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201. Evolving Insights into the Molecular Neuropathology of Diffuse Gliomas in Adults

Author

Barthel, Floris P., Johnson, Kevin C., Wesseling, Pieter, and Verhaak, Roel G.W.

Abstract

Recent advances in molecular analysis and genome sequencing have prompted a paradigm shift in neuropathology. This article discusses the discovery and clinical relevance of molecular biomarkers in diffuse gliomas in adults and how these biomarkers led to revision of the World Health Organization classification of these tumors. We relate progress in clinical classification to an overview of studies using molecular profiling to study gene expression and DNA methylation to categorize diffuse gliomas in adults and issues dealing with intratumoral heterogeneity. These efforts will refine the taxonomy of diffuse gliomas, facilitate selection of appropriate treatment regimens, and ultimately improve patient’s lives.

Published
2018
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202. GPs' referral to mental health care during the past 25 years

Author

Verhaak, P F, van de Lisdonk, E H, Bor, J H, and Hutschemaekers, G J

Subjects
Adult, Male, Mental Health Services, Adolescent, Mental Disorders, Infant, Newborn, Infant, Middle Aged, Child, Preschool, Humans, Female, Longitudinal Studies, Child, Family Practice, Referral and Consultation, Research Article, Aged, Netherlands
Abstract

Previous research has shown that mental disorder in the community has remained fairly constant over the past 30 years. As a result there has been a shift in mental health care from primary care to specialised mental health care. This shift should be visible in higher referral figures from general practice. In this longitudinal analysis of mental health referrals (1971 to 1997), the authors aimed to answer whether these higher referral rates have occurred, whether there are increases in referral for specific groups, and whether the referral pattern has changed. The results demonstrate an increase in referral rate with a factor of 4.5. It is concluded that we are witnessing a pull from mental health care together with a push from general practice, thus reinforcing each other.

Published
2000

203. Two-year course of depressive and anxiety disorders: Results from the Netherlands Study of Depression and Anxiety (NESDA)

Author

Penninx, B.W.J.H., Nolen, W.A., Lamers, F., Zitman, F.G., Smit, J.H., Spinhoven, P., Cuijpers, P., Jong, P.J. de, Marwijk, H.W.J. van, Meer, K. van der, Verhaak, P., Laurant, M.G.H., Graaf, R. de, Hoogendijk, W.J.G., Wee, N.J.A. van der, Ormel, J., Dyck, R. van, Beekman, A.T., Penninx, B.W.J.H., Nolen, W.A., Lamers, F., Zitman, F.G., Smit, J.H., Spinhoven, P., Cuijpers, P., Jong, P.J. de, Marwijk, H.W.J. van, Meer, K. van der, Verhaak, P., Laurant, M.G.H., Graaf, R. de, Hoogendijk, W.J.G., Wee, N.J.A. van der, Ormel, J., Dyck, R. van, and Beekman, A.T.

Abstract

Item does not contain fulltext, BACKGROUND: Whether course trajectories of depressive and anxiety disorders are different, remains an important question for clinical practice and informs future psychiatric nosology. This longitudinal study compares depressive and anxiety disorders in terms of diagnostic and symptom course trajectories, and examines clinical prognostic factors. METHODS: Data are from 1209 depressive and/or anxiety patients residing in primary and specialized care settings, participating in the Netherlands Study of Depression and Anxiety. Diagnostic and Life Chart Interviews provided 2-year course information. RESULTS: Course was more favorable for pure depression (n=267, median episode duration = 6 months, 24.5% chronic) than for pure anxiety (n=487, median duration = 16 months, 41.9% chronic). Worst course was observed in the comorbid depression-anxiety group (n=455, median duration > 24 months, 56.8% chronic). Independent predictors of poor diagnostic and symptom trajectory outcomes were severity and duration of index episode, comorbid depression-anxiety, earlier onset age and older age. With only these factors a reasonable discriminative ability (C-statistic 0.72-0.77) was reached in predicting 2-year prognosis. LIMITATION: Depression and anxiety cases concern prevalent - not incident - cases. This, however, reflects the actual patient population in primary and specialized care settings. CONCLUSIONS: Their differential course trajectory justifies separate consideration of pure depression, pure anxiety and comorbid anxiety-depression in clinical practice and psychiatric nosology.

Published
2011

205. Perceived need for mental health care and barriers to care in the Netherlands and Australia

Author

Prins, M, Meadows, G, Bobevski, I, Graham, A, Verhaak, P, van der Meer, K, Penninx, B, Bensing, J, Prins, M, Meadows, G, Bobevski, I, Graham, A, Verhaak, P, van der Meer, K, Penninx, B, and Bensing, J

Abstract

PURPOSE: This study of Australian and Dutch people with anxiety or depressive disorder aims to examine people's perceived needs and barriers to care, and to identify possible similarities and differences. METHODS: Data from the Australian National Survey of Mental Health and Well-Being and the Netherlands Study of Depression and Anxiety were combined into one data set. The Perceived Need for Care Questionnaire was taken in both studies. Logistic regression analyses were performed to check if similarities or differences between Australia and the Netherlands could be observed. RESULTS: In both countries, a large proportion had unfulfilled needs and self-reliance was the most frequently named barrier to receive care. People from the Australian sample (N = 372) were more likely to perceive a need for medication (OR 1.8; 95% CI 1.3-2.5), counselling (OR 1.4; 95% CI 1.0-2.0) and practical support (OR 1.8; 95% CI 1.2-2.7), and people's overall needs in Australia were more often fully met compared with those of the Dutch sample (N = 610). Australians were more often pessimistic about the helpfulness of medication (OR 3.8; 95% CI 1.4-10.7) and skills training (OR 3.0; 95% CI 1.1-8.2) and reported more often financial barriers for not having received (enough) information (OR 2.4; 95% CI 1.1-5.5) or counselling (OR 5.9; 95% CI 2.9-11.9). CONCLUSIONS: In both countries, the vast majority of mental health care needs are not fulfilled. Solutions could be found in improving professionals' skills or better collaboration. Possible explanations for the found differences in perceived need and barriers to care are discussed; these illustrate the value of examining perceived need across nations and suggest substantial commonalities of experience across the two countries.

Published
2011

206. Which physician and practice characteristics are associated with adherence to evidence-based guidelines for depressive and anxiety disorders?

Author

Smolders, M., Laurant, M.G.H., Verhaak, P., Prins, M., Marwijk, H. van, Penninx, B.W.J.H., Wensing, M.J.P., Grol, R.P.T.M., Smolders, M., Laurant, M.G.H., Verhaak, P., Prins, M., Marwijk, H. van, Penninx, B.W.J.H., Wensing, M.J.P., and Grol, R.P.T.M.

Abstract

1 maart 2010, Contains fulltext : 87437.pdf (publisher's version ) (Closed access), BACKGROUND: Research on quality of care for depressive and anxiety disorders has reported low rates of adherence to evidence-based depression and anxiety guidelines. To improve this care, we need a better understanding of the factors determining guideline adherence. OBJECTIVE: To investigate how practice- and professional-related factors are associated with adherence to these guidelines. DESIGN: Cross-sectional cohort study. PARTICIPANTS: A total of 665 patients with a composite interview diagnostic instrument diagnosis of depressive or anxiety disorders, and 62 general practitioners from 21 practices participated. MEASURES: Actual care data were derived from electronic medical record data. The measurement of guideline adherence was based on performance indicators derived from evidence-based guidelines. Practice-, professional-, and patient-related characteristics were measured with questionnaires. The characteristics associated with guideline adherence were assessed by multivariate multilevel regression analysis. RESULTS: A number of practice and professional characteristics showed a significant univariate association with guideline adherence. The multivariate multilevel analyses revealed that, after controlling for patient characteristics, higher rates of guideline adherence were associated with stronger confidence in depression identification, less perceived time limitations, and less perceived barriers for guideline implementation. These professional-related determinants differed among the overall concept of guideline adherence and the various treatment options. CONCLUSIONS: This study showed that rates of adherence to guidelines on depressive and anxiety disorders were not associated with practice characteristics, but to some extent with physician characteristics. Although most of the identified professional-related determinants are very difficult to change, our results give some directions for improving depression and anxiety care.

Published
2010

207. The course of untreated anxiety and depression, and determinants of poor one-year outcome: a one-year cohort study

Author

van Beljouw, I.M.J., Verhaak, P., Cuijpers, P., van Marwijk, H.W.J., Penninx, B.W.J.H., van Beljouw, I.M.J., Verhaak, P., Cuijpers, P., van Marwijk, H.W.J., and Penninx, B.W.J.H.

Abstract

Background: Little is known about the course and outcome of untreated anxiety and depression in patients with and without a self-perceived need for care. The aim of the present study was to examine the one-year course of untreated anxiety and depression, and to determine predictors of a poor outcome.Method: Baseline and one-year follow-up data were used of 594 primary care patients with current anxiety or depressive disorders at baseline (established by the Composite Interview Diagnostic Instrument (CIDI)), from the Netherlands Study of Depression and Anxiety (NESDA). Receipt of and need for care were assessed by the Perceived Need for Care Questionnaire (PNCQ).Results: In depression, treated and untreated patients with a perceived treatment need showed more rapid symptom decline but greater symptom severity at follow-up than untreated patients without a self-perceived mental problem or treatment need. A lower education level, lower income, unemployment, loneliness, less social support, perceived need for care, number of somatic disorders, a comorbid anxiety and depressive disorder and symptom severity at baseline predicted a poorer outcome in both anxiety and depression. When all variables were considered at the same time, only baseline symptom severity appeared to predict a poorer outcome in anxiety. In depression, a poorer outcome was also predicted by more loneliness and a comorbid anxiety and depressive disorder.Conclusion: In clinical practice, special attention should be paid to exploring the need for care among possible risk groups (e.g. low social economic status, low social support), and support them in making an informed decision on whether or not to seek treatment. © 2010 van Beljouw et al; licensee BioMed Central Ltd.

Published
2010
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208. Patient factors associated with guideline-concordant treatment of anxiety and depression in primary care

Author

Prins, M.A., Verhaak, P., Smolders, M., Laurant, M.G.H., van der Meer, K, Spreeuwenberg, P., van Marwijk, H.W.J., Penninx, B.W.J.H., Bensing, J.M., Prins, M.A., Verhaak, P., Smolders, M., Laurant, M.G.H., van der Meer, K, Spreeuwenberg, P., van Marwijk, H.W.J., Penninx, B.W.J.H., and Bensing, J.M.

Abstract

Objective: To identify associations of patient characteristics (predisposing, enabling and need factors) with guideline-concordant care for anxiety and depression in primary care. Design: Analysis of data from the Netherlands Study of Depression and Anxiety (NESDA). Participants: Seven hundred and twenty-one patients with a current anxiety or depressive disorder, recruited from 67 general practitioners (GPs), were included. Measures: Diagnoses according to the Diagnostic and Statistic Manual of Mental Disorders, fourth edition (DSM-IV) were made using a structured and widely validated assessment. Socio-demographic and enabling characteristics, severity of symptoms, disability, (under treatment for) chronic somatic conditions, perceived need for care, beliefs and evaluations of care were measured by questionnaires. Actual care data were derived from electronic medical records. Criteria for guideline-concordant care were based on general practice guidelines, issued by the Dutch College of General Practitioners. Results: Two hundred and eighty-one (39%) patients received guideline-concordant care. High education level, accessibility of care, comorbidity of anxiety and depression, and severity and disability scores were positively associated with receiving guideline-concordant care in univariate analyses. In multivariate multi-level logistic regression models, significant associations with the clinical need factors disappeared. Positive evaluations of accessibility of care increased the chance (OR∈=∈1.31; 95%-CI∈=∈1.05-1.65; p∈=∈0.02) of receiving guideline-concordant care, as well as perceiving any need for medication (OR∈=∈2.99; 95%-CI∈=∈1.84-4.85; p∈<∈0.001), counseling (OR∈=∈2.25; 95%-CI∈=∈1. 29-3.95; p∈=∈0.005) or a referral (OR∈=∈1.83; 95%-CI∈=∈1.09-3.09; p∈=∈0.02). A low educational level decreased the odds (OR∈=∈0.33; 95%-CI∈=∈0.11-0.98; p∈=∈0.04) of receiving guideline-concordant care. Conclusions: This study shows that education level, accessibility of care

Published
2010
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211. Adherence to evidence-based guidelines for depression and anxiety disorders is associated with recording of the diagnosis.

Author

Smolders, M., Laurant, M.G.H., Verhaak, P., Prins, M., Marwijk, H.W.J. van, Penninx, B.W.J.H., Wensing, M.J.P., Grol, R.P.T.M., Smolders, M., Laurant, M.G.H., Verhaak, P., Prins, M., Marwijk, H.W.J. van, Penninx, B.W.J.H., Wensing, M.J.P., and Grol, R.P.T.M.

Abstract

Contains fulltext : 79866.pdf (publisher's version ) (Closed access), OBJECTIVES: To assess professionals' adherence to evidence-based guidelines and to investigate whether or not this is influenced by recording of the diagnosis and symptom severity. METHOD: Analysis of baseline cross-sectional data of a cohort study of 721 primary care patients with a confirmed diagnosis of a depressive or anxiety disorder. Information on the management of depressive and anxiety disorders was gathered from the electronic medical patient records. Guideline adherence was measured by an algorithm, based on performance indicators. RESULTS: Forty-two percent of the patients with a depressive disorder was treated in accordance with the guideline, whereas 27% of the patients with an anxiety disorder received guideline-consistent care. The provision of care in line with current depression and anxiety guidelines was around 50% for persons with both types of disorders. Documentation of an International Classification of Primary Care diagnosis of depression or anxiety disorder appeared to have a strong influence on guideline adherence. Symptom severity, however, did not influence guideline adherence. CONCLUSIONS: Adherence to depression and anxiety guidelines can be improved, even when the general practitioner makes the diagnosis and records it. Data on actual health care delivery and quality of care provide insight and may be useful in developing quality improvement activities.

Published
2009

212. Studying a complex tumor: potential and pitfalls.

Author

Zheng, Siyuan, Chheda, Milan G, Verhaak, Roel GW, and Verhaak, Roel G W

Abstract

Glioblastoma multiforme is a histopathologically heterogeneous disease with few treatment options. Therapy based on genomic alterations is rapidly gaining popularity because of the high response rate and high specificity. DNA copy number and exon-sequencing studies of glioblastoma multiforme samples have revealed recurrent genomic alterations in genes such as TP53, EGFR, and IDH1, but to date, this has not resulted in novel glioblastoma multiforme therapies. Identification of expression subtypes has resulted in new insights such as the association between genomic abnormalities and expression signatures. This review describes the types of genomic studies that have been performed and that are underway, the most prominent results, and the implications of genomic research for the development of clinical treatment modalities. [ABSTRACT FROM AUTHOR]

Published
2012
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213. Depressed and a co-morbid condition: more psychotropics prescribed!

Author

Smolders, M., Laurant, M.G.H., Rijswijk, E. van, Mulder, J., Braspenning, J.C.C., Verhaak, P., Wensing, M.J.P., Grol, R.P.T.M., Smolders, M., Laurant, M.G.H., Rijswijk, E. van, Mulder, J., Braspenning, J.C.C., Verhaak, P., Wensing, M.J.P., and Grol, R.P.T.M.

Abstract

Contains fulltext : 69756.pdf (publisher's version ) (Closed access), BACKGROUND: Depression often occurs simultaneously with a variety of somatic, psychiatric, and social conditions. Knowledge about differences in the pharmacological treatment of depressed patients with and without co-morbidity is lacking. OBJECTIVE: To compare GPs' pharmacological treatment of depressed patients with and without co-morbidity. METHODS: Data were extracted from the computerized medical records of 77 general practices participating in the Dutch National Information Network of General Practice (LINH). We used diagnosis and prescription data of newly diagnosed depressed patients aged 18-65 years (n=4372). A mixed-model technique was used for analyzing the medical data. RESULTS: During the year after diagnosing depression, depressed patients who also suffered from chronic somatic or psychiatric morbidity were prescribed more psychotropics than patients with depression only. Prescription patterns of psychotropic drugs for depressed patients with and without co-morbid social problems differed only during the first 3 months after diagnosis. For the whole 1-year period after diagnosis, the pharmacological treatment of depression in patients with and without co-morbid social problems did not differ. CONCLUSION: Our results indicate that chronic somatic or psychiatric co-morbidity in depressed patients leads to higher GP prescription levels of psychotropics, whereas co-morbid social problems do not seem to influence GPs' pharmacological treatment decisions for depression.

Published
2008

214. The impact of co-morbidity on GPs' pharmacological treatment decisions for patients with an anxiety disorder.

Author

Smolders, M., Geurts-Laurant, M.G.H., Rijswijk, E. van, Mulder, J., Braspenning, J.C.C., Verhaak, P., Wensing, M.J.P., Grol, R.P.T.M., Smolders, M., Geurts-Laurant, M.G.H., Rijswijk, E. van, Mulder, J., Braspenning, J.C.C., Verhaak, P., Wensing, M.J.P., and Grol, R.P.T.M.

Abstract

Contains fulltext : 51466.pdf (publisher's version ) (Closed access), BACKGROUND: Co-morbidity may influence GPs' treatment decisions for patients with anxiety. However, knowledge about differences in the pharmacological treatment of anxiety disorders in patients with and without co-morbidity is lacking. OBJECTIVE: To compare GPs' pharmacological treatment patterns for anxiety in patients with and without co-morbidity. METHODS: Data were extracted from computerized medical records of 77 general practices participating in the Dutch National Information Network of General Practice (LINH). We used diagnosis and prescription data of patients, aged 18-65 years, with a newly diagnosed anxiety disorder (n = 4604). A mixed model technique was used to determine if there was a difference in the pharmacological treatment of anxiety with and without co-morbidity. RESULTS: During the year after diagnosing anxiety, anxious patients who also suffered from chronic somatic morbidity or social problems were prescribed more benzodiazepines (effect size [ES] = 0.44, 95% confidence interval [CI] = 0.16-0.72 and ES = 0.67, 95% CI = 0.22-1.25, respectively) but no more antidepressants than patients with anxiety only. Compared to patients with a single diagnosis of anxiety, anxious patients who suffered simultaneously from other psychiatric conditions received twice as many antidepressant prescriptions (ES = 2.07, 95% CI = 1.89-2.56) as well as twice as many benzodiazepine prescriptions (ES = 1.98, 95% CI = 1.84-2.60) during the year after diagnosing anxiety. For all subgroups, the prescription rate of benzodiazepines remained high throughout the year after diagnosing anxiety. CONCLUSION: Our results indicate that psychiatric co-morbidity in anxious patients leads to higher prescription levels of both antidepressants and benzodiazepines. Chronic somatic co-morbidity and co-morbid social problems also lead to higher prescription levels of benzodiazepines, but does not seem to influence GPs' prescribing of antidepressants. The prescription pattern of benzodiaz

Published
2007

215. Effects of a nationwide programme: interventions to reduce perceived barriers to collaboration and to increase structural one-on-one contact.

Author

Heideman, J.M.C., Geurts-Laurant, M.G.H., Verhaak, P., Wensing, M.J.P., Grol, R.P.T.M., Heideman, J.M.C., Geurts-Laurant, M.G.H., Verhaak, P., Wensing, M.J.P., and Grol, R.P.T.M.

Abstract

Contains fulltext : 52597.pdf (publisher's version ) (Closed access), OBJECTIVE: To describe the implementation of a nationwide programme and to determine the effects of specific quality improvement (QI) interventions within this programme on perceived barriers to collaboration between general practitioner (GPs) and mental health professionals and frequency of structural one-on-one contact regarding individual patients. METHODS: The implementation of regional QI-interventions, perceived barriers to collaboration, and frequency of structural one-on-one contact, were assessed in a cohort study involving two surveys (2001 and 2003) among a random sample of 2757 GPs. RESULTS: 1336 and 1358 GPs returned baseline and follow-up questionnaires respectively. Most of the interventions were only offered to a minority of GPs. Less than 25% of GPs that had been offered interventions actually participated. The frequency of structural one-on-one contact with mental health professionals did not change, but barriers to collaboration decreased between 2001 and 2003. For GPs who actually participated in interactive small group meetings or in intervention in which mental health professionals were integrated in general practice, a reduction of perceived barriers could be observed as well as an increase in the frequency of structural one-on-one contact. CONCLUSION: Interventions that could be characterized as interactive small group meetings as well as interventions that involved the integration of mental health professionals in general practice led to a reduction of perceived barriers as well as an increase in the frequency of structural one-on-one contact. These findings add to the knowledge of which interventions have an effect on the collaboration between different health care providers.

Published
2007

216. Parental quality of life in complex paediatric neurologic disorders of unknown aetiology.

Author

van Nimwegen, K.J.M., Kievit, W., van der Wilt, G.J., Schieving, J.H., Willemsen, M.A.A.P., Donders, A.R.T., Verhaak, C.M., and Grutters, J.P.C.

Abstract

Complex paediatric neurology (CPN) patients generally present with non-specific symptoms, such as developmental delay, impaired movement and epilepsy. The diagnostic trajectory in these disorders is usually complicated and long-lasting, and may be burdensome to the patients and their parents. Additionally, as caring for a chronically ill child can be stressful and demanding, parents of these patients may experience impaired health-related quality of life (HRQoL). This study aims to assess parental HRQoL and factors related to it in CPN. Physical and mental HRQoL of 120 parents was measured and compared to the general population using the SF-12 questionnaire. Parents also completed this questionnaire for the measurement of patient HRQoL. Additional questionnaires were used to measure parental uncertainty (Visual Analogue Scale) and worry phenomena (Penn State Worry Questionnaire), and to obtain socio-demographic data. A linear mixed model with random effect was used to investigate which of these variables were associated with parental HRQoL. As compared to the general population, HRQoL of these parents appeared diminished. Fathers showed both lowered physical (51.76, p < 0.05) and mental (49.41, p < 0.01) HRQoL, whereas mothers only showed diminished mental (46.46, p < 0.01) HRQoL. Patient HRQoL and parental worry phenomena were significantly correlated with overall and mental parental HRQoL. The reduction in parental mental HRQoL is alarming, also because children strongly rely on their parents and parental mental health is known to influence children's health. Awareness of these problems among clinicians, and supportive care if needed are important to prevent exacerbation of the problems. [ABSTRACT FROM AUTHOR]

Published
2016
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218. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

Author

Farshidfar, Farshad, Zheng, Siyuan, Gingras, Marie-Claude, Newton, Yulia, Shih, Juliann, Robertson, A. Gordon, Hinoue, Toshinori, Hoadley, Katherine A., Gibb, Ewan A., Roszik, Jason, Covington, Kyle R., Wu, Chia-Chin, Shinbrot, Eve, Stransky, Nicolas, Hegde, Apurva, Yang, Ju Dong, Reznik, Ed, Sadeghi, Sara, Pedamallu, Chandra Sekhar, Ojesina, Akinyemi I., Hess, Julian M., Auman, J. Todd, Rhie, Suhn K., Bowlby, Reanne, Borad, Mitesh J., Akbani, Rehan, Allotey, Loretta K., Ally, Adrian, Alvaro, Domenico, Andersen, Jesper B., Appelbaum, Elizabeth L., Arora, Arshi, Auman, J. Todd, Balasundaram, Miruna, Balu, Saianand, Bardeesy, Nabeel, Bathe, Oliver F., Baylin, Stephen B., Beroukhim, Rameen, Berrios, Mario, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S., Borad, Mitesh J., Bowen, Jay, Bowlby, Reanne, Bragazzi, Maria Consiglia, Brooks, Denise, Cardinale, Vincenzo, Carlsen, Rebecca, Carpino, Guido, Carvalho, Andre L., Chaiteerakij, Roongruedee, Chandan, Vishal C., Cherniack, Andrew D., Chin, Lynda, Cho, Juok, Choe, Gina, Chuah, Eric, Chudamani, Sudha, Cibulskis, Carrie, Cordes, Matthew G., Covington, Kyle R., Crain, Daniel, Curley, Erin, De Rose, Agostino Maria, Defreitas, Timothy, Demchok, John A., Deshpande, Vikram, Dhalla, Noreen, Ding, Li, Evason, Kimberley, Farshidfar, Farshad, Felau, Ina, Ferguson, Martin L., Foo, Wai Chin, Franchitto, Antonio, Frazer, Scott, Fronick, Catrina C., Fulton, Lucinda A., Fulton, Robert S., Gabriel, Stacey B., Gardner, Johanna, Gastier-Foster, Julie M., Gaudio, Eugenio, Gehlenborg, Nils, Genovese, Giannicola, Gerken, Mark, Getz, Gad, Giama, Nasra H., Gibbs, Richard A., Gingras, Marie-Claude, Giuliante, Felice, Grazi, Gian Luca, Hayes, D. Neil, Hegde, Apurva M., Heiman, David I., Hess, Julian M., Hinoue, Toshinori, Hoadley, Katherine A., Holbrook, Andrea, Holt, Robert A., Hoyle, Alan P., Huang, Mei, Hutter, Carolyn M., Jefferys, Stuart R., Jones, Steven J.M., Jones, Corbin D., Kasaian, Katayoon, Kelley, Robin K., Kim, Jaegil, Kleiner, David E., Kocher, Jean-Pierre A., Kwong, Lawrence N., Lai, Phillip H., Laird, Peter W., Lawrence, Michael S., Leraas, Kristen M., Lichtenberg, Tara M., Lin, Pei, Liu, Wenbin, Liu, Jia, Lolla, Laxmi, Lu, Yiling, Ma, Yussanne, Mallery, David, Mardis, Elaine R., Marra, Marco A., Matsushita, Marcus M., Mayo, Michael, McLellan, Michael D., McRee, Autumn J., Meier, Sam, Meng, Shaowu, Meyerson, Matthew, Mieczkowski, Piotr A., Miller, Christopher A., Mills, Gordon B., Moore, Richard A., Morris, Scott, Mose, Lisle E., Moser, Catherine D., Mounajjed, Taofic, Mungall, Andrew J., Mungall, Karen, Murray, Bradley A., Naresh, Rashi, Newton, Yulia, Noble, Michael S., O’Brien, Daniel R., Ojesina, Akinyemi I., Parker, Joel S., Patel, Tushar C., Paulauskis, Joseph, Pedamallu, Chandra Sekhar, Penny, Robert, Perou, Charles M., Perou, Amy H., Pihl, Todd, Radenbaugh, Amie J., Ramirez, Nilsa C., Rathmell, W. Kimryn, Reznik, Ed, Rhie, Suhn K., Roach, Jeffrey, Roberts, Lewis R., Robertson, A. Gordon, Sadeghi, Sara, Saksena, Gordon, Sander, Chris, Schein, Jacqueline E., Schmidt, Heather K., Schumacher, Steven E., Shelton, Candace, Shelton, Troy, Shen, Ronglai, Sheth, Margi, Shi, Yan, Shih, Juliann, Shinbrot, Eve, Shroff, Rachna, Simons, Janae V., Sipahimalani, Payal, Skelly, Tara, Sofia, Heidi J., Soloway, Matthew G., Stoppler, Hubert, Stransky, Nicolas, Stuart, Josh, Sun, Qiang, Tam, Angela, Tan, Donghui, Tarnuzzer, Roy, Thiessen, Nina, Thorne, Leigh B., Torbenson, Michael S., Van Den Berg, David J., Veluvolu, Umadevi, Verhaak, Roel G.W., Voet, Doug, Wan, Yunhu, Wang, Zhining, Weinstein, John N., Weisenberger, Daniel J., Wheeler, David A., Wilson, Richard K., Wise, Lisa, Wong, Tina, Wu, Chia-Chin, Wu, Ye, Xi, Liu, Yang, Ju Dong, Yang, Liming, Zenklusen, Jean C., Zhang, Hailei, Zhang, Jiashan (Julia), Zheng, Siyuan, Zmuda, Erik, Zhu, Andrew X., Stuart, Josh M., Sander, Chris, Akbani, Rehan, Cherniack, Andrew D., Deshpande, Vikram, Mounajjed, Taofic, Foo, Wai Chin, Torbenson, Michael S., Kleiner, David E., Laird, Peter W., Wheeler, David A., McRee, Autumn J., Bathe, Oliver F., Andersen, Jesper B., Bardeesy, Nabeel, Roberts, Lewis R., and Kwong, Lawrence N.

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDHmutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDHmutant subtype. More broadly, we found that IDHmutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

Published
2017
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219. Systematic analysis of telomere length and somatic alterations in 31 cancer types

Author

Barthel, Floris P, Wei, Wei, Tang, Ming, Martinez-Ledesma, Emmanuel, Hu, Xin, Amin, Samirkumar B, Akdemir, Kadir C, Seth, Sahil, Song, Xingzhi, Wang, Qianghu, Lichtenberg, Tara, Hu, Jian, Zhang, Jianhua, Zheng, Siyuan, and Verhaak, Roel G W

Abstract

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat–containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

Published
2017
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220. Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation

Author

Shingu, Takashi, Ho, Allen L, Yuan, Liang, Zhou, Xin, Dai, Congxin, Zheng, Siyuan, Wang, Qianghu, Zhong, Yi, Chang, Qing, Horner, James W, Liebelt, Brandon D, Yao, Yu, Hu, Baoli, Chen, Yiwen, Fuller, Gregory N, Verhaak, Roeland G W, Heimberger, Amy B, and Hu, Jian

Abstract

Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten−/−; Trp53−/−background helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2; QkL/L; PtenL/L; Trp53L/Lmice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.

Published
2017
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231. Coping with chronic pain

Author

Verhaak, P. F. M., primary, Kerssens, J. J., additional, Bensing, J. M., additional, Sorbi, M., additional, Kruise, D. A., additional, and Peeters, M. L., additional

Published
2004
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233. Human genome meeting 2016

Author

Srivastava, A., Wang, Y., Huang, R., Skinner, C., Thompson, T., Pollard, L., Wood, T., Luo, F., Stevenson, R., Polimanti, R., Gelernter, J., Lin, X., Lim, I., Wu, Y., Teh, A., Chen, L., Aris, I., Soh, S., Tint, M., MacIsaac, J., Yap, F., Kwek, K., Saw, S., Kobor, M., Meaney, M., Godfrey, K., Chong, Y., Holbrook, J., Lee, Y., Gluckman, P., Karnani, N., Kapoor, A., Lee, D., Chakravarti, A., Maercker, C., Graf, F., Boutros, M., Stamoulis, G., Santoni, F., Makrythanasis, P., Letourneau, A., Guipponi, M., Panousis, N., Garieri, M., Ribaux, P., Falconnet, E., Borel, C., Antonarakis, S., Kumar, S., Curran, J., Blangero, J., Chatterjee, S., Kapoor, A., Akiyama, J., Auer, D., Berrios, C., Pennacchio, L., Chakravarti, A., Donti, T., Cappuccio, G., Miller, M., Atwal, P., Kennedy, A., Cardon, A., Bacino, C., Emrick, L., Hertecant, J., Baumer, F., Porter, B., Bainbridge, M., Bonnen, P., Graham, B., Sutton, R., Sun, Q., Elsea, S., Hu, Z., Wang, P., Zhu, Y., Zhao, J., Xiong, M., Bennett, David, Hidalgo-Miranda, A., Romero-Cordoba, S., Rodriguez-Cuevas, S., Rebollar-Vega, R., Tagliabue, E., Iorio, M., D’Ippolito, E., Baroni, S., Kaczkowski, B., Tanaka, Y., Kawaji, H., Sandelin, A., Andersson, R., Itoh, M., Lassmann, T., Hayashizaki, Y., Carninci, P., Forrest, A., Semple, C., Rosenthal, E., Shirts, B., Amendola, L., Gallego, C., Horike-Pyne, M., Burt, A., Robertson, P., Beyers, P., Nefcy, C., Veenstra, D., Hisama, F., Bennett, R., Dorschner, M., Nickerson, D., Smith, J., Patterson, K., Crosslin, D., Nassir, R., Zubair, N., Harrison, T., Peters, U., Jarvik, G., Menghi, F., Inaki, K., Woo, X., Kumar, P., Grzeda, K., Malhotra, A., Kim, H., Ucar, D., Shreckengast, P., Karuturi, K., Keck, J., Chuang, J., Liu, E., Ji, B., Tyler, A., Ananda, G., Carter, G., Nikbakht, H., Montagne, M., Zeinieh, M., Harutyunyan, A., Mcconechy, M., Jabado, N., Lavigne, P., Majewski, J., Goldstein, J., Overman, M., Varadhachary, G., Shroff, R., Wolff, R., Javle, M., Futreal, A., Fogelman, D., Bravo, L., Fajardo, W., Gomez, H., Castaneda, C., Rolfo, C., Pinto, J., Akdemir, K., Chin, L., Futreal, A., Patterson, S., Statz, C., Mockus, S., Nikolaev, S., Bonilla, X., Parmentier, L., King, B., Bezrukov, F., Kaya, G., Zoete, V., Seplyarskiy, V., Sharpe, H., McKee, T., Letourneau, A., Ribaux, P., Popadin, K., Basset-Seguin, N., Chaabene, R., Santoni, F., Andrianova, M., Guipponi, M., Garieri, M., Verdan, C., Grosdemange, K., Sumara, O., Eilers, M., Aifantis, I., Michielin, O., de Sauvage, F., Antonarakis, S., Likhitrattanapisal, S., Lincoln, S., Kurian, A., Desmond, A., Yang, S., Kobayashi, Y., Ford, J., Ellisen, L., Peters, T., Alvarez, K., Hollingsworth, E., Lopez-Terrada, D., Hastie, A., Dzakula, Z., Pang, A., Lam, E., Anantharaman, T., Saghbini, M., Cao, H., Gonzaga-Jauregui, C., Ma, L., King, A., Rosenzweig, E., Krishnan, U., Reid, J., Overton, J., Dewey, F., Chung, W., Small, K., DeLuca, A., Cremers, F., Lewis, R., Puech, V., Bakall, B., Silva-Garcia, R., Rohrschneider, K., Leys, M., 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Abstract

O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. Chakravarti O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells C. Maercker, F. Graf, M. Boutros O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis O7 Role of microRNA in LCL to IPSC reprogramming S. Kumar, J. Curran, J. Blangero O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti O9 Metabolomic profiling for the diagnosis of neurometabolic disorders T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. 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Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu O16 Modeling genetic interactions associated with molecular subtypes of breast cancer B. Ji, A. Tyler, G. Ananda, G. Carter O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski O18 Predictive biomarkers to metastatic pancreatic cancer treatment J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. Likhitrattanapisal O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4 C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13 K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía P28 Genetic modifiers of Alström syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escareño, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the LDLRgene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar

Published
2016
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234. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas

Author

Campbell, Joshua D, Alexandrov, Anton, Kim, Jaegil, Wala, Jeremiah, Berger, Alice H, Pedamallu, Chandra Sekhar, Shukla, Sachet A, Guo, Guangwu, Brooks, Angela N, Murray, Bradley A, Imielinski, Marcin, Hu, Xin, Ling, Shiyun, Akbani, Rehan, Rosenberg, Mara, Cibulskis, Carrie, Ramachandran, Aruna, Collisson, Eric A, Kwiatkowski, David J, Lawrence, Michael S, Weinstein, John N, Verhaak, Roel G W, Wu, Catherine J, Hammerman, Peter S, Cherniack, Andrew D, Getz, Gad, Artyomov, Maxim N, Schreiber, Robert, Govindan, Ramaswamy, and Meyerson, Matthew

Abstract

To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor–normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase–Ras–Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.

Published
2016
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236. The Eurocommunication study. An international comparative study in six European countries on doctor-patient communication in general practice

Author

van den Brink-Muinen, A., primary, Verhaak, P. F. M., additional, Bensing, J. M., additional, Bahrs, O., additional, Deveugele, M., additional, Gask, L., additional, Mead, N., additional, Leiva-Fernandez, F., additional, Perez, A., additional, Messeri-i, V., additional, Oppizzi, L., additional, and Peltenburg, M., additional

Published
2000
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237. Correlates of Alcohol Abstinence and At-Risk Alcohol Consumption in Older Adults with Depression: the NESDO Study.

Author

van den Berg, Julia F., Kok, Rob M., van Manvijk, Harm W. J., van der Mast, Roos C., Naarding, Paul, Voshaar, Richard C. Oude, Stek, Max L., Verhaak, Peter F. M., de Waal, Margot W. M., and Comijs, Hannie C.

Abstract

The article discusses research which was conducted to compare alcohol use between depressed and non-depressed older adults and to investigate alcohol abstinence and at risk alcohol consumption in depressed older adults. Researchers evaluated 373 adults who had been diagnosed with depression and 128 non-depressed adults. They found that alcohol abstinence was more common in depressed adults and that 19% of depressed adults were at risk drinkers.

Published
2014
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240. Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study

Author

Kox, Matthijs, van Eijk, Lucas, Verhaak, Tim, Frenzel, Tim, Kiers, Harmke, Gerretsen, Jelle, van der Hoeven, Johannes, Kornet, Lilian, Scheiner, Avram, and Pickkers, Peter

Abstract

Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5–C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0–10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg−1Escherichia colilipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. Clinicaltrials.gov NCT01944228. Registered 12 September 2013.

Published
2015
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241. EtsFactors Regulate Neural Stem Cell Depletion and Gliogenesis in RasPathway Glioma

Author

Breunig, Joshua J., Levy, Rachelle, Antonuk, C. Danielle, Molina, Jessica, Dutra-Clarke, Marina, Park, Hannah, Akhtar, Aslam Abbasi, Kim, Gi Bum, Town, Terrence, Hu, Xin, Bannykh, Serguei I., Verhaak, Roel G.W., and Danielpour, Moise

Abstract

As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Raspathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Etssubfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Etsaxis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

Published
2015
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242. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

Author

Kim, Hoon, Zheng, Siyuan, Amini, Seyed S., Virk, Selene M., Mikkelsen, Tom, Brat, Daniel J., Grimsby, Jonna, Sougnez, Carrie, Muller, Florian, Hu, Jian, Sloan, Andrew E., Cohen, Mark L., Van Meir, Erwin G., Scarpace, Lisa, Laird, Peter W., Weinstein, John N., Lander, Eric S., Gabriel, Stacey, Getz, Gad, Meyerson, Matthew, Chin, Lynda, Barnholtz-Sloan, Jill S., and Verhaak, Roel G.W.

Abstract

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ∼7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity.

Published
2015
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245. Prevalence, presentation and prognosis of delirium in older people in the population, at home and in long term care: a review.

Author

Lange, E., Verhaak, P. F. M., and Meer, K.

Subjects
*DELIRIUM in old age, *INSTITUTIONAL care of older people, *NURSING home patients, *GERIATRIC psychiatry, *PSYCHOLOGY, *DISEASE risk factors
Abstract

Objective The aim of this study is to provide an overview of prevalence, symptoms, risk factors and prognosis of delirium in primary care and institutionalized long-term care. Design The method used in this study is a systematic PubMed search and literature review. Results The prevalence of delirium in the population among the elderly aged 65+ years is 1-2%. Prevalence rises with age: 10% among a 'general' population aged 85+ years. Prevalence rises up to 22% in populations with higher percentages of demented elder. In long-term care, prevalence ranges between 1.4% and 70%, depending on diagnostic criteria and on the prevalence of dementia. There is a significant increase of the risk of delirium with age and cognitive decline in all groups. Concerning prognosis, most studies agree that older people who previously experienced delirium have a higher risk of dementia and a higher mortality rate. Population and long-term care studies show the same tendency. Conclusions Delirium in a non-selected population aged 65+ years is uncommon. However, prevalence rises very quickly in selected older groups. Primary care doctors should be aware of a relatively high risk of delirium among the elderly in long-term care, those older than 85 years and those with dementia. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2013
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248. Effects of a nationwide programme: interventions to reduce perceived barriers to collaboration and to increase structural one-on-one contact.

Author

Heideman J, Laurant M, Verhaak P, Wensing M, and Grol R

Abstract

OBJECTIVE: To describe the implementation of a nationwide programme and to determine the effects of specific quality improvement (QI) interventions within this programme on perceived barriers to collaboration between general practitioner (GPs) and mental health professionals and frequency of structural one-on-one contact regarding individual patients. METHODS: The implementation of regional QI-interventions, perceived barriers to collaboration, and frequency of structural one-on-one contact, were assessed in a cohort study involving two surveys (2001 and 2003) among a random sample of 2757 GPs. RESULTS: 1336 and 1358 GPs returned baseline and follow-up questionnaires respectively. Most of the interventions were only offered to a minority of GPs. Less than 25% of GPs that had been offered interventions actually participated. The frequency of structural one-on-one contact with mental health professionals did not change, but barriers to collaboration decreased between 2001 and 2003. For GPs who actually participated in interactive small group meetings or in intervention in which mental health professionals were integrated in general practice, a reduction of perceived barriers could be observed as well as an increase in the frequency of structural one-on-one contact. CONCLUSION: Interventions that could be characterized as interactive small group meetings as well as interventions that involved the integration of mental health professionals in general practice led to a reduction of perceived barriers as well as an increase in the frequency of structural one-on-one contact. These findings add to the knowledge of which interventions have an effect on the collaboration between different health care providers. [ABSTRACT FROM AUTHOR]

Published
2007
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