y. Tan

    2014-02-01

    Full Text Available This article explores the views of general practitioners and specialists on their referral of patients with suspected Lynch syndrome to cancer genetic services. Using a purposive maximum variation sampling strategy, we conducted semi-structured interviews face-to-face with 28 general practitioners and specialists in public or private hospitals and specialist clinics between March and August 2011. General practitioners and specialists were recruited in a major metropolitan area in Australia. Interview transcripts were reviewed by two independent researchers, and thematic analysis was performed using NVivo10 software. The main barriers and motivators identified were: (1 clinician-related (e.g., familiarity with Lynch syndrome and family history knowledge; (2 patient-related (e.g., patients’ interests and personal experience with cancer; and (3 organizational-related (e.g., access to services, guidelines and referral pathway. Referral of patients with suspected Lynch syndrome to cancer genetic services is motivated and hindered by a range of individual, interpersonal and organizational factors. In order to improve the care and quality of life of patients and family with suspected Lynch syndrome, further research is needed to develop supportive tools for clinicians.

  7. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).

    Science.gov (United States)

    Buchanan, Daniel D; Rosty, Christophe; Clendenning, Mark; Spurdle, Amanda B; Win, Aung Ko

    2014-01-01

    Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic

  8. The effectiveness of the double B-lynch suture as a modification in the treatment of intractable postpartum haemorrhage.

    Science.gov (United States)

    Şahin, Hanifi; Soylu Karapınar, Oya; Şahin, Eda Adeviye; Dolapçıoğlu, Kenan; Baloğlu, Ali

    2018-03-20

    A broader range of more effective compression techniques are needed in the patients who have an intractable postpartum haemorrhage due to uterine atony despite medical treatment and B-Lynch sutures. The aim of this study was to report the outcome of a series of patients with haemorrhage who were managed by double B-Lynch suture. Fourteen patients who were treated in a tertiary hospital between July 2010 and February 2015 were included in the study. The intractable haemorrhage rate was 0.35% over 5 years (14/4000 births). Bleeding was controlled in all the patients with a double B-Lynch suture. The mean age of the patients was 24 ± 3.4 years. The mean estimated blood loss was 1696 ± 272.075 mL, and the mean transfusion rate was 4.2 ± 2.5 units. Pregnancy was observed in five patients at follow up. The double B-Lynch suture seems to be an effective and reliable solution to an intractable postpartum haemorrhage resulting from uterine atony and has no unfavourable impacts on fertility. It should be considered before the use of any aggressive surgical techniques such as a hypogastric artery ligation or a hysterectomy. This the first study to investigate the effectiveness of the double B-Lynch suture, and we showed that the hysterectomy and/or hypogastric artery ligation rate can be decreased by adding a second B-Lynch suture in cases where the medical treatment or a single B-Lynch has failed. Impact statement What is already known on the subject? Uterine atony is the most common cause of a primary postpartum haemorrhage. When a simple massage of the uterus and medication failed to manage this condition, various surgical solutions have been sought, including uterine compression sutures, uterine artery ligation, devascularisation of the uterus, internal iliac artery ligation and, ultimately, a hysterectomy. The B-Lynch suturing technique is particularly useful because of its simplicity of application, life-saving potential, relative safety and capacity

  9. Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

    Science.gov (United States)

    Chen, Jinyun; Etzel, Carol J; Amos, Christopher I; Zhang, Qing; Viscofsky, Nancy; Lindor, Noralane M; Lynch, Patrick M; Frazier, Marsha L

    2009-11-01

    Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

  10. Patient-reported disease knowledge and educational needs in Lynch syndrome: findings of an interactive multidisciplinary patient conference.

    Science.gov (United States)

    Bannon, Sarah A; Mork, Maureen; Vilar, Eduardo; Peterson, Susan K; Lu, Karen; Lynch, Patrick M; Rodriguez-Bigas, Miguel A; You, Yiqian Nancy

    2014-02-05

    Patients with Lynch Syndrome, the most common hereditary colorectal cancer syndrome, benefit from genetic education and family counseling regarding diagnostic testing and cancer surveillance/prevention recommendations. Although genetic counseling is currently the most common venue where such education and counseling takes place, little is known about the level of disease knowledge and education needs as directly reported by patients and families with Lynch Syndrome. Furthermore, experiences with forums for larger-scale knowledge transfer have been limited in the current literature. We conducted a one-day interactive multidisciplinary patient conference, designed to complement individual genetic counseling for updating disease knowledge, supportive networking and needs assessment among Lynch Syndrome patients and their family members. The patient conference was designed utilizing the conceptual framework of action research. Paired pre- and post-conference surveys were administered to 44 conference participants anonymously to assess patient-reported disease knowledge and education needs. A multidisciplinary team of expert providers utilized a variety of educational formats during the one-day conference. Four main focus areas were: genetic testing, surveillance/prevention, living with Lynch Syndrome, and update on research. Thirty-two participants (73%) completed the pre-conference, and 28 (64%) participants completed the post-conference surveys. Nineteen respondents were affected and the remaining were unaffected. The scores of the disease-knowledge items significantly increased from 84% pre- to 92% post-conference (p = 0.012). Patients reported a high level of satisfaction and identified further knowledge needs in nutrition (71%), surveillance/prevention options (71%), support groups (36%), cancer risk assessment (32%), active role in medical care (32%), and research opportunities (5%). Our experience with a dedicated patient education conference focused on

  11. Heredity of chronic bronchitis

    DEFF Research Database (Denmark)

    Meteran, Howraman; Backer, Vibeke; Kyvik, Kirsten Ohm

    2014-01-01

    BACKGROUND: Smoking is a major risk factor for lung diseases and lower respiratory symptoms, but since not all smokers develop chronic bronchitis and since chronic bronchitis is also diagnosed in never-smokers, it has been suggested that some individuals are more susceptible to develop chronic br...

  12. Heredity for triangular operators

    Directory of Open Access Journals (Sweden)

    Henry Crawford Rhaly Jr.

    2013-12-01

    Full Text Available A proof is given that if the lower triangular infinite matrix $T$ acts boundedly on $\\ell^2$ and U is the unilateral shift, the sequence $(U^*^nTU^n$ inherits from $T$ the following properties: posinormality, dominance, $M$-hyponormality, hyponormality, normality, compactness, and noncompactness.  Also, it is demonstrated that the upper triangular matrix $T^*$ is dominant if and only if $T$ is a diagonal matrix.

  13. Theoretical Insight of Physical Adsorption for a Single Component Adsorbent + Adsorbate System: II. The Henry Region

    KAUST Repository

    Chakraborty, Anutosh; Saha, Bidyut Baran; Ng, Kim Choon; Koyama, Shigeru; Srinivasan, Kandadai

    2009-01-01

    evaluated and compared with experimental data. It is found that the adsorbents with higher specific surface areas tend to possess lower heat of adsorption (ΔH°) at the Henry regime. In this paper, we have established the definitive relation between Ai and ΔH

  14. Paul Henry Latimer (1925-2011): discoverer of selective scattering in photosynthetic systems.

    Science.gov (United States)

    Latimer, Margaret Gwyn; Bannister, Thomas T; Govindjee

    2017-10-01

    We provide here a brief tribute to Paul Henry Latimer (November 25, 1925 to October 1, 2011), a dedicated biological physicist, discoverer of selective scattering in biological systems, a wonderful teacher, husband, and father. We provide here a glimpse of his personal and professional life, including reminiscences from F. Dudley Bryant, Dan A. Cross, Bobby E. Pyle, Bryan L. Seiber, and Bruce A. Seiber.

  15. Visualizing the Life and Legacy of Henry VIII: Guiding Students with Eight Types of Graphic Organizers

    Science.gov (United States)

    Gallavan, Nancy P.; Kottler, Ellen

    2010-01-01

    Delving into the life and legacy of Henry VIII is both complex and captivating. People seem compelled to learn more abut his critical contributions and controversial conduct that range from the significant to the scandalous. Reflecting on the history of the world would be incomplete without investigating the events and escapades associated with…

  16. Henri Wallon's Theory of Early Child Development: The Role of Emotions.

    Science.gov (United States)

    Van der Veer, Rene

    1996-01-01

    Discusses the stage theory of early child development of French theorist Henri Wallon. Describes Wallon's efforts (in contrast to contemporary Piaget) to describe emotional development and the role emotions play in establishing the child-caregiver bond. Argues that Wallon's theory is unique in its focus, influenced theorists such as Vygotsky, and…

  17. The Heuristic Method, Precursor of Guided Inquiry: Henry Armstrong and British Girls' Schools, 1890-1920

    Science.gov (United States)

    Rayner-Canham, Geoff; Rayner-Canham, Marelene

    2015-01-01

    Though guided-inquiry learning, discovery learning, student-centered learning, and problem-based learning are commonly believed to be recent new approaches to the teaching of chemistry, in fact, the concept dates back to the late 19th century. Here, we will show that it was the British chemist, Henry Armstrong, who pioneered this technique,…

  18. The Royal Entries of Henry VI in a London Civic Manuscript

    DEFF Research Database (Denmark)

    Bourassa, Kristin

    2016-01-01

    London Metropolitan Archives, MS Letter Book K, contains descriptions of Henry VI’s royal entries into both Paris (1431) and London (1432). Their placement one after the other in a London Letter Book was likely the work of the city’s common clerk, John Carpenter, who was the author of the descrip...

  19. 76 FR 63906 - Henry Gordy International, Inc., Provisional Acceptance of a Settlement Agreement and Order

    Science.gov (United States)

    2011-10-14

    ... International, Inc., containing a civil penalty of $1,100,000.00. DATES: Any interested person may ask the... report of a death involving a Target Set on or about May 1, 2006, after an 8-year-old boy choked on a dart and died on March 9, 2006. 8. In response to the death reported on or about May 1, 2006, Henry...

  20. The Snake Charmer(ess intermedia dialogue between Henri Rousseau's Painting and Sylvia Plath's poetry

    Directory of Open Access Journals (Sweden)

    Milovanov Dajana

    2017-01-01

    Full Text Available The paper examines possible interpretations of poetry and poetic image analysing the dialogue between the arts of literature and painting. The paper studies the poet Sylvia Plath's referencing Henri Rousseau's painting The Snake Charmer in her poem 'Snakecharmer'. What is analysed is the creative superstructure based upon nonliterary reference, as well as the visual elements attained through two diverse artistic media.

  1. Ernest Henry Starling: the history of cardiovascular endocrinology and the continuous need for developing animal models

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl

    2014-01-01

    The English physiologist, Ernest Henry Starling (1866–1927) (Fig. 1) in 1896, provided a quantitative explanation of the transcapillary transport of fluid. Six years later, he discovered the first hormone and introduced the concept of hormones in 1905, and at the time of the First World War, he f......’s achievements in cardiovascular physiology and endocrinology....

  2. W.E. Henry Symposium Compendium, Lawrence Berkeley National Laboratory, September 19, 1997

    Science.gov (United States)

    1997-09-19

    Society • Philosophical Society of Washington • Washington Academy of Sciences • New York Academy of Sciences • Institut International du Froid ...Powered Magnets" Reports of NRL Progress, Nov. 1958. 29. Henry, Warren E. "Aimantation dans les champs forts et approche a la saturation absolue du

  3. Enter the Madcap Prince of Wales: Students Directing "Henry IV, Part I."

    Science.gov (United States)

    Earthman, Elise Ann

    1993-01-01

    Argues that William Shakespeare's "Henry IV, Part I" is an appropriate and useful text for secondary English classrooms. Shows how the play lends itself to performance-based instruction. Outlines ways of accomplishing student engagement, using film versions, and assigning written work. (HB)

  4. Community Arts Programs: Cohesion and Difference Case Studies. Henry Street Settlement and El Museo del Barrio

    Science.gov (United States)

    Kiebert-Gruen, Cathleen

    2009-01-01

    A comparative case study of two cultural institutions, Henry Street Settlement and El Museo del Barrio, founded almost eighty years apart, were involved in social justice causes and community arts. Although both of these institutions participated in the political activism of their time, they also demonstrated an important adaptability. They were…

  5. Pornografia e transgressão na obra literária de Henry Miller

    Directory of Open Access Journals (Sweden)

    Raquel Catunda Pereira

    2016-07-01

    Full Text Available The North American writer Henry Miller was marginalized by literary critics since the first publications of his works in the 40s. Accused of being a pornographic text, the book Tropic of Cancer (1934 was forbidden in many countries. This article aims to analyze the obscene in Henry Miller’s work to prove that, beyond the erotic intention, Miller’s books are an expression of freedom and rejection of moral standards. In order to achieve our goal, we will use as theoretical basis the articles Criticismo e sexualidade: uma leitura de Tropico of Capricorn de Henry Miller, by Flávia Andréa Rodrigues Benfatt, and Literatura marginal americana: do épico confessional ao niilismo erótico, by Lainister de Oliveira. The texts mentioned above grant us the argumentation necessary to the analysis of pornographic discourse in Henry Miller’s literary works as the author’s aesthetics choice of taking himself as a transgressor in a decadent society.

  6. Henry Evelyn Bliss--The Other Immortal, or a Prophet without Honour?

    Science.gov (United States)

    Broughton, Vanda

    2008-01-01

    The paper takes a retrospective look at the work of Henry Evelyn Bliss, classificationist theorist and author of the "Bibliographic Classification". Major features of his writings and philosophy are examined and evaluated for the originality of their contribution to the corpus of knowledge in the discipline. Reactions to Bliss's work are analysed,…

  7. Mounting a Curricular Revolution: An Interview with Henry Louis Gates, Jr.

    Science.gov (United States)

    von Zastrow, Claus

    2009-01-01

    This article presents an interview with Henry Louis Gates, Jr., Harvard professor and cultural critic who has captured 25 million viewers with his PBS documentary series, African American Lives (WNET). Using genealogical research and DNA science, Gates traces the family history of 19 famous African Americans. What results is a rich and moving…

  8. The 'Overly-Broad' Selden Patent, Henry Ford and Development in the Early US Automobile Industry

    DEFF Research Database (Denmark)

    Howells, John; Katznelson, Ron D

    of the Selden patent claims. We use new primary sources to show how Henry Ford and others engaged in what today is called “Freedom to Operate” patent analysis when it most mattered commercially. We show that Ford correctly anticipated that a future court adjudication of the Selden patent claims would...

  9. Fin-de-Siecle Advances in Neuroeducation: Henry Herbert Donaldson and Reuben Post Halleck

    Science.gov (United States)

    Theodoridou, Zoe D.; Triarhou, Lazaros C.

    2009-01-01

    This article focuses on two early attempts at bridging neuroscience and education, made by Henry Herbert Donaldson (1857-1938), a neurologist, and Reuben Post Halleck (1859-1936), an educator. Their works, respectively entitled "The Growth of the Brain: A Study of the Nervous System in Relation to Education" (1895) and "The Education of the…

  10. Heredity of flake- and stripe-variegated traits and their introduction into Japanese day-neutral winter-flowering sweet pea (Lathyrus odoratus L.) cultivars.

    Science.gov (United States)

    Yagishita, Yoshimi; Hara, Yasuhide; Nakayama, Masayoshi

    2018-01-01

    Sweet pea ( Lathyrus odoratus L.) is a major cut flower in Japan, generally grown in greenhouses in winter to spring. The wild-type sweet pea is a long-day summer-flowering plant. The day-neutral winter-flowering ability, which allows cut-flower production in Japan, is a recessive phenotype that emerged by spontaneous mutation. Although Japanese winter-flowering cultivars and additionally spring-flowering cultivars, which have semi-long-day flowering ability generated by crossing the winter- and summer-flowering cultivars, have superior phenotypes for cut flowers, they have limited variation in color and fragrance. In particular, variegated phenotypes do not appear in modern winter- and spring-flowering cultivars, only in summer-flowering cultivars. We try to expand the phenotypic diversity of Japanese cut flower cultivars. In the processes, we introduced the variegated phenotypes by crossing with summer-flowering cultivars, and succeeded in breeding some excellent cultivars. During breeding, we analyzed the segregation ratios and revealed the heredity of the phenotypes. Here we review the heredity of these variegated phenotypes and winter-flowering phenotypes and their related genes. We also describe how we introduced the trait into winter-flowering cultivars, tracing their pedigrees to show both phenotypes and genotypes of the progeny at each generation. This knowledge is useful for the efficient breeding of new variegated cultivars.

  11. [Summary of results of a study of heredity of intelligence in a sample of the Czech population. III. Longitudinal and genealogic study of twins and their families].

    Science.gov (United States)

    Drábková, H

    1993-06-01

    The author presents further results of the longitudinal study of inheritance of intelligence, its components and structure in twins. Summarized results are presented for the age period from 0-15 years as well as detailed results of individual components and the global IQ in the age group of 8-15 years. The paper follows after two previous ones published in 1988 where the applied methods and statistical evaluation were described. Evidence was provided that heredity of intelligence is involved in children from a very early age, i.e. 0-3 years. After the age of 4 heredity predominates markedly over environmental influences up to the age of 15 years investigated so far by the author. (A slight decline occurs during the prepubertal period-age 13 and 14 years.) The author found that in particular the following components of intellect are inborn: abstract thinking, logic, talent for mathematics, concentration, inquisitiveness. Very detailed tables are presented for possible comparison with data in the literature and data from adults. The author found that the development of intelligence from childhood to adult age is very irregular. This uneven character is also mostly inborn. Statistical evaluation revealed several basic types of developmental curves and extreme variants. This will, however, be discussed in another paper. The theoretical results can be used also in practice in school education, counselling psychologic and psychiatric out-patient departments.

  12. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

    Science.gov (United States)

    Guindalini, Rodrigo Santa Cruz; Win, Aung Ko; Gulden, Cassandra; Lindor, Noralane M; Newcomb, Polly A; Haile, Robert W; Raymond, Victoria; Stoffel, Elena; Hall, Michael; Llor, Xavier; Ukaegbu, Chinedu I; Solomon, Ilana; Weitzel, Jeffrey; Kalady, Matthew; Blanco, Amie; Terdiman, Jonathan; Shuttlesworth, Gladis A; Lynch, Patrick M; Hampel, Heather; Lynch, Henry T; Jenkins, Mark A; Olopade, Olufunmilayo I; Kupfer, Sonia S

    2015-11-01

    African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  13. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

    Science.gov (United States)

    Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka; Macrae, Finlay; Möslein, Gabriela; Olschwang, Sylviane; Bisgaard, Marie-Luise; Ramesar, Raj; Eccles, Diana; Maher, Eamonn R; Bertario, Lucio; Jarvinen, Heikki J; Lindblom, Annika; Evans, D Gareth; Lubinski, Jan; Morrison, Patrick J; Ho, Judy W C; Vasen, Hans F A; Side, Lucy; Thomas, Huw J W; Scott, Rodney J; Dunlop, Malcolm; Barker, Gail; Elliott, Faye; Jass, Jeremy R; Fodde, Ricardo; Lynch, Henry T; Mathers, John C

    2008-12-11

    Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.) 2008 Massachusetts Medical Society

  14. Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

    Directory of Open Access Journals (Sweden)

    Stulp Rein P

    2008-02-01

    Full Text Available Abstract Lynch syndrome (HNPCC is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable, it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.

  15. Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

    Science.gov (United States)

    Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

    2015-12-01

    The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

  16. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype....... In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect...... to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....

  17. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Gruber, Stephen B; Raymond, Victoria M

    2010-01-01

    Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs......, and this right truncation effect is more pronounced in children than in parents. In this study, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare...... the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation...

  18. 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...

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

  20. Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome.

    Science.gov (United States)

    Burton-Chase, A M; Hovick, S R; Sun, C C; Boyd-Rogers, S; Lynch, P M; Lu, K H; Peterson, S K

    2014-08-01

    We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75-80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers

    Science.gov (United States)

    Park, Daniel J.; Tao, Kayoko; Le Calvez-Kelm, Florence; Nguyen-Dumont, Tu; Robinot, Nivonirina; Hammet, Fleur; Odefrey, Fabrice; Tsimiklis, Helen; Teo, Zhi L.; Thingholm, Louise B.; Young, Erin L.; Voegele, Catherine; Lonie, Andrew; Pope, Bernard J.; Roane, Terrell C.; Bell, Russell; Hu, Hao; Shankaracharya; Huff, Chad D.; Ellis, Jonathan; Li, Jun; Makunin, Igor V.; John, Esther M.; Andrulis, Irene L.; Terry, Mary B.; Daly, Mary; Buys, Saundra S.; Snyder, Carrie; Lynch, Henry T.; Devilee, Peter; Giles, Graham G.; Hopper, John L.; Feng, Bing J.; Lesueur, Fabienne; Tavtigian, Sean V.; Southey, Melissa C.; Goldgar, David E.

    2014-01-01

    Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del) and c.1207G>T (p.D403Y). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003). PMID:25050558

  2. HNPCC (Lynch Syndrome: Differential Diagnosis, Molecular Genetics and Management - a Review

    Directory of Open Access Journals (Sweden)

    Lynch Henry T

    2003-12-01

    Full Text Available Abstract HNPCC (Lynch syndrome is the most common form of hereditary colorectal cancer (CRC, wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

  3. Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome

    Science.gov (United States)

    Burton-Chase, AM; Hovick, SR; Sun, CC; Boyd-Rogers, S; Lynch, PM; Lu, KH; Peterson, SK

    2014-01-01

    We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75–80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence. PMID:23906188

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-28

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

  5. Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

    Science.gov (United States)

    Umar, Asad; Boland, C. Richard; Terdiman, Jonathan P.; Syngal, Sapna; de la Chapelle, Albert; Rüschoff, Josef; Fishel, Richard; Lindor, Noralane M.; Burgart, Lawrence J.; Hamelin, Richard; Hamilton, Stanley R.; Hiatt, Robert A.; Jass, Jeremy; Lindblom, Annika; Lynch, Henry T.; Peltomaki, Païvi; Ramsey, Scott D.; Rodriguez-Bigas, Miguel A.; Vasen, Hans F. A.; Hawk, Ernest T.; Barrett, J. Carl; Freedman, Andrew N.; Srivastava, Sudhir

    2010-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing. PMID:14970275

  6. HNPCC (Lynch Syndrome): Differential Diagnosis, Molecular Genetics and Management - a Review

    Science.gov (United States)

    2003-01-01

    HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

  7. Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome: Implications for Stratified Surveillance Strategies.

    Science.gov (United States)

    Ryan, Neil A J; Morris, Julie; Green, Kate; Lalloo, Fiona; Woodward, Emma R; Hill, James; Crosbie, Emma J; Evans, D Gareth

    2017-12-01

    Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed. To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers. A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England. Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement). Age at cancer diagnosis. A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years [children were included in the database, but no children developed cancer]). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating

  8. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study.

    Science.gov (United States)

    Botma, Akke; Vasen, Hans F A; van Duijnhoven, Fränzel J B; Kleibeuker, Jan H; Nagengast, Fokko M; Kampman, Ellen

    2013-02-01

    Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in LS patients was assessed. In the GEOLynch cohort of 486 persons with LS, dietary information was collected, using a food frequency questionnaire. Dietary pattern scores were obtained by principal components analysis. Hazard ratios (HR) between dietary patterns and colorectal adenomas were calculated using Cox regression models. Robust sandwich variance estimates were used to control for dependency within families. Final models were adjusted for age, sex, smoking habits, colorectal adenoma history, and extent of colon resection. During a median follow-up of 20 months, colorectal adenomas were detected in 58 persons. Four dietary patterns were identified: a "Prudent," "Meat," "Snack," and "Cosmopolitan" pattern. Individuals within the highest tertile of the "Prudent" pattern had a HR of 0.73 (95% confidence interval [CI], 0.32-1.66) for colorectal adenomas, compared with the lowest tertile. Those with high "Meat" pattern scores had a HR of 1.70 (95% CI, 0.83-3.52). A high "Snack" pattern was associated with an increased risk of colorectal adenomas (HR, 2.16; 95% CI, 1.03-4.49). A HR of 1.25 (95% CI, 0.61-2.55) was observed for persons in the highest tertile of the "Cosmopolitan" pattern. These findings suggest that dietary patterns may be associated with development of colorectal adenoma in patients with Lynch syndrome. The directions of these findings are corroborative with those observed in studies investigating sporadic colorectal cancer. Copyright © 2012 American Cancer Society.

  9. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

    Science.gov (United States)

    Jansen, Anne M L; Geilenkirchen, Marije A; van Wezel, Tom; Jagmohan-Changur, Shantie C; Ruano, Dina; van der Klift, Heleen M; van den Akker, Brendy E W M; Laros, Jeroen F J; van Galen, Michiel; Wagner, Anja; Letteboer, Tom G W; Gómez-García, Encarna B; Tops, Carli M J; Vasen, Hans F; Devilee, Peter; Hes, Frederik J; Morreau, Hans; Wijnen, Juul T

    2016-01-01

    Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  10. Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

    Science.gov (United States)

    Vilar, Eduardo; Mork, Maureen E; Cuddy, Amanda; Borras, Ester; Bannon, Sarah A; Taggart, Melissa W; Ying, Jun; Broaddus, Russell R; Luthra, Rajyalakshmi; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; You, Yi-Qian Nancy

    2014-01-01

    Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. The Use of Social Media to Recruit Participants With Rare Conditions: Lynch Syndrome as an Example.

    Science.gov (United States)

    Burton-Chase, Allison M; Parker, Wendy M; Hennig, Kelsey; Sisson, Faith; Bruzzone, Linda L

    2017-01-23

    Social media is increasingly being used as a means of recruiting participants, particularly for investigators whose areas of interest involve rare conditions or hard-to-reach populations. However, much of the literature to date has focused on paid advertisement recruitment. We used Lynch syndrome (LS), a rare hereditary cancer syndrome, as a model to demonstrate the successful partnership between researchers and a Web-based patient education and advocacy organization to facilitate participant recruitment. Recruitment was undertaken in partnership with Lynch Syndrome International (LSI), an advocacy organization with a strong social media presence. After LSI published our study information, participants followed up via email or phone call. Following prescreening and consent, interested and eligible participants were then sent a secure survey link. Within 36 hours of a single Facebook post by the site administrators for LSI, over 150 individuals responded via phone or email. Sixty-five individuals were sent the survey link and 57 individuals completed the survey (88% response rate). Of note, these 57 individuals were geographically diverse within the Unites States, representing LS patients from 26 different states. This approach has several advantages, including recruitment through a trusted source outside of a clinical setting, higher response rates, and cost-effectiveness with a small research team in a relatively short amount of time. Overall, social media recruitment with a trusted online partner can be highly effective in hard-to-reach clinical populations, such as patients with LS. However, this approach requires additional effort for eligibility screening. ©Allison M Burton-Chase, Wendy M Parker, Kelsey Hennig, Faith Sisson, Linda L Bruzzone. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 23.01.2017.

  12. Lynch Syndrome

    Science.gov (United States)

    ... be affected by your diagnosis, such as: Your privacy. The results of your genetic test will be listed in your medical record, ... to tell family members that you're having genetic testing and what that the results mean. By Mayo Clinic ... Conditions and Privacy Policy linked below. Terms and Conditions Privacy Policy ...

  13. Lynch Syndrome Associated Colon Adenocarcinoma Resembling Lymphoma on Fluoro-Deoxyglucose-Positron Emission Tomography/Computed Tomography

    International Nuclear Information System (INIS)

    Aparici, Carina Mari; Win, Aung Zaw

    2015-01-01

    The patient was a 46-year-old Asian male diagnosed with lynch syndrome associated colon adenocarcinoma in the right ascending colon. A presurgical staging 18-fluoro-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) found increased metabolic activity in the cervical, axillary, mediastinal, supraclavicular, para-aortic and mesenteric lymph nodes. This pattern of metastasis was very unusual for lynch syndrome associated colon adenocarcinoma and the involvement of those lymph nodes resembles the pattern of spread of lymphoma. He underwent right hemicolectomy and he was subsequently treated with 12 cycles of folinic acid (leucovorin), fluorouracil (5-FU), irinotecan. A restaging FDG-PET/CT at the end of the chemotherapy showed interval decrease in size and metabolic activity in the affected lymph nodes. FDG-PET/CT is a useful imaging modality in following-up the treatment response in colon adenocarcinoma

  14. Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

    Science.gov (United States)

    Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

    2018-01-01

    Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

  15. Using Social Media Data to Understand the Impact of Promotional Information on Laypeople’s Discussions: A Case Study of Lynch Syndrome

    Science.gov (United States)

    Salloum, Ramzi G; Guo, Yi; Wang, Mo; Prosperi, Mattia; Zhang, Hansi; Du, Xinsong; Ramirez-Diaz, Laura J; He, Zhe

    2017-01-01

    Background Social media is being used by various stakeholders among pharmaceutical companies, government agencies, health care organizations, professionals, and news media as a way of engaging audiences to raise disease awareness and ultimately to improve public health. Nevertheless, it is unclear what effects this health information has on laypeople. Objective This study aimed to provide a detailed examination of how promotional health information related to Lynch syndrome impacts laypeople’s discussions on a social media platform (Twitter) in terms of topic awareness and attitudes. Methods We used topic modeling and sentiment analysis techniques on Lynch syndrome–related tweets to answer the following research questions (RQs): (1) what are the most discussed topics in Lynch syndrome–related tweets?; (2) how promotional Lynch syndrome–related information on Twitter affects laypeople’s discussions?; and (3) what impact do the Lynch syndrome awareness activities in the Colon Cancer Awareness Month and Lynch Syndrome Awareness Day have on laypeople’s discussions and their attitudes? In particular, we used a set of keywords to collect Lynch syndrome–related tweets from October 26, 2016 to August 11, 2017 (289 days) through the Twitter public search application programming interface (API). We experimented with two different classification methods to categorize tweets into the following three classes: (1) irrelevant, (2) promotional health information, and (3) laypeople’s discussions. We applied a topic modeling method to discover the themes in these Lynch syndrome–related tweets and conducted sentiment analysis on each layperson’s tweet to gauge the writer’s attitude (ie, positive, negative, and neutral) toward Lynch syndrome. The topic modeling and sentiment analysis results were elaborated to answer the three RQs. Results Of all tweets (N=16,667), 87.38% (14,564/16,667) were related to Lynch syndrome. Of the Lynch syndrome–related tweets, 81

  16. Henry's Constants of Persistent Organic Pollutants by a Group-Contribution Method Based on Scaled-Particle Theory.

    Science.gov (United States)

    Razdan, Neil K; Koshy, David M; Prausnitz, John M

    2017-11-07

    A group-contribution method based on scaled-particle theory was developed to predict Henry's constants for six families of persistent organic pollutants: polychlorinated benzenes, polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, polychlorinated naphthalenes, and polybrominated diphenyl ethers. The group-contribution model uses limited experimental data to obtain group-interaction parameters for an easy-to-use method to predict Henry's constants for systems where reliable experimental data are scarce. By using group-interaction parameters obtained from data reduction, scaled-particle theory gives the partial molar Gibbs energy of dissolution, Δg̅ 2 , allowing calculation of Henry's constant, H 2 , for more than 700 organic pollutants. The average deviation between predicted values of log H 2 and experiment is 4%. Application of an approximate van't Hoff equation gives the temperature dependence of Henry's constants for polychlorinated biphenyls, polychlorinated naphthalenes, and polybrominated diphenyl ethers in the environmentally relevant range 0-40 °C.

  17. [Crusading and Chronicle Writing on the Medieval Baltic Frontier: A Companion to the Chronicle of Henry of Livonia] / Michael Amundsen

    Index Scriptorium Estoniae

    Amundsen, Michael

    2012-01-01

    Arvustus: Crusading and chronicle writing on the medieval Baltic frontier : a companion to the Chronicle of Henry of Livonia / edited by Marek Tamm, Linda Kaljundi, Carsten Selch Jensen. Farnham : Ashgate, 2011

  18. The Henry-Saltwater Intrusion Benchmark – Alternatives in Multiphysics Formulations and Solution Strategies

    Directory of Open Access Journals (Sweden)

    E Holzbecher

    2016-03-01

    Full Text Available In a classical paper Henry set up a conceptual model for simulating saltwater intrusion into coastal aquifers. Up to now the problem has been taken up by software developers and modellers as a benchmark for codes simulating coupled flow and transport in porous media. The Henry test case has been treated using different numerical methods based on various formulations of differential equations. We compare several of these approaches using multiphysics software. We model the problem using Finite Elements, utilizing the primitive variables and the streamfunction approach, both with and without using the Oberbeck-Boussinesq assumption. We compare directly coupled solvers with segregated solver strategies. Changing finite element orders and mesh refinement, we find that models based on the streamfunction converge 2-4 times faster than runs based on primitive variables. Concerning the solution strategy, we find an advantage of Picard iterations compared to monolithic Newton iterations.

  19. DNA-Catalyzed Henry Reaction in Pure Water and the Striking Influence of Organic Buffer Systems

    Directory of Open Access Journals (Sweden)

    Marleen Häring

    2015-03-01

    Full Text Available In this manuscript we report a critical evaluation of the ability of natural DNA to mediate the nitroaldol (Henry reaction at physiological temperature in pure water. Under these conditions, no background reaction took place (i.e., control experiment without DNA. Both heteroaromatic aldehydes (e.g., 2-pyridinecarboxaldehyde and aromatic aldehydes bearing strong or moderate electron-withdrawing groups reacted satisfactorily with nitromethane obeying first order kinetics and affording the corresponding β-nitroalcohols in good yields within 24 h. In contrast, aliphatic aldehydes and aromatic aldehydes having electron-donating groups either did not react or were poorly converted. Moreover, we discovered that a number of metal-free organic buffers efficiently promote the Henry reaction when they were used as reaction media without adding external catalysts. This constitutes an important observation because the influence of organic buffers in chemical processes has been traditionally underestimated.

  20. A French description of German psychology laboratories in 1893 by Victor Henri, a collaborator of Binet.

    Science.gov (United States)

    Nicolas, Serge; Barnes, Marissa E; Murray, David J

    2015-05-01

    There is a rich tradition of writings about the foundation of psychology laboratories, particularly in the United States but also in France. Various documents exist concerning former German laboratories in American and French literature. But the most interesting French paper was certainly written by a young psychologist named Victor Henri (1872-1940) who was a close collaborator of Alfred Binet (1857-1911) in the 1890s. Visiting various psychology laboratories, he wrote, in 1893, a clear description of the laboratories of Wundt, G. E. Müller, Martius and Ebbinghaus. An English translation is given of Henri's paper and the historical importance of his contribution is here expounded by contrasting the German and French psychologies of the time.

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

    Science.gov (United States)

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

    2011-08-01

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

  2. Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

    Directory of Open Access Journals (Sweden)

    Francesca Duraturo

    2013-01-01

    Full Text Available Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency. This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

  3. Prospective Study of Combined Colon and Endometrial Cancer Screening in Women With Lynch Syndrome: A Patient-Centered Approach

    Science.gov (United States)

    Huang, Marilyn; Sun, Charlotte; Boyd-Rogers, Stephanie; Burzawa, Jennifer; Milbourne, Andrea; Keeler, Elizabeth; Yzquierdo, Rebecca; Lynch, Patrick; Peterson, Susan K.; Lu, Karen

    2011-01-01

    Background: Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend annual endometrial biopsy (EMB) and regular colonoscopies. We assessed the feasibility of concurrently performing EMB and colonoscopy and evaluated women's perception of pain, satisfaction, and acceptability. Methods: From July 2002 to December 2009, women who had a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high-risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and postprocedure questionnaires assessing pain, level of satisfaction, and acceptability. The Wilcoxon rank test and Mann-Whitney test were used to compare pain scores. Results: Forty-two women completed the study. Median age was 37 years (range, 25 to 73). Nineteen had previously had an EMB in the office setting. Women reported significantly lower median levels of pain in the combined procedure compared with previous office setting biopsies (P Lynch syndrome screening recommendations. PMID:21532810

  4. Interval colon cancer in a Lynch syndrome patient under annual colonoscopic surveillance: a case for advanced imaging techniques?

    Directory of Open Access Journals (Sweden)

    Oxentenko Amy S

    2012-05-01

    Full Text Available Abstract Background Lynch syndrome confers increased risk for various malignancies, including colorectal cancer. Colonoscopic surveillance programs have led to reduced incidence of colorectal cancer and reduced mortality from colorectal cancer. Colonoscopy every 1–2 years beginning at age 20–25, or 10 years earlier than the first diagnosis of colorectal cancer in a family, with annual colonoscopy after age 40, is the recommended management for mutation carriers. Screening programs have reduced colon cancer mortality, but interval cancers may occur. Case presentation We describe a 48-year-old woman with Lynch syndrome who was found to have an adenoma with invasive colorectal cancer within one year after a normal colonoscopy. Conclusion Our patient illustrates two current concepts about Lynch syndrome: 1 adenomas are the cancer precursor and 2 such adenomas may be “aggressive,” in the sense that the adenoma progresses more readily and more rapidly to carcinoma in this setting compared to usual colorectal adenomas. Our patient’s resected tumor invaded only into submucosa and all lymph nodes were negative; in that sense, she represents a success for annual colonoscopic surveillance. Still, this case does raise the question of whether advanced imaging techniques are advisable for surveillance colonoscopy in these high-risk patients.

  5. "Audacity or Precision": The Paradoxes of Henri Villat's Fluid Mechanics in Interwar France

    OpenAIRE

    Aubin , David

    2010-01-01

    In Interwar France, Henri Villat became the true leader of theoretical researches on fluid mechanics. Most of his original work was done before the First World War; it was highly theoretical and its applicability was questioned. After having organized the first post-WWI International Congress of Mathematicians in 1920, Villat became the editor of the famous Journal de math\\'ematiques pure et appliqu\\'es and the director of the influential book series "M\\'emorial des sciences math\\'ematiques."...

  6. Henry Fayol’s 14 Principles of Management: Implications for Libraries and Information Centres

    OpenAIRE

    Uzuegbu, C. P.; Nnadozie, C. O.

    2015-01-01

    This paper focuses generally on the ‘fourteen principles of management’ by Henri Fayol. However, it specifically analyses their application to and implications for libraries and information centres. An extensive review of published works on management generally, and library management in particular, was conducted. This yielded vital insights on the original meaning and later modifications of these principles, as well as their application in the management of various organisation...

  7. Staging Henry Fielding: The Author-Narrator in Tom Jones On Screen

    OpenAIRE

    Løfaldli, Eli

    2017-01-01

    As recent adaptation theory has shown, classic-novel adaptation typically sets issues connected to authorship and literal and figurative ownership into play. This key feature of such adaptations is also central to the screen versions of Henry Fielding’s Tom Jones (1749). In much of Fielding’s fiction, the narrator, typically understood as an embodiment of Fielding himself, is a particularly prominent presence. The author-narrator in Tom Jones is no exception: not only is his presence strongly...

  8. VIDEO: Dr. Henry Rodriguez - Proteogenomics in Cancer Medicine | Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    Dr. Henry Rodriguez, director of the Office of Cancer Clinical Proteomics Research (OCCPR) at NCI, speaks with ecancer television at WIN 2017 about the translation of the proteins expressed in a patient's tumor into a map for druggable targets. By combining genomic and proteomic information (proteogenomics), leading scientists are gaining new insights into ways to detect and treat cancer due to a more complete and unified understanding of complex biological processes.

  9. Henry Agard Wallace, the Iowa Corn Yield Tests, and the Adoption of Hybrid Corn

    OpenAIRE

    Richard C. Sutch

    2008-01-01

    This research report makes the following claims: 1] There was not an unambiguous economic advantage of hybrid corn over the open-pollinated varieties in 1936. 2] The early adoption of hybrid corn before 1937 can be better explained by a sustained propaganda campaign conducted by the U.S. Department of Agriculture at the direction of the Secretary of Agriculture, Henry Agard Wallace. The Department's campaign echoed that of the commercial seed companies. The most prominent hybrid seed company,...

  10. Review: Henry E. Brady & David Collier (Hrsg.) (2004). Rethinking Social Inquiry: Diverse Tools, Shared Standards

    OpenAIRE

    Catón, Matthias

    2006-01-01

    Das Buch Rethinking Social Inquiry, herausgegeben von Henry E. BRADY und David COLLIER, ist eine Antwort auf den Band von KING, KEOHANE und VERBA (1994), in dem versucht wird, Standards der quantitativen Forschung in der qualitativen Forschung einzuführen. Die Autoren des hier rezensierten Buchs kritisieren viele der Vorschläge, da sie argumentieren, dass qualitative Forschung anderer Werkzeuge bedürfe. Trotzdem stimmen sie zu, dass die Grundlagen des Forschungsaufbaus ähnlich sind. Das Buch ...

  11. Review: Henry E. Brady & David Collier (Eds.) (2004). Rethinking Social Inquiry: Diverse Tools, Shared Standards

    OpenAIRE

    Matthias Catón

    2006-01-01

    Das Buch Rethinking Social Inquiry, herausgegeben von Henry E. BRADY und David COLLIER, ist eine Antwort auf den Band von KING, KEOHANE und VERBA (1994), in dem versucht wird, Standards der quantitativen Forschung in der qualitativen Forschung einzuführen. Die Autoren des hier rezensierten Buchs kritisieren viele der Vorschläge, da sie argumentieren, dass qualitative Forschung anderer Werkzeuge bedürfe. Trotzdem stimmen sie zu, dass die Grundlagen des Forschungsaufbaus ähnlich sind. Das Buch ...

  12. Pelecitus helicinus Railliet & Henry, 1910 (Filarioidea, Dirofilariinae and Other Nematode Parasites of Brazilian Birds

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    Oniki Yoshika

    2002-01-01

    Full Text Available We report Pelecitus helicinus Railliet & Henry, 1910 from 13 species of birds of 2 orders and 7 families, collected from the states of São Paulo and Mato Grosso, Brazil. All 13 constitute new host records for this nematode. In addition, we report the first record of Aprocta golvani Diaz-Ungria, 1963 from Brazil and Monasa nigrifrons (Bucconidae, as well as a number of other nematode records from Neotropical birds.

  13. Henri Fayol, théoricien de l’entreprise innovante

    OpenAIRE

    Hatchuel , Armand; Segrestin , Blanche

    2016-01-01

    International audience; Have we correctly read Henri Fayol? His work is still reduced to general principles of administration that seem rigid and trivial. Yet, he has been a great innovative leader that considered scientific research as a major task of the business executive. A new reading of Fayol's masterpiece shows that he introduced sophisticated notions: " the unknown " , " the program of action " , " the advancement " , which meaning was erased by his translators or forgotten. Coming fr...

  14. Henri Fayol. Performativity of his ideas and oblivion of their creator

    OpenAIRE

    Dumez , Hervé

    2018-01-01

    Henri Fayol formulated one of the first theories of management and allows us to see how one of the first scientific approaches of management could or could not perform management practices. Therefore, Fayol is particularly interesting from the point of view of performativity (Callon, 1998, 2007, MacKenzie et al., 2007, Muniesa, 2014). The case is all the richer because it presents the rare characteristic of a direct confrontation between two rival theories, his and Taylor's, at the level of t...

  15. Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.

    Science.gov (United States)

    Yokoyama, Takanori; Takehara, Kazuhiro; Sugimoto, Nao; Kaneko, Keika; Fujimoto, Etsuko; Okazawa-Sakai, Mika; Okame, Shinichi; Shiroyama, Yuko; Yokoyama, Takashi; Teramoto, Norihiro; Ohsumi, Shozo; Saito, Shinya; Imai, Kazuho; Sugano, Kokichi

    2018-05-21

    Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer. Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome. Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

  16. Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

    Science.gov (United States)

    Cohen, Stacey A; Laurino, Mercy; Bowen, Deborah J; Upton, Melissa P; Pritchard, Colin; Hisama, Fuki; Jarvik, Gail; Fichera, Alessandro; Sjoding, Britta; Bennett, Robin L; Naylor, Lorraine; Jacobson, Angela; Burke, Wylie; Grady, William M

    2016-02-01

    Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. © 2015 American Cancer Society.

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

    Science.gov (United States)

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

    2009-06-01

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

  18. The delusion of the Master: the last days of Henry James.

    Science.gov (United States)

    Bartolomeo, Paolo

    2013-11-01

    The novelist Henry James shared with his brother William, the author of the Principles of Psychology, a deep interest in the ways in which personal identity is built through one's history and experiences. At the end of his life, Henry James suffered a vascular stroke in the right hemisphere and developed a striking identity delusion. He dictated in a perfectly clear and coherent manner two letters as if they were written by Napoleon Bonaparte. He also showed signs of reduplicative paramnesia. Negative symptoms resulting from right hemisphere damage may disrupt the feelings of "warmth and intimacy and immediacy" and the "resemblance among the parts of a continuum of feelings (especially bodily feelings)", which are the foundation of personal identity according to William James. On the other hand, a left hemisphere receiving inadequate input from the damaged right hemisphere may produce positive symptoms such as delusional, confabulatory narratives. Other fragments dictated during Henry James's final disease reveal some form of insight, if partial and disintegrated, into his condition. Thus, even when consciousness is impaired by brain damage, something of its deep nature may persist, as attested by the literary characteristics of the last fragments of the Master.

  19. Should bulk cloudwater or fogwater samples obey Henry's law

    Energy Technology Data Exchange (ETDEWEB)

    Pandis, S.N.; Seinfeld, J.H. (Department of Chemical Engineering and Environmental Quality Laboratory, California Institute of Technology, Pasadena, CA (USA))

    1991-06-20

    In this work we prove that mixing of droplets with different {ital p}H that are individually in Henry's law equilibrium with the surrounding atmosphere always results in a bulk mixture that is supersaturated with weak acids like S(IV) and HCOOH and bases like NH{sub 3} with respect to the original atmosphere. The degree of supersaturation of the bulk liquid water sample for a particular species depends on its dissociation constant, on the initial {ital p}H of the bulk droplet mixture, and on the distribution of the {ital p}H and of the liquid water over the droplet spectrum. High supersaturations result only when the {ital p}H of the bulk droplet mixture exceeds the {ital p}K{sub {ital a}} of the species, in which {ital p}H range large {ital p}H differences among droplets of different sizes lead to large deviations from Henry's law for the bulk mixture. The deviation is shown to depend on the ratio of the arithmetic mean to the harmonic mean of the hydrogen ion concentrations of the droplets with the liquid water content used was weighting factor in the calculation of the means. The theory developed can explain observed discrepancies from Henry's law in atmospheric samples and also other observed phenomena like the reported increase of {ital p}H values of bulk aqueous samples during storage. {copyright} American Geophysical Union 1991

  20. The last ride of Henry II of France: orbital injury and a king's demise.

    Science.gov (United States)

    Eftekhari, Kian; Choe, Christina H; Vagefi, M Reza; Eckstein, Lauren A

    2015-01-01

    Jousting was a popular pastime for royalty in the Renaissance era. Injuries were common, and the eye was particularly at risk from the splinters of the wooden lance. On June 30, 1559, Henry II of France participated in a jousting tournament to celebrate two royal weddings. In the third match, Gabriel de Montgomery struck Henry on the right shoulder and the lance splintered, sending wooden shards into his face and right orbit. Despite being cared for by the prominent physicians Ambroise Paré and Andreas Vesalius, the king died 10 days later and was found to have a cerebral abscess. The wound was not explored immediately after the injury; nevertheless, wooden foreign bodies were discovered in the orbit at the time of autopsy. The dura had not been violated, suggesting that an infection may have traveled from the orbit into the brain. Nostradamus and Luca Guarico, the astrologer to the Medici family, had prophesied the death of Henry II of France, but he ignored their warnings and thus changed the course of history in Renaissance Europe. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Oxalate Content of the Herb Good-King-Henry, Blitum Bonus-Henricus

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    Wanying Li

    2015-05-01

    Full Text Available The total, soluble and insoluble oxalate contents of the leaves, stems and buds of Good-King-Henry (Blitum Bonus-Henricus were extracted and measured using HPLC chromatography. The large, mature leaves contained 42% more total oxalate than in the small leaves and the soluble oxalate content of the large leaves was 33% higher than the smaller leaves. Cooking the mixed leaves, stems and buds in boiling water for two minutes significantly (p < 0.05 reduced the total oxalate when compared to the raw plant parts. Pesto sauce made from mixed leaves contained 257 mg total oxalate/100 g fresh weight; this was largely made up of insoluble oxalates (85% of the total oxalate content. Soup made from mixed leaves contained lower levels of total oxalates (44.26 ± 0.49 mg total oxalate/100 g fresh weight and insoluble oxalate made up 49% of the oxalate contents. The levels of oxalates in the Good-King-Henry leaves were high, suggesting that the leaves should be consumed occasionally as a delicacy because of their unique taste rather than as a significant part of the diet. However, the products made from Good-King-Henry leaves indicated that larger amounts could be consumed as the oxalate levels were reduced by dilution and processing.

  2. Effectiveness of an implementation optimisation intervention aimed at increasing parent engagement in HENRY, a childhood obesity prevention programme - the Optimising Family Engagement in HENRY (OFTEN) trial: study protocol for a randomised controlled trial.

    Science.gov (United States)

    Bryant, Maria; Burton, Wendy; Cundill, Bonnie; Farrin, Amanda J; Nixon, Jane; Stevens, June; Roberts, Kim; Foy, Robbie; Rutter, Harry; Hartley, Suzanne; Tubeuf, Sandy; Collinson, Michelle; Brown, Julia

    2017-01-24

    Family-based interventions to prevent childhood obesity depend upon parents' taking action to improve diet and other lifestyle behaviours in their families. Programmes that attract and retain high numbers of parents provide an enhanced opportunity to improve public health and are also likely to be more cost-effective than those that do not. We have developed a theory-informed optimisation intervention to promote parent engagement within an existing childhood obesity prevention group programme, HENRY (Health Exercise Nutrition for the Really Young). Here, we describe a proposal to evaluate the effectiveness of this optimisation intervention in regard to the engagement of parents and cost-effectiveness. The Optimising Family Engagement in HENRY (OFTEN) trial is a cluster randomised controlled trial being conducted across 24 local authorities (approximately 144 children's centres) which currently deliver HENRY programmes. The primary outcome will be parental enrolment and attendance at the HENRY programme, assessed using routinely collected process data. Cost-effectiveness will be presented in terms of primary outcomes using acceptability curves and through eliciting the willingness to pay for the optimisation from HENRY commissioners. Secondary outcomes include the longitudinal impact of the optimisation, parent-reported infant intake of fruits and vegetables (as a proxy to compliance) and other parent-reported family habits and lifestyle. This innovative trial will provide evidence on the implementation of a theory-informed optimisation intervention to promote parent engagement in HENRY, a community-based childhood obesity prevention programme. The findings will be generalisable to other interventions delivered to parents in other community-based environments. This research meets the expressed needs of commissioners, children's centres and parents to optimise the potential impact that HENRY has on obesity prevention. A subsequent cluster randomised controlled pilot

  3. Henri Fayol’un Yönetim Düşüncesi Üzerine Notlar(Notes on Managerial Thought of Henry Fayol

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    Ramazan ŞENGÜL

    2007-01-01

    Full Text Available Henri Fayol, developed a managerial approach which is a perfect guide for both private and public sectors through focusing systematically upon managerial process. A major advantage of Fayol in creating a general managerial doctrine was his pratician side. His managerial thought which was developed in the early 20th century lasted up to our times. The distinguished characteristic of Fayol’s thought was studying the administrative reality through separating it into its functions, in that it helps to understand evolution and operation of organisations. The importance of his doctrine for today is that adapting contemporary managerial techniques into organisations of various kinds needs to refer Fayol’s managerial aproach in one way or another.

  4. Causes of Cancer Death Among First-Degree Relatives in Japanese Families with Lynch Syndrome.

    Science.gov (United States)

    Tanakaya, Kohji; Yamaguchi, Tatsuro; Ishikawa, Hideki; Hinoi, Takao; Furukawa, Yoichi; Hirata, Keiji; Saida, Yoshihisa; Shimokawa, Mototsugu; Arai, Masami; Matsubara, Nagahide; Tomita, Naohiro; Tamura, Kazuo; Sugano, Kokichi; Ishioka, Chikashi; Yoshida, Teruhiko; Ishida, Hideyuki; Watanabe, Toshiaki; Sugihara, Kenichi

    2016-04-01

    To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS). The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed. Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003). In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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

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    Jose Miguel Moreno-Ortiz

    2016-01-01

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

  6. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    Science.gov (United States)

    Campos, Sara; Amaro, Pedro; Cunha, Inês; Fraga, João; Cipriano, Maria Augusta; Tomé, Luís

    2017-01-01

    Introduction Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. Case In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short-term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. Conclusion This case raises several issues: (1) the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2) pitfalls in the interpretation of MMR proteins immunochemistry; (3) the role of endoscopic resection in LS. PMID:29255760

  7. Molecular profile of the Lynch Syndrome in the Republic of Macedonia

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    Marija Hiljadnikova-Bajro

    2012-12-01

    Full Text Available The most frequent type of hereditary colorectal cancer, the one occurring in the setting of the Lynch syndrome (LS is considered a phenotypic manifestation of a germline defect in the mismatch repair mechanism i.e. in the MLH1, MSH2, MSH6 or PMS2 gene. Aiming towards establishment of a standardized protocol involving molecular analyses for diagnosis of this syndrome and developing a unique national register of families with hereditary colorectal cancer syndromes in the Republic of Macedonia, we began a prospective study to reveal the genetic defects among Macedonian patients with colorectal cancer (CRC and identifying families with hereditary CRC. A total of 53 patients fulfilling the revised Bethesda criteria for MSI-genetic testing were compared to 350 patients with sporadic CRC. The results reveal significant differences in age at diagnosis (p=0.03, involvement of microsatellite instability (pG nonsense mutation with a possible founder effect in the Macedonian population, the MLH1 ex.3-12 deletion, as well as the c.244A>G mutation, IVS14- 19A>G and IVS4+65A>C changes in MLH1 without confirmed pathological significance. The observed high frequency (87.5% of the Ile219Val (c.655A>G variant in MLH1 among the LS suspects prompts further analyses to evaluate its involvement in the development of hereditary CRC by itself or as a risk modifying factor among the patients from the Republic of Macedonia.

  8. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    Directory of Open Access Journals (Sweden)

    Sara Campos

    2017-03-01

    Full Text Available Introduction: Lynch syndrome (LS, the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR genes leading to an increased cancer risk, namely colorectal cancer. Case: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short-term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. Conclusion: This case raises several issues: (1 the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2 pitfalls in the interpretation of MMR proteins immunochemistry; (3 the role of endoscopic resection in LS.

  9. The changing landscape of Lynch syndrome due to PMS2 mutations.

    Science.gov (United States)

    Blount, J; Prakash, A

    2018-07-01

    DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

    Science.gov (United States)

    Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

    2014-06-01

    Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.

    Science.gov (United States)

    Abu Freha, Naim; Leibovici Weissman, Yaara; Fich, Alexander; Barnes Kedar, Inbal; Halpern, Marisa; Sztarkier, Ignacio; Behar, Doron M; Arbib Sneh, Orly; Vilkin, Alex; Baris, Hagit N; Gingold, Rachel; Lejbkowicz, Flavio; Niv, Yaron; Goldberg, Yael; Levi, Zohar

    2018-01-01

    We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type /normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype.

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Science.gov (United States)

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

    2016-04-01

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

  14. 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.

  15. Recognition of Lynch Syndrome Amongst Newly Diagnosed Colorectal Cancers at St. Paul’s Hospital

    Directory of Open Access Journals (Sweden)

    Steven Pi

    2017-01-01

    Full Text Available Background. Lynch Syndrome (LS is the most common cause of inherited colorectal cancer (CRC. In British Columbia, most centres still use clinical criteria (Amsterdam II, Revised Bethesda, or the BC Cancer Agency’s criteria to determine who should undergo further first-line testing in the form of microsatellite instability or immunohistochemistry staining. Given the limitations with this strategy, LS is thought to be underrecognized. Objective. To investigate whether LS is truly underrecognized when compared to the reported prevalence. Methods. A retrospective chart review of all CRC cases diagnosed at St. Paul’s Hospital from 2010 to 2013 was conducted. Results. 246 patients met inclusion criteria. 76% (83/109 with a family history of malignancy were unable to recall the specific malignancy or age of diagnosis. 18% (43/235 were only asked about a history of gastrointestinal related malignancy and 26% (65/246 met at least one of the three criteria but only 21% (13/63 received further investigation. Only 1.6% (4/246 had LS compared to the reported prevalence of 2–5% of all CRC cases. Conclusion. This data supports our hypothesis that LS is underrecognized. Issues at the patient, physician, and systems level need to be evaluated to determine where the limitations preventing appropriate testing are occurring.

  16. Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers.

    Directory of Open Access Journals (Sweden)

    Cecilia Egoavil

    Full Text Available Lynch syndrome (LS is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population.Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI, immunohistochemistry (IHC for mismatch-repair (MMR protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed.One hundred and seventy-three EC (average age, 63 years were screened. Sixty-one patients (35% had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs. Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques.The prevalence of LS among EC patients was 4.6% (8/173; with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.

  17. Novel germline MSH2 mutation in lynch syndrome patient surviving multiple cancers

    Directory of Open Access Journals (Sweden)

    Janavicius Ramunas

    2012-01-01

    Full Text Available Abstract Lynch syndrome (LS individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers. We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear. In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.

  18. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

    Science.gov (United States)

    Lynch, HT; Lynch, PM; Lanspa, SJ; Snyder, CL; Lynch, JF; Boland, CR

    2010-01-01

    More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (~30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10–25% of familial CRC. PMID:19659756

  19. Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

    Directory of Open Access Journals (Sweden)

    Hellen Houlleberghs

    2017-05-01

    Full Text Available Lynch syndrome (LS is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.

  20. Las cartas privadas de Wanda Morla Lynch: entre género discursivo y fuente documental

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    Carolina Miranda

    2016-11-01

    Full Text Available This essay is an approach to the private letters of Wanda Morla Lynch, a Chilean woman from the early XX century. This approach considers the epistolary genre as a complex and often contradictory genre, propitious to describe a feminine intimacy, feelings and subjectivity, due to the relationship of complicity between the letters and the historically acquired status of subordination, imposed by the patriarchal society. In this sense, this epistolary corpus will allow us establishing a characterization of these private letters as they have a formal/discursive singularity in relation to other genres that conform the corpus of autobiographic writing, as well as exploring and rescuing the value of those letters as a documentary source as they unveil the voice of a woman, who was a privileged witness of the changes that took place in Paris in the 1920’s, epicenter of the modernist avant-garde of the time. Regarding this last consideration, Wanda Morla Lynch’s letters can be also described as a “journey diary” (historically known as a particularly masculine experience, giving us the possibility of reading these letters as a secretly transgressor gesture towards the social conventions of an era.

  1. Staging Henry Fielding: The Author-Narrator in Tom Jones On Screen

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    Eli Løfaldli

    2017-06-01

    Full Text Available As recent adaptation theory has shown, classic-novel adaptation typically sets issues connected to authorship and literal and figurative ownership into play. This key feature of such adaptations is also central to the screen versions of Henry Fielding’s Tom Jones (1749. In much of Fielding’s fiction, the narrator, typically understood as an embodiment of Fielding himself, is a particularly prominent presence. The author-narrator in Tom Jones is no exception: not only is his presence strongly felt throughout the novel, but through a variety of means, ‘The History of Tom Jones, A Foundling’ is also distinctly marked as being under his control and ownership. The two adaptations of Fielding’s novel, a 1963 film and a 1997 television series, both retain the figure of the author-narrator, but differ greatly in their handling of this device and its consequent thematic ramifications. Although the 1963 film de-emphasises Henry Fielding’s status as proprietor of the story, the author-narrator as represented in the film’s voiceover commentary is a figure of authority and authorial control. In contrast, the 1997 adaptation emphasises Fielding’s ownership of the narrative and even includes the author-narrator as a character in the series, but this ownership is undermined by the irreverent treatment to which he is consistently subjected. The representations of Henry Fielding in the form of the author-narrator in both adaptations are not only indicative of shifting conceptions of authorship, but also of the important interplay between authorship, ownership and adaptation more generally.

  2. Development of low-energy X-ray spectrometry at the Laboratoire National Henri Becquerel

    International Nuclear Information System (INIS)

    Lepy, M.C.; Plagnard, J.

    2007-01-01

    In the frame of the French Metrology Institute, the Laboratoire National Henri Becquerel performs accurate characterization of semiconductor detectors that are in use in a number of applications. Their efficiency calibration, energy resolution and the detailed shape of their response function are parameters of interest for accurate processing of low-energy X-ray spectra to be applied to elements identification and fundamental research studies. The tools specifically developed for low-energy detectors calibration and characterization are described, from the use of radioactivity standard to the development of a tunable monochromatic X-ray source. (Author)

  3. Literary Practice according to Michel Henry: A Philosophical Introduction to his Novels

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    Jean-Baptiste Dussert

    2012-12-01

    Full Text Available Although the author of four novels, Michel Henry never produced an aesthetics of literature. The purpose of this article is, after a presentation of his philosophy of immanence and his concept of life, to locate where the literary practice takes place in his system. In this study, we are not interested in the poetic quality of his works, but in the possibility to base his singular creativity on his philosophical reflection. This leads us to insert literature in the vast phenomenon of culture and ethics, and to grasp the function of poetics in the struggle against barbarism.

  4. Ernest Henry Starling (1866-1927): the scientist and the man

    DEFF Research Database (Denmark)

    Henriksen, Jens H

    2005-01-01

    The pre-eminent achievements of the English physician and physiologist Ernest Henry Starling were his quantitative explanation of the transcapillary transport of fluid, the discovery of the first hormone, secretin, and his formulation of the law of the heart. In some ways Starling was an outsider...... and he was the centre of several scientific and social controversies. However, throughout his life he stressed fundamental scientific attitudes and ideas with remarkable persistence and power, although also balance, and his scientific achievements have stood the test of time....

  5. Elementos de política de gestión en Henry Mintzberg

    OpenAIRE

    García-Álvarez, S. (Santiago); García-Martínez, A.N. (Alejandro Néstor); Múgica, F. (Fernando)

    2016-01-01

    El trabajo de investigación consistió en estudiar un buen número de los escritos de Henry Mintzberg y prácticamente todas sus obras relacionadas con los elementos de política de gestión: no únicamente los libros, sino numerosos artículos y textos relacionados. He leído también muchos libros y artículos de otros autores de management, como Drucker, Collins, Kotter, Pfeffer, Peters y varios más, para enriquecer el texto y contrastar posturas. He estudiado con particular interés y detenimiento l...

  6. Henri Walon: por uma teoria dialética na educação

    Directory of Open Access Journals (Sweden)

    Maria Inês Naujorks

    2000-04-01

    Full Text Available O texto aborda as principais idéias desenvolvidas por Henri Wallon. Tendo como método o materialismo dialético, seu projeto foi o de formular uma "ciência do homem". Para o autor o desenvolvimento é a síntese dialética do biológico e do social e só pode ser entendido à luz das contradições de um processo que se estende por toda vida toda.

  7. Confronting empty spaces: between interpretation and experience in "The Turn of the Screw" by Henry James

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    Antonia Spinelli

    2015-01-01

    Full Text Available The Turn of the Screw by Henry James has inspired the most various critical debates for over a century. What is hidden in the folds of the story? What kind of impact does it have on the reader? Like a borderless nebula who attracts and reflects light from other stars, this novella is permeated by a vide fascinant, by a chaotic and disturbing matter “such stuff as dreams are made”. This feeling of absence and uncertainty, that characterizes the story, developed trough the contribution of readers and critics and it found a further still precious echo in The Innocents, a film directed by Jack Clayton in 1961.

  8. Considerations and management of a patient with three metachronous cancers in association with Lynch syndrome and ileal Crohn’s disease: A case report

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    Kaleb Lourensz

    2015-01-01

    Conclusion: The surgical treatment of patients with Lynch syndrome requires a sound knowledge of the possible neoplastic conditions that can arise in the syndrome. Early detection is paramount, either by implementation of evidence based surveillance programs or at least by a heightened clinical awareness of the features of this disease. Ideally this will result in both reduced surgical morbidity and improved oncologic outcome. Furthermore, the medical treatment of Crohn’s disease in a patient with tumors arising from Lynch syndrome must be undertaken with at least a consideration of the possibility that the use of immunosuppressive medication might increase the risk of cancer recurrence.

  9. Environmental liabilities in Billings reservoir and its impacts on hydropower generation Plant Henry Borden; Os passivos ambientais no reservatorio Billings e os seus impactos na geracao hidroenergetica da Usina Henry Borden

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Daniel Ladeira [Universidade Federal do ABC (UFABC), Santo Andre, SP (Brazil)

    2010-07-01

    The primary assertion is that this article argues that the recovery in production of hydropower in Henry Borden (UHB) is the reduction of environmental liabilities in the Billings reservoir. In this context, the aim of this paper is to provide a first consideration of the possibility of recovery of production Henry Borden hydropower plant of recovering the multiple uses of the reservoir. From this perspective, we interviewed representatives of CETESB (Sanitation Environmental Technology Company) and EMAE (Metropolitan Water and Energy Company SA) for consideration of actions that include environmental policies aimed at increasing the production of electricity in Henry Borden in order to obtain results that may contribute to the multiple uses of the Billings reservoir. Noting that the range of laws aimed at protecting the water sources was limited to disjointed public policy that has reduced the resilience of the Billings reservoir. (author)

  10. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.

    Science.gov (United States)

    Pinto, Diana; Pinto, Carla; Guerra, Joana; Pinheiro, Manuela; Santos, Rui; Vedeld, Hege Marie; Yohannes, Zeremariam; Peixoto, Ana; Santos, Catarina; Pinto, Pedro; Lopes, Paula; Lothe, Ragnhild; Lind, Guro Elisabeth; Henrique, Rui; Teixeira, Manuel R

    2018-02-01

    Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2017-03-01

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

  12. Ecrire et souffrir : L’inspiration partagée de Constance Fenimore Woolson et de Henry James Literature and Grief: Constance Fenimore Woolson and Henry James, A Common Inspiration

    Directory of Open Access Journals (Sweden)

    Jeannine Hayat

    2007-01-01

    Full Text Available Miss Grief is a story by Constance Fenimore Woolson, an American novelist who often wrote about the difficulty a woman had in becoming an artist — a writer or a painter — in the nineteenth century. This tale is a very strange text, a kind of anticipation of a meeting to come, in Italy, in 1880, between Woolson and Henry James, and a friendship which lasted until the former’s death in 1894. For thirteen years, both writers would share a common inspiration. Death itself could not break the links between the two authors, who were connected even when settled in different European countries. William James, who was a member of the American Society for Psychical Research, probably helped his brother Henry to communicate — or so it appears — in some way with Woolson, even after her fatal accident, or possible suicide, in Venice. Henry James probably had in mind Miss Grief, a story by his dead friend, before writing some of his books. Indeed, Woolson had been the first to develop the image of “the figure in the carpet,” which was later transformed by Henry James. Woolson was also the first to devise a plot which Henry James would later use as a canvas for his novel The Wings of the Dove. What is an author and what is authorship? It seems impossible to separate what is Woolson’s and what is Henry James’s in four works of fiction that are in fact to be read together : Miss Grief, The Figure in the Carpet, The Beast in the Jungle, The Wings of the Dove.

  13. A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome

    OpenAIRE

    Wu, Bin; Ji, Wuyang; Liang, Shengran; Ling, Chao; You, Yan; Xu, Lai; Zhong, Min-Er; Xiao, Yi; Qiu, Hui-Zhong; Lu, Jun-Yang; Banerjee, Santasree

    2017-01-01

    Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five ge...

  14. Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome

    DEFF Research Database (Denmark)

    Ou, Jianghua; Rasmussen, Merete; Westers, Helga

    2009-01-01

    for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels...... comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary...

  15. Kierkegaard se, drei grossen ideen” en die ini- siasie van henry van eeden (sewe dae b y die silbersteins

    Directory of Open Access Journals (Sweden)

    L. S. Venter

    1977-03-01

    Full Text Available Die doel van Henry se verblyf by die Silbersteins word vroeg in Sewe dae verwoord as Jock tydens die eerste aandbyeenkoms sê dat Henry „van sekere gevestigde idees” (p. 16 ontslae moet raak. Ook mrs. Silberstein beskou dit as noodsaaklik dat sy on­ skuld vemietig moet word (p. 22. Op die oggendwandeling van die tweede dag herhaal Jock sy stelling van die vorige aand en voeg daaraan toe dat daar baie dinge is wat Henry ,,sal moet leer en verleer” (p. 28. Vir die modeme mens, wat „van die vrug van kennis geëet” het, is daar „geen illussies meer nie” (p. 32.

  16. Human Heredity and Health (H3) in Africa Kidney Disease Research Network: A Focus on Methods in Sub-Saharan Africa.

    Science.gov (United States)

    Osafo, Charlotte; Raji, Yemi Raheem; Burke, David; Tayo, Bamidele O; Tiffin, Nicki; Moxey-Mims, Marva M; Rasooly, Rebekah S; Kimmel, Paul L; Ojo, Akinlolu; Adu, Dwomoa; Parekh, Rulan S

    2015-12-07

    CKD affects an estimated 14% of adults in sub-Saharan Africa, but very little research has been done on the cause, progression, and prevention of CKD there. As part of the Human Heredity and Health in Africa (H3Africa) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization and analyzing environmental and genetic factors from nine clinical centers in four African countries (Ghana, Nigeria, Ethiopia, and Kenya) over a 5-year period. Approximately 4000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants age research infrastructure can be successfully established in Africa. This study will provide clinical, biochemical, and genotypic data that will greatly increase the understanding of CKD in sub-Saharan Africa. Copyright © 2015 by the American Society of Nephrology.

  17. Theoretical Insight of Physical Adsorption for a Single Component Adsorbent + Adsorbate System: II. The Henry Region

    KAUST Repository

    Chakraborty, Anutosh

    2009-07-07

    The Henry coefficients of a single component adsorbent + adsorbate system are calculated from experimentally measured adsorption isotherm data, from which the heat of adsorption at zero coverage is evaluated. The first part of the papers relates to the development of thermodynamic property surfaces for a single-component adsorbent + adsorbate system1 (Chakraborty, A.; Saha, B. B.; Ng, K. C.; Koyama, S.; Srinivasan, K. Langmuir 2009, 25, 2204). A thermodynamic framework is presented to capture the relationship between the specific surface area (Ai) and the energy factor, and the surface structural and the surface energy heterogeneity distribution factors are analyzed. Using the outlined approach, the maximum possible amount of adsorbate uptake has been evaluated and compared with experimental data. It is found that the adsorbents with higher specific surface areas tend to possess lower heat of adsorption (ΔH°) at the Henry regime. In this paper, we have established the definitive relation between Ai and ΔH° for (i) carbonaceous materials, metal organic frameworks (MOFs), carbon nanotubes, zeolites + hydrogen, and (ii) activated carbons + methane systems. The proposed theoretical framework of At and AH0 provides valuable guides for researchers in developing advanced porous adsorbents for methane and hydrogen uptake. © 2009 American Chemical Society.

  18. Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer.

    Science.gov (United States)

    Siraj, Abdul K; Prabhakaran, Sarita; Bavi, Prashant; Bu, Rong; Beg, Shaham; Hazmi, Mohsen Al; Al-Rasheed, Maha; Al-Assiri, Mohammed; Sairafi, Rami; Al-Dayel, Fouad; Al-Sanea, Nasser; Uddin, Shahab; Al-Kuraya, Khawla S

    2015-06-01

    Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives. © 2015 American Cancer Society.

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

    Science.gov (United States)

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

    2015-04-01

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

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

    Science.gov (United States)

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

    2014-12-01

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

  1. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome.

    Science.gov (United States)

    Nebgen, Denise R; Lu, Karen H; Rimes, Sue; Keeler, Elizabeth; Broaddus, Russell; Munsell, Mark F; Lynch, Patrick M

    2014-10-01

    Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification

    Directory of Open Access Journals (Sweden)

    Alessia Tognetto

    2017-09-01

    Full Text Available BackgroundLynch syndrome (LS is the most common hereditary colon cancer syndrome, accounting for 3–5% of colorectal cancer (CRC cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS.MethodsWe performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate.ResultsWe identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%.ConclusionThis systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.

  3. The Risk of Extra-colonic, Extra-endometrial Cancer in the Lynch Syndrome

    Science.gov (United States)

    Watson, Patrice; Vasen, Hans F.A.; Mecklin, Jukka-Pekka; Bernstein, Inge; Aarnio, Markku; Järvinen, Heikki J.; Myrhøj, Torben; Sunde, Lone; Wijnen, Juul T.; Lynch, Henry T.

    2009-01-01

    Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract, and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less-common cancers require accurate, age-specific risk estimation. We pooled data from four LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6041 members of 261 families with LS-associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N=98) had an overall lifetime risk (to age 70) of 8.4% (95%CI: 6.6–10.8); risks were higher in males (p<0.02) and members of MSH2 families (p<0.0001). Ovarian cancer (N=72) had an lifetime risk of 6.7% (95%CI: 5.3–9.1); risks were higher in women born after the median year of birth (p<0.008) and in members of MSH2 families (p<0.006). Brain tumors and cancers of the small bowel, stomach, breast, and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions. PMID:18398828

  4. A comparison between Lynch syndrome and sporadic colorectal cancer survivors' satisfaction with their healthcare providers.

    Science.gov (United States)

    Burton-Chase, Allison M; Parker, Wendy M; Polivka, Katrina M; Gritz, Ellen R; Amos, Christopher I; Lu, Karen H; Lynch, Patrick M; Rodriguez-Bigas, Miguel A; Nancy You, Y; Peterson, Susan K

    2017-03-01

    This study evaluated provider satisfaction in a sample of colorectal cancer (CRC) survivors with and without Lynch syndrome (LS). Participants were case-case-matched CRC survivors with (n = 75) or without (n = 75) LS (mean age of 55; range: 27-93). Participants completed a mailed questionnaire assessing demographics, clinical characteristics, healthcare utilization, psychosocial variables, and provider satisfaction. LS CRC survivors reported lower provider satisfaction scores on three subscales of the Primary Care Assessment Survey: communication (78.14 vs. 83.96; P < 0.05), interpersonal treatment (78.58 vs. 85.30; P < 0.05), and knowledge of the patient (60.34 vs. 69.86; P < 0.01). Among LS CRC survivors, predictors for mean communication and trust subscale scores were location of treatment and socioeconomic status. Higher mean depression scores also were associated with trust, while social support predicted higher satisfaction with communication. Sporadic CRC survivor satisfaction is driven largely by age (communication, interpersonal treatment) and patient anxiety (communication), while seeing a provider more often was associated with increased satisfaction with knowledge of the patient. LS CRC survivors reported lower levels of provider satisfaction than sporadic CRC survivors. LS survivors who received care at The University of Texas MD Anderson Cancer Center, a comprehensive cancer center (CCC), reported higher satisfaction than those receiving care at other institutions. Depressive symptoms and socioeconomic status may impact provider satisfaction ratings. Exploration of other potential predictors of provider satisfaction should be examined in this population. Additionally, further research is needed to examine the potential impact of provider satisfaction on adherence to medical recommendations in LS CRC survivors, particularly those being treated outside of CCCs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  5. Teaching the “Grandsons of Balzac” a Lesson: Henry James in the 1890’s

    Directory of Open Access Journals (Sweden)

    Dennis F. TREDY

    2004-06-01

    Full Text Available Lyall H. Powers, in Henry James and the Naturalist Movement, dubs the period spanning from “The Art of Fiction” in 1884 to The Tragic Muse in 1890 Henry James’s “Naturalist Experiment”, and rightfully so (Powers 3. There is much evidence, in James’s own notebooks, that The Bostonians was influenced by Daudet’s L’Évangeliste, The Princess Casamassima by Turgeneff’s Virgin Soil, and The Tragic Muse by the narrative techniques of Maupassant (NB 47, Powers 91, NB 92, and Powers effectively show...

  6. Endoscopic detection rate of sessile serrated lesions in Lynch syndrome patients is comparable with an age- and gender-matched control population: case-control study with expert pathology review.

    Science.gov (United States)

    Vleugels, Jasper L A; Sahin, Husna; Hazewinkel, Yark; Koens, Lianne; van den Berg, Jose G; van Leerdam, Monique E; Dekker, Evelien

    2018-05-01

    Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) because of microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients with a matched control population. We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals. Control subjects undergoing elective colonoscopy from 2011 and onward for symptoms or surveillance were selected from a prospectively collected database. Patients were matched 1:1 for age, gender, and index versus surveillance colonoscopy. An expert pathology review of serrated polyps was performed. The primary outcomes included the detection rates and distribution of SSLs. We identified 321 patients with Lynch syndrome who underwent at least 1 colonoscopy. Of these, 223 Lynch syndrome patients (mean age, 49.3; 59% women; index colonoscopy, 56%) were matched to 223 control subjects. SSLs were detected in 7.6% (95% confidence interval, 4.8-11.9) of colonoscopies performed in Lynch syndrome patients and in 6.7% (95% confidence interval, 4.1-10.8) of control subjects (P = .86). None of the detected SSLs in Lynch syndrome patients contained dysplasia. The detection rate of SSLs in Lynch syndrome patients undergoing colonoscopy is comparable with a matched population. These findings suggest that the role of the serrated neoplasia pathway in CRC development in Lynch syndrome seems to be comparable with that in the general population. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

  7. Mapping Henry: Synchrotron-sourced X-ray fluorescence mapping and ultra-high-definition scanning of an early Tudor portrait of Henry VIII

    Energy Technology Data Exchange (ETDEWEB)

    Dredge, Paula; Ives, Simon [Art Gallery of New South Wales (AGNSW), Sydney, NSW (Australia); Howard, Daryl L.; Spiers, Kathryn M. [Australian Synchrotron, Clayton, VIC (Australia); Yip, Andrew [Art Gallery of New South Wales (AGNSW), Sydney, NSW (Australia); University of New South Wales, Laboratory for Innovation in Galleries, Libraries, Archives and Museums (iGLAM), National Institute for Experimental Arts, Sydney, NSW (Australia); Kenderdine, Sarah [University of New South Wales, Laboratory for Innovation in Galleries, Libraries, Archives and Museums (iGLAM), National Institute for Experimental Arts, Sydney, NSW (Australia)

    2015-11-15

    A portrait of Henry VIII on oak panel c. 1535 has recently undergone technical examination to inform questions regarding authorship and the painting's relationship to a group of similar works in the collections of the National Portrait Gallery, London, and the Society of Antiquaries. Due to previous conservation treatments of the painting, the conventional transmission X-radiograph image was difficult to interpret. As a result, the painting underwent high-definition X-ray fluorescence (XRF) elemental mapping on the X-ray fluorescence microscopy beamline of the Australian Synchrotron. Scans were conducted at 12.6 and 18.5 keV, below and above the lead (Pb) L edges, respectively. Typical scan parameters were 120 μm pixel size at 7 ms dwell time, with the largest scan covering an area 545 x 287 mm{sup 2} collected in 23 h (10.8 MP). XRF mapping of the panel has guided the conservation treatment of the painting and the revelation of previously obscured features. It has also provided insight into the process of making of the painting. The informative and detailed elemental maps, alongside ultra-high-definition scans of the painting undertaken before and after varnish and over-paint removal, have assisted in comparison of the finely painted details with the London paintings. The resolution offered by the combination of imaging techniques identifies pigment distribution at an extremely fine scale, enabling a new understanding of the artist's paint application. (orig.)

  8. Mapping Henry: Synchrotron-sourced X-ray fluorescence mapping and ultra-high-definition scanning of an early Tudor portrait of Henry VIII

    International Nuclear Information System (INIS)

    Dredge, Paula; Ives, Simon; Howard, Daryl L.; Spiers, Kathryn M.; Yip, Andrew; Kenderdine, Sarah

    2015-01-01

    A portrait of Henry VIII on oak panel c. 1535 has recently undergone technical examination to inform questions regarding authorship and the painting's relationship to a group of similar works in the collections of the National Portrait Gallery, London, and the Society of Antiquaries. Due to previous conservation treatments of the painting, the conventional transmission X-radiograph image was difficult to interpret. As a result, the painting underwent high-definition X-ray fluorescence (XRF) elemental mapping on the X-ray fluorescence microscopy beamline of the Australian Synchrotron. Scans were conducted at 12.6 and 18.5 keV, below and above the lead (Pb) L edges, respectively. Typical scan parameters were 120 μm pixel size at 7 ms dwell time, with the largest scan covering an area 545 x 287 mm 2 collected in 23 h (10.8 MP). XRF mapping of the panel has guided the conservation treatment of the painting and the revelation of previously obscured features. It has also provided insight into the process of making of the painting. The informative and detailed elemental maps, alongside ultra-high-definition scans of the painting undertaken before and after varnish and over-paint removal, have assisted in comparison of the finely painted details with the London paintings. The resolution offered by the combination of imaging techniques identifies pigment distribution at an extremely fine scale, enabling a new understanding of the artist's paint application. (orig.)

  9. Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.

    Science.gov (United States)

    van der Klift, Heleen M; Tops, Carli M; Hes, Frederik J; Devilee, Peter; Wijnen, Juul T

    2012-07-01

    Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders. © 2012 Wiley Periodicals, Inc.

  10. Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers.

    Science.gov (United States)

    Hiatt, Molly J; Casey, Murray Joseph; Lynch, Henry T; Snyder, Carrie L; Stacey, Mark; Walters, Ryan W

    2017-11-08

    This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers. Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery. One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery. Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers. Lynch syndrome mutation carriers are still at 27% risk for metachronous colorectal cancer after proximal colectomy for right-sided first colorectal cancers, but this study found no difference in survival through 25 years follow-up compared with those treated with total and subtotal colectomy. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. La mujer en el radiador en Cabeza borradora (Eraserhead, 1972-1976) de David Lynch: disección utópica del ojo

    OpenAIRE

    Villaplana Ruiz, Virginia

    1998-01-01

    Villaplana, V. (1998). La mujer en el radiador en Cabeza borradora (Eraserhead, 1972-1976) de David Lynch: disección utópica del ojo. Banda aparte. (11):29-31. http://hdl.handle.net/10251/43165. 29 31 11

  12. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

    NARCIS (Netherlands)

    Klift, H.M. van der; Mensenkamp, A.R.; Drost, M.; Bik, E.C.; Vos, Y.J.; Gille, H.J.; Redeker, B.E.; Tiersma, Y.; Zonneveld, J.B.; Garcia, E.G.; Letteboer, T.G.; Olderode-Berends, M.J.; Hest, L.P. van; Os, T.A. van; Verhoef, S.; Wagner, A.; Asperen, C.J. van; Broeke, S.W. ten; Hes, F.J.; Wind, N. de; Nielsen, M.; Devilee, P.; Ligtenberg, M.J.L.; Wijnen, J.T.; Tops, C.M.

    2016-01-01

    Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are

  13. Development of in vitro and in vivo functional assays to enable diagnosis of Variants of Uncertain Significance in the common cancer predisposition Lynch syndrome

    NARCIS (Netherlands)

    Drost, Mark

    2014-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose

  14. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

    NARCIS (Netherlands)

    van der Klift, Heleen M.; Mensenkamp, Arjen R.; Drost, Mark; Bik, Elsa C.; Vos, Yvonne J.; Gille, Hans J. J. P.; Redeker, Bert E. J. W.; Tiersma, Yvonne; Zonneveld, Jose B. M.; Garcia, Encarna Gomez; Letteboer, Tom G. W.; Olderode-Berends, Maran J. W.; van Hest, Liselotte P.; van Os, Theo A.; Verhoef, Senno; Wagner, Anja; van Asperen, Christi J.; ten Broeke, Sanne W.; Hes, Frederik J.; de Wind, Niels; Nielsen, Maartje; Devilee, Peter; Ligtenberg, Marjolijn J. L.; Wijnen, Juul T.; Tops, Carli M. J.

    Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are

  15. Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

    NARCIS (Netherlands)

    Klift, H.M. van der; Tops, C.M.; Bik, E.C.; Boogaard, M.W.; Borgstein, A.M.; Hansson, K.B.; Ausems, M.G.E.M.; Gomez Garcia, E.; Green, A.; Hes, F.J.; Izatt, L.; Hest, L.P. van; Alonso, A.M.; Vriends, A.H.; Wagner, A.; Zelst-Stams, W.A.G. van; Vasen, H.F.; Morreau, H.; Devilee, P.; Wijnen, J.T.

    2010-01-01

    Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We

  16. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome

    NARCIS (Netherlands)

    van der Klift, Heleen M; Mensenkamp, Arjen R; Drost, Mark; Bik, Elsa C; Vos, Yvonne J; Gille, Hans J J P; Redeker, Bert E J W; Tiersma, Yvonne; Zonneveld, José B M; García, Encarna Gómez; Letteboer, Tom G W; Olderode-Berends, Maran J W; van Hest, Liselotte P; van Os, Theo A; Verhoef, Senno; Wagner, Anja; van Asperen, Christi J; Ten Broeke, Sanne W; Hes, Frederik J; de Wind, Niels; Nielsen, Maartje; Devilee, Peter; Ligtenberg, Marjolijn J L; Wijnen, Juul T; Tops, Carli M J

    2016-01-01

    Monoallelic PMS2 germline mutations cause 5-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional MMR deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA and RNA-based strategies are applied to

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

    Science.gov (United States)

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

    2017-03-01

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

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

    Science.gov (United States)

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

    2015-10-01

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

  19. A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

    DEFF Research Database (Denmark)

    Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

    2011-01-01

    Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...

  20. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer : a report from the prospective Lynch syndrome database

    NARCIS (Netherlands)

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

    2016-01-01

    Objective Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do

  1. Dietary B vitamin and methionine intake and MTHFR C677T genotype on risk of colorectal tumors in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Jung, A.Y.; van Duijnhoven, F.J.B.; Nagengast, F.M.; Botma, A.; Heine-Broring, R.C.; Kleibeuker, J.H.; Vasen, H.F.A.; Harryvan, J.L.; Winkels, R.M.; Kampman, E.

    2014-01-01

    Purpose: Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given

  2. Prospective, Multi-center Randomized Intermediate Biomarker Study of Oral Contraceptive vs. Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

    Science.gov (United States)

    Lu, Karen H.; Loose, David S.; Yates, Melinda S.; Nogueras-Gonzalez, Graciela M.; Munsell, Mark F.; Chen, Lee-may; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S.; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M.; Broaddus, Russell R.

    2013-01-01

    Women with Lynch syndrome have a 40–60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have demonstrated that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown if they are effective in women with Lynch syndrome. Asymptomatic women age 25–50 with Lynch syndrome were randomized to receive the progestin compounds depo-Provera (depoMPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were performed before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depoMPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results demonstrate that women with Lynch syndrome do show an endometrial response to short term exogenous progestins, suggesting that OCP and depoMPA may be reasonable chemopreventive agents in this high-risk patient population. PMID:23639481

  3. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.

    Science.gov (United States)

    Lu, Karen H; Loose, David S; Yates, Melinda S; Nogueras-Gonzalez, Graciela M; Munsell, Mark F; Chen, Lee-May; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M; Broaddus, Russell R

    2013-08-01

    Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population.

  4. Community Practice Implementation of a Self-administered Version of PREMM1,2,6 to Assess Risk for Lynch Syndrome.

    Science.gov (United States)

    Luba, Daniel G; DiSario, James A; Rock, Colleen; Saraiya, Devki; Moyes, Kelsey; Brown, Krystal; Rushton, Kristen; Ogara, Maydeen M; Raphael, Mona; Zimmerman, Dayna; Garrido, Kimmie; Silguero, Evelyn; Nelson, Jonathan; Yurgelun, Matthew B; Kastrinos, Fay; Wenstrup, Richard J; Syngal, Sapna

    2018-01-01

    Lynch syndrome is a genetic disorder that greatly increases risk for colorectal and other cancers, although it is underdiagnosed. Prediction of MLH1, MSH2, and MSH6 (PREMM 1,2,6 ) is a web-based tool that analyzes individuals' personal/family histories of cancer to quantify their likelihood of carrying a germline mutation associated with Lynch syndrome. We investigated the feasibility of systematic risk assessment for Lynch syndrome in a community gastroenterology practice using a patient-completed version of PREMM 1,2,6 . PREMM 1,2,6 was adapted into a computer tablet version designed for self-administration by patients. Individuals presenting to a community gastroenterology office and endoscopy facility in California completed the PREMM 1,2,6 assessment before their visit (n = 3134). The total study duration (8 months) comprised a 2-month initiation period (May 1-June 30, 2013) and a 6-month study period (July 1-December 31, 2013). Genetic counseling and germline analysis for mutations in genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) were offered to individuals with PREMM 1,2,6 scores of 5% or higher. Patients and providers completed surveys to evaluate the feasibility and satisfaction with the process. Of the 3134 individuals assessed by PREMM 1,2,6 during the 6-month study period, 177 individuals (5.6%) had scores of 5% or higher. Of these, 146 individuals underwent genetic testing, along with 28 additional participants recruited nonconsecutively during the initiation period. Mutations associated with Lynch syndrome were detected in 3 of the 146 individuals (2.1%) with PREMM 1,2,6 scores of 5% or higher who underwent germline testing, and 3 of the 28 patients (10.7%) recruited during study initiation with PREMM 1,2,6 scores of 5% or higher. Of the participants who underwent genetic analysis, 98.6% stated that they understood the information provided to them. All of the surveyed providers stated that they were satisfied with the

  5. Exploring clinicians' attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no personal diagnosis of colorectal cancer.

    Science.gov (United States)

    Chen, Yanni; Peate, Michelle; Kaur, Rajneesh; Meiser, Bettina; Wong, Tim; Kirk, Judy; Ward, Robyn L; Goodwin, Annabel; Macrae, Finlay; Hiller, Janet; Trainer, Alison H; Mitchell, Gillian

    2017-01-01

    Recent research has shown that aspirin reduces the risk of cancers associated with Lynch Syndrome. However, uncertainty exists around the optimal dosage, treatment duration and whether the benefits of aspirin as a risk-reducing medication (RRM) outweigh adverse medication related side-effects. Little is known about clinicians' attitudes, current practice, and perceived barriers to recommending aspirin as a RRM. To explore the attitudes of clinicians who discuss risk management options with patients with Lynch Syndrome towards using aspirin as a RRM. Clinicians were invited through professional organisations to complete an online survey. Topics included their clinical experience with Lynch Syndrome, views and practice of recommending aspirin as a RRM, and knowledge about clinical risk management guidelines for Lynch Syndrome. Comparison of attitudes was made between three professional groups. 181 respondents were included in the analysis: 59 genetics professionals (genetic counsellors and clinical geneticists, medical oncologists with specialist training in familial cancer), 49 gastroenterologists and 73 colorectal surgeons. Most clinicians (76 %) considered aspirin to be an effective RRM and most (72 %) were confident about discussing it. In all professional categories, those who were confident about discussing aspirin with patients perceived it to be an effective RRM (OR = 2.8 [95 % CI = 1.8-4.2], p Lynch Syndrome patients compared to 69 % of gastroenterologists and 68 % of colorectal surgeons. Those who considered aspirin as an effective RRM or who felt confident in their knowledge of the aspirin literature were more likely (OR = 10 [95 % CI = 1.5-65], p = 0.010, OR = 6 [95 % CI = 2.2-16], p Lynch Syndrome per year were more likely to be confident in their knowledge of the aspirin literature and discussing it with patients (OR = 4.1 [95 % CI = 1.6-10.2], p = 0.003). Explicit recommendations to take aspirin, was reported by 65

  6. Publicações póstumas de Henri Fayol: revisitando sua teoria administrativa.

    Directory of Open Access Journals (Sweden)

    Edson Miranda de Souza

    2011-02-01

    Full Text Available O engenheiro francês Henri Fayol (1841-1925 é usualmente apresentado aos estudantes de Administração como o Pai da Escola Clássica de Administração, o que demonstra uma representação limitada da amplitude de sua contribuição para a evolução do pensamento administrativo. Além disso, é frequentemente associado ao seu contemporâneo, o teórico norte-americano Frederick Taylor, sendo aos dois atribuída a defesa de um modelo autoritário de administração. Entretanto, recentemente, pesquisadores descobriram, através do exame de documentos raros e inéditos, um desconhecido retrato desse pioneiro. Este trabalho resulta de uma investigação que buscou levantar fontes de informação bibliográfica disponíveis, publicadas ou não, incluindo resultados de trabalhos de pesquisadores da França, dos Estados Unidos, do Canadá, da Austrália e do Japão. Esses pesquisadores compõem um reduzido grupo de estudiosos, aqui denominados “novos fayolistas” porque retomam, depois de anos de quase amnésia no meio acadêmico, o interesse pelas contribuições de Henri Fayol. Tais estudos revelam conceitos desenvolvidos por Fayol que antecipam aspectos de teorias e práticas da Administração que, somente mais tarde, seriam desenvolvidas, como a Escola de Relações Humanas, a Teoria Contingencial e o Planejamento Estratégico. Ao apresentar as recentes pesquisas sobre o homem e o teórico Henri Fayol, este estudo permite, aos docentes e estudantes de língua portuguesa, acesso a escritos e palestras de sua autoria que, até então, permaneciam desconhecidos.

  7. Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer.

    Science.gov (United States)

    Yamada, Rin; Yamaguchi, Tatsuro; Iijima, Takeru; Wakaume, Rika; Takao, Misato; Koizumi, Koichi; Hishima, Tsunekazu; Horiguchi, Shin-Ichiro

    2018-06-01

    The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55-37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50-45.0, P = 0.176). Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

  8. Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

    Science.gov (United States)

    Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano

    2018-04-01

    Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

  9. The study of patient henry Molaison and what it taught us over past 50 years: Contributions to neuroscience

    Directory of Open Access Journals (Sweden)

    Bigya Shah

    2014-01-01

    Full Text Available This section provides a historical perspective and contributions from one of the most studied patients in neuroscience, Henry Molaison (1926-2008, known as H.M during his life to protect his privacy. The peculiar memory deficits seen after an experimental operation for intractable epilepsy led to some critical discoveries pertaining to memory organization in human brain.

  10. All Are Worthy to Know the Earth: Henry De la Beche and the Origin of Geological Literacy

    Science.gov (United States)

    Clary, Renee M.; Wandersee, James H.

    2009-01-01

    Henry T. De la Beche (1796-1855) began his geological career within an elite circle (Geological Society of London, 1817; FRS, 1819), collaborating with influential gentlemen geologists and publishing original research. When his independent income dwindled, De la Beche managed to secure governmental funding for his mapping projects. This led to…

  11. "Undoubtedly a Powerful Influence": Victor Henry's "Antinomies linguistiques" (1896) with an Annotated Translation of the First Chapter.

    Science.gov (United States)

    Joseph, John E.

    1996-01-01

    Discusses Victor Henry's innovative presentation of some underlying contradictions in the premises on which linguistics is founded, cast in the Kantian form of antinomies. The review argues that no science remains more strongly contested than linguistics, a science whose origins are paradoxical and that contains outdated concepts. (30 references)…

  12. Measurement of Henry's Law Constants Using Internal Standards: A Quantitative GC Experiment for the Instrumental Analysis or Environmental Chemistry Laboratory

    Science.gov (United States)

    Ji, Chang; Boisvert, Susanne M.; Arida, Ann-Marie C.; Day, Shannon E.

    2008-01-01

    An internal standard method applicable to undergraduate instrumental analysis or environmental chemistry laboratory has been designed and tested to determine the Henry's law constants for a series of alkyl nitriles. In this method, a mixture of the analytes and an internal standard is prepared and used to make a standard solution (organic solvent)…

  13. The discovery of uranic rays: a short step for Henri Becquerel but a giant step for science

    International Nuclear Information System (INIS)

    Genet, M.

    1995-01-01

    In March 1896, Antoine Henri Becquerel discovered radioactivity. This success is largely due to a tradition of high-level scientific research which prevailed over three generations in the Becquerel family. The circumstances of the discovery and the controversies which followed are reviewed within the framework of their scientific and historical context. (orig.)

  14. Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.

    Directory of Open Access Journals (Sweden)

    Felipe Carneiro da Silva

    Full Text Available Lynch syndrome (LS accounts for 3-5% of all colorectal cancers (CRC and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR, mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2, and 11 variants of unknown significance (VUS were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45, whereas the three MMR genes (MSH6, PMS1 and PMS2 accounted for 11% (5/45. We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.

  15. Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan.

    Directory of Open Access Journals (Sweden)

    Ying-Erh Chen

    Full Text Available Patients with Lynch syndrome (LS have a significantly increased risk of developing colorectal cancer (CRC and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes (i.e., the DNA mismatch repair genes in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population-specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing

  16. A Note on Child Neglect in American Victorianism: Henry James’ "The Pupil"

    Directory of Open Access Journals (Sweden)

    F. Gül KOÇSOY

    2016-12-01

    Full Text Available In this study, the theme of “neglected child” in Henry James’ “The Pupil” (1891 is explored. Morgan is a neglected child with unscrupulous parents who hold strictly on the Victorian values which reflect American cultural consciousness in the last decades of 19th century. Although he is a brilliant boy, the family does not love him; because he reminds them of their vulgarity. They neglect him physically and emotionally, seeing him as a burden. Although his tutor tries to keep the boy from the family’s corruption, he contributes to his death; he neglects his illness and deserts him when he is most needy. As an interpreter, James draws attention to the situation of children that are not working but being tutored at home. He criticizes this culture’s general attitude towards children. It is a disturbing social reality and he shows how that materialistic culture victimizes children in terms of neglectful parenting

  17. Design of a gap tunable flux qubit with FastHenry

    Science.gov (United States)

    Akhtar, Naheed; Zheng, Yarui; Nazir, Mudassar; Wu, Yulin; Deng, Hui; Zheng, Dongning; Zhu, Xiaobo

    2016-12-01

    In the preparations of superconducting qubits, circuit design is a vital process because the parameters and layout of the circuit not only determine the way we address the qubits, but also strongly affect the qubit coherence properties. One of the most important circuit parameters, which needs to be carefully designed, is the mutual inductance among different parts of a superconducting circuit. In this paper we demonstrate how to design a gap-tunable flux qubit by layout design and inductance extraction using a fast field solver FastHenry. The energy spectrum of the gap-tunable flux qubit shows that the measured parameters are close to the design values. Project supported by the National Natural Science Foundation of China (Grant Nos. 11374344, 11404386, and 91321208), the National Basic Research Program of China (Grant No. 2014CB921401), and the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB07010300).

  18. Henri Mitterand – Critique génétique et sociocritique

    OpenAIRE

    Mitterand, Henri; Biasi, Pierre-Marc de; Herschberg Pierrot, Anne

    2013-01-01

    Henri Mitterand est l’un des fondateurs de la sociocritique en France, et de la génétique zolienne. Il est aussi linguiste, sémioticien et stylisticien. Nous l’avons interrogé sur les relations complexes de la génétique et de la sociocritique. Sociocritique et sociogenèse Pierre-Marc de Biasi – Après une trentaine d’années de recul et d’expérience, quelle place donneriez-vous à la sociocritique et à la sociogenèse dans la construction du nouveau rapport critique qui s’est institué avec les ma...

  19. The Right to the City: From Henri Lefebvre to the Analysis about the Contemporary Capitalist City

    Directory of Open Access Journals (Sweden)

    Frank Molano Camargo

    2016-06-01

    Full Text Available The right to the city, defined by Henri Lefebvre in 1967 as the right of urban inhabitants to build, decide and create the city, and make of it a privileged space of anti-capitalist struggle, is again at the center of political debate. Social scientists, social movements, international aid agencies and States take it as a benchmark for policy analysis and to discuss the urban changes in contemporary capitalist cities. This article discusses the assumptions made by Lefebvre in 1967 and the transformation that the concept of right to the city has had from authors such as David Harvey, Edward Soja and Ana Fani Alessandri Carlos.

  20. About Time. Physics, Philosophy and the Battle Between Albert Einstein and Henri Bergson

    Science.gov (United States)

    Frank, Adam

    The historical relationship between physics and philosophy has had many famous high and low points. The two function best when both can challenge and support each other. In this talk I explore the famous debate between Albert Einstein and Henri Bergson over the nature of time. While history rightly judged Einstein to have won the debate in terms of relativity, there were deeper aspects of Bergsons critique that remain unappreciated. We will explore the different ways philosophy approaches the issue of time. In particular, we will look at the Continental Schools\\x9D, such as Phenomenology, which brings a unique perspective to the debate lying outside the traditional approach of physicists. From this perspective questions related to the act of being an observer, its essential subjective nature and the proper context of physics can be explored.