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Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
- Author
- Ahlqvist Emma
- Almgren Peter
- Barker Adam
- Barker David J.P.
- Barnes Daniel
- Barroso Inês
- Boehnke Michael
- Bouatia-Naji Nabila
- Chambers John
- Chen Han
- Clarke Robert
- Collins Francis S.
- Cooper Cyrus C.
- Danesh John
- Dedoussis George V.
- Deloukas Panos
- Dennison Elaine M.
- Dermitzakis Emmanouil T.
- Dimas Antigone S.
- Dupuis Josée
- Eriksson Johan G.
- Eriksson Per
- Eury Elodie
- Ferrannini Ele
- Florez Jose Carlos
- Folkersen Lasse
- Forsen Tom J.
- Fox Caroline
- Franzosi Maria Grazia
- Frayling Timothy M.
- Froguel Philippe
- Gloyn Anna L.
- Goel Anuj
- Groop Leif
- Gu Harvest F.
- Gustafsson Stefan
- Hamsten Anders
- Hopewell Jemma C.
- Horikoshi Momoko
- Ingelsson Erik
- Isomaa Bo
- Jackson Anne U.
- Jameson Karen A.
- Johnson Paul
- Kajantie Eero
- Kanoni Stavroula
- Kerr-Conte Julie
- Kooner Jaspal
- Kuulasmaa Teemu
- Kuusisto Johanna
- Laakso Markku
- Langenberg Claudia
- Lind Lars
- Loos Ruth J.F.
- Luan Jian'an
- Lyssenko Valeriya
- Makrilakis Konstantinos
- Manning Alisa K
- Martínez-Larrad María Teresa
- McCarthy Mark I.
- Meigs James Benjamin
- Mälarstig Anders
- Narisu Narisu
- Nastase Mannila Maria
- Nica Alexandra
- Ongen Halit
- Osmond Clive
- Parish Sarah
- Pascoe Laura
- Pattou François
- Payne Felicity
- Peden John F.
- Petrie John R.
- Prokopenko Inga
- Rybin Denis
- Saleheen Danish
- Sayer Avan A.
- Seedorf Udo
- Sennblad Bengt
- Serrano-Ríos Manuel
- Silveira Angela
- Stančáková Alena
- Stirrups Kathy
- Strawbridge Rona J.
- Swift Amy J.
- Syvänen Ann-Christine
- Taneera Jalal
- Travers Mary E.
- Tuomi Tiinamaija
- Turrini Fabiola
- van 't Hooft Ferdinand M.
- Voight Benjamin F.
- Walker Mark
- Wareham Nicholas J.
- Watanabe Richard M.
- Watkins Hugh
- Weedon Michael N.
- Wheeler Eleanor
- Xie Weijia
- Zabena Carina
- Zethelius Björn
- Öhrvik John
- Östenson Claes-Göran
- Publication venue
- 'American Diabetes Association'
- Publication date
- 10/04/2013
- Field of study
OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis
No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.
- Author
- Aadahl Mette
- Arking Dan E
- Barnes Daniel
- Barroso Inês
- Bergmann Sven
- Boehnke Michael
- Boerwinkle Eric
- Bonnycastle Lori L
- Bornstein Stefan R
- Bouatia-Naji Nabila
- Brage Soren
- Brunner Eric
- Bumpstead Suzannah J
- Carlson Olga D
- Chen Han
- Chen Yii-Der Ida
- Chines Peter S
- Chu Audrey Y
- Collins Francis S
- Cooper Cyrus
- Couper David J
- Dennison Elaine M
- Dowling Nicole F
- Dupuis Josée
- Egan Josephine S
- Ekelund Ulf
- Erdos Michael R
- Ferrucci Luigi
- Florez Jose C
- Forouhi Nita G
- Fox Caroline S
- Franks Paul W
- Froguel Philippe
- Glazer Nicole L
- Goodarzi Mark O
- Grarup Niels
- Groop Leif
- Grässler Jürgen
- Gustafsson Stefan
- Hallmans Göran
- Hansen Torben
- Hingorani Aroon
- Hivert Marie-France
- Holloway John W
- Hu Frank B
- Ingelsson Erik
- Isomaa Bo
- Jackson Anne U
- Jameson Karen A
- Johansson Ingegerd
- Jonsson Anna
- Jørgensen Torben
- Kao WH Linda
- Kivimaki Mika
- Kovacs Peter
- Kumari Meena
- Kutalik Zoltán
- Kuusisto Johanna
- Laakso Markku
- Lagou Vasiliki
- Langenberg Claudia
- Lecoeur Cécile
- Li Guo
- Loos Ruth JF
- Lyssenko Valeri
- Lévy-Marchal Claire
- Manning Alisa K
- Marek Diana
- Marmot Michael
- Marques-Vidal Pedro
- Meigs James B
- Morken Mario A
- Müller Gabriele
- North Kari E
- Pankow James S
- Payne Felicity
- Pedersen Oluf
- Prokopenko Inga
- Psaty Bruce M
- Rasmussen-Torvik Laura J
- Renström Frida
- Rice Ken
- Rotter Jerome I
- Rybin Denis
- Sandholt Camilla H
- Sayer Avan A
- Schwarz Peter EH
- Scott Robert A
- Shrader Peter
- Shungin Dmitry
- Siscovick David S
- Stancáková Alena
- Stringham Heather M
- Stumvoll Michael
- Tanaka Toshiko
- Teslovich Tanya M
- Tönjes Anke
- Vollenweider Peter
- Waeber Gérard
- Walker Mark
- Wareham Nicholas J
- Watanabe Richard M
- Williams Gordon H
- Witte Daniel R
- Wood Andrew R
- Xie Weijia
- Yesupriya Ajay
- Publication venue
- Diabetes
- Publication date
- 01/01/2012
- Field of study
Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions
Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.
- Author
- Abecasis Goncalo
- Abecasis Gonçalo R.
- Aben Katja K.
- Absher Devin
- Aherrahrou Zouhair
- Ahlqvist Emma
- Ahmadi Kourosh
- Ahmed Nabeel
- Alavere Helene
- Alibrandi Maria T S
- Allayee Hooman
- Almgren Peter
- Altshuler David
- Amin Najaf
- Anand Sonia S.
- Andersen Karl
- Anderson Jeffrey L.
- Ardissino Diego
- Ardlie Kristin
- Armitage Jane
- Arnold Alice M.
- Aspelund Thor
- Assimes Themistocles L.
- Assmann Gerd
- Atwood Larry D.
- Aulchenko Yurii S.
- Azhar Muhammad
- Balkau Beverley
- Ball Stephen G.
- Balmforth Anthony J.
- Barbalic Maja
- Barker Adam
- Barker David J P
- Barlassina Christina
- Barlera Simona
- Barnes Daniel
- Barnes Timothy A.
- Barrett Amy
- Barroso H
- Barroso Inês
- Bataille Veronique
- Becker Diane M.
- Becker Lewis C.
- Beckmann Jacques S.
- Beilby John P.
- Ben-Shlomo Yoav
- Benediktsson Rafn
- Bennett Amanda J.
- Berger Klaus
- Bergman Richard N.
- Bergmann Sven
- Bernd Sonja I.
- Berndt Sonja I
- Biebermann Heike
- Bis Joshua C.
- Blagieva Roza
- Blakemore Alexandra I F
- Blankenberg Stefan
- Boehm Bernhard O.
- Boehnke Michael
- Boehnke Mike
- Boeing Heiner
- Boekholdt S. Matthijs
- Boerwinkle Eric
- Boes Tanja
- Bonnycastle Lori L.
- Boomsma Dorret I.
- Borecki Ingrid B.
- Bornstein Stefan R.
- Boström Kristina Bengtsson
- Bouatia-Naji Nabila
- Bowman Louise
- Bragi Walters G.
- Braund Peter S.
- Bravenboer Bert
- Brown Morris J.
- Buchanan Thomas A.
- Bumpstead Suzannah
- Burnett Mary Susan
- Burtt Noisël P.
- Busonero Fabio
- Buysschaert Ian
- Cambien Francois
- Campbell Harry
- Cappuccio Francesco P.
- Cardiogenics [Unknown]
- Carlquist John F.
- Cauchi Stephane
- Caulfield Mark
- Cavalcanti-Proença Christine
- Chambers John C.
- Chanock Stephen J.
- Charpentier Guillaume
- Chasman Daniel I.
- Chatterjee Nilanjan
- Chen Chih Mei
- Chen Han
- Chen Li
- Chines Peter S.
- Cichon Sven
- Clarke Robert
- Codd Veryan
- Coin Lachlan
- Collins Francis S.
- Collins Rory
- Connell John
- Cooper Cyrus C.
- Cooper Matthew N.
- Cornelis Marilyn
- Couper David J.
- Crawford Gabe
- Cupples L. Adrienne
- Daly Mark J.
- Danesh John
- Davies Robert W.
- Day Ian N M
- de Faire Ulf
- Dedoussis George
- Dehghan Abbas
- Deloukas Panos
- Demissie Serkalem
- den Heijer Martin
- Dennison Elaine M.
- Dermitzakis Emmanouil T.
- Devaney Joseph M.
- di Meglio Paola
- Diemert Patrick
- Dimas Antigone S.
- Dina Christian
- Dixon Anna L.
- Do Ron
- Doering Angela
- Doney Alex S F
- Donnelly Peter
- Dorret I Boomsma
- Duan Jubao
- Dupuis Josée
- Durbin Richard
- Ebrahim Shah
- Eifert Sandra
- Eiriksdottir Gudny
- El Mokhtari Nour Eddine
- Elliott Amanda L.
- Elliott Katherine S.
- Elliott Paul
- Ellis Stephen G.
- Elosua Roberto
- Engert James C.
- Epstein Stephen E.
- Erdmann Jeanette
- Erdos Michael R.
- Eric E Schadt
- Eriksson Johan G.
- Eriksson Per
- Esko Tõnu
- Estrad Karol
- Estrada Karol
- Eury Elodie
- Facheris Maurizio F.
- Farooqi I. Sadaf
- Farrall Martin
- Feitosa Mary F.
- Felix Stephan B.
- Ferrannini Ele
- Ferreir Teresa
- Ferreira Teresa
- Fischer Marcus
- Fischer-Posovszky Pamela
- Fisher Eva
- Florez Jose C.
- Folkersen Lasse
- Folsom Aaron R.
- Forsen Tom J.
- Fox Caroline S.
- Franklin Christopher S.
- Franzosi Maria Grazia
- Frayling Timothy M.
- Freimer Nelson B.
- Freyer Jennifer
- Friedrich Nele
- Froguel Philippe
- Frossard Philippe
- Fu Mao
- Gaget Stefan
- Ganser Martha
- Gardezi Ali
- Gejman Pablo V.
- Geus Eco J C
- Gieger Christian
- Gigante Bruna
- Girelli Domenico
- Gjesing Anette P.
- Glass Daniel
- Glazer Nicole L.
- Gloyn Anna L.
- Goddard Michael E.
- Goel Anuj
- Goodall Alison H.
- Goyette Philippe
- Grallert Harald
- Grarup Niels
- Green Fiona
- Green Todd
- Greenawalt Danielle M.
- Gretarsdottir Solveig
- Griffin Simon
- Groop Leif
- Groop Leif C.
- Groves Christopher J.
- Grundberg Elin
- Gräßler Jürgen
- Grönberg Henrik
- Gu Harvest
- Gudnason Vilmundur
- Guiducci Candace
- Gulcher Jeffrey R.
- Gustafsso Stefan
- Gustafsson Stefan
- Gyllensten Ulf
- Hadjadj Samy
- Hall Alistair S.
- Hall Per
- Halperin Eran
- Hammond Christopher J.
- Hammond Naomi
- Hamsten Anders
- Han Chen
- Hansen Torben
- Haritunians Talin
- Harris Tamara B.
- Hartikainen Anna Liisa
- Hassanali Neelam
- Hattersley Andrew T.
- Havulinna Aki S.
- Hayes Richard B.
- Hayward Caroline
- Hazen Stanley L.
- Heard-Costa Nancy L.
- Heath Andrew C.
- Hebebrand Johannes
- Hedman Åsa K.
- Hei Iris M.
- Heid Iris M
- Heinrich Joachim
- Hellénius Mai Lis
- Hengstenberg Christian
- Herder Christian
- Hicks Andrew A.
- Hide Winston A.
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- Hirschhorn Joel N.
- Hitman Graham A.
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- Hofman Albert
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- Hveem Kristian
- Ida Chen Yii Der
- Igl Wilmar
- Illig Thomas
- Ingelsson Erik
- Ingle Catherine
- Iribarren Carlos
- Ishaq Muhammad
- Isomaa Bo
- Jackso Anne U.
- Jackson Anne U.
- Jacobs Kevin B.
- James Alan L.
- Jameson Karen A.
- Jansson John Olov
- Jarick Ivonne
- Jarvelin Marjo Riitta
- Jewell Elizabeth
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- John Ulrich
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- Johnson Toby
- Jones Gregory T.
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- Jukema J. Wouter
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- Karpe Fredrik
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- Kerr-Conte Julie
- Ketkar Shamika
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- Kiemeney Lambertus A.
- Kilpeläine Tuomas O.
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- Klopp Norman
- Knowles Joshua W.
- Kolcic Ivana
- Kolovou Genovefa
- Kong Augustine
- Kooner Angad S.
- Kooner Jaspal S.
- Koskinen Seppo
- Kovacs Peter
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- Krude Heiko
- Kutalik Zoltán
- Kuulasmaa Teemu
- Kuusisto Johanna
- Kvaløy Kirsti
- Kyriakou Theodosios
- Kähönen Mika
- König Inke R.
- Laakso Markku
- Laaksonen Reijo
- Laitinen Jaana
- Lambrechts Diether
- Lamina Claudia
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- Lantieri Olivier
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- MAGIC [Unknown]
- Makrilakis Konstantinos
- Mallick Nadeem
- Mangino Massimo
- Mannila Maria Nastase
- Manning Alisa K.
- Mannucci Pier M.
- Manunta Paolo
- Maouche Seraya
- Marek Diana
- Marre Michel
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- Martínez-Larrad María Teresa
- McArdle Wendy L.
- McCarroll Steve A.
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- McCarthy Anne
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- McKeown Pascal P.
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- Meigs James B.
- Meisinger Christa
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- Wild Sarah H.
- Wilk Alicja
- Wille Cristen J.
- Willemsen Gonneke
- Willenborg Christina
- Willer Cristen J.
- Wilson James F.
- Winkle Thomas W.
- Winkler Thomas W
- Witte Daniel R.
- Witteman Jacqueline
- Witteman Jacqueline C.
- Witteman Jaqueline C M
- Woo Andrew R.
- Wood Andrew R
- Workalemah Tsegaselassie
- Workalemahu Tsegaselassie
- Wright Alan F.
- Wright Benjamin J.
- Wu Guanming
- Xie Weijia
- Xu Jianfeng
- Yang Jian
- Yang Tsun Po
- Ye Shu
- Zabena Carina
- Zaidi Moazzam
- Zaman Khan Shah
- Zeggini Eleftheria
- Zeller Tanja
- Zethelius Björn
- Zgaga Lina
- Zhang Qunyuan
- Zhang Weihua
- Zhao Jing Hua
- Ziegler Andreas
- Zillikens M. Carola
- Zitting Paavo
- Zondervan Krina T.
- Öhrvik John
- Östenson Claes Göran
- Publication venue
- Diabetes
- Publication date
- 01/01/2011
- Field of study
OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis
New genetic loci link adipose and insulin biology to body fat distribution.
- Author
- Aalto Ville
- Aasarød Knut
- Abecasis Goncalo R
- Abecasis Gonçalo
- Absher Devin
- Adair Linda S
- Adam Martin
- Adeyemo Adebowale
- Ahlqvist Emma
- Ahmadi Kourosh R
- Ahola Aila
- Ainali Chrysanthi
- Akylbekova Ermeg
- Ala-Korpela Mika
- Alavere Helen
- Albagha Omar M E
- Albrecht Eva
- Alen Markku
- Alexander Myriam
- Alhenc-Gelas François
- Alizadeh Behrooz Z
- Allison Matthew A
- Alonso Nerea
- Altshuler David
- Ambite Jose Luis
- Amin Najaf
- Amouyel Philippe
- An Ping
- Anderson Carl A
- Anderson Denise
- Anderson Garnet
- Andrews Jeanette S
- Antonella Mulas
- Antti Jula
- Aragaki Aaron K
- Arking Dan E
- Arnold Alice
- Arnold Alice M
- Arora Pankaj
- Arscott Gillian M
- Artigas Maria Soler
- Arveiler Dominique
- Asiki Gershim
- Aspelund Thor
- Assimes Themistocles L
- Atalay Mustafa
- Atkinson Elizabeth J
- Aulchenko Yurii
- Avery Christy
- Bain Stephen C
- Bakker Stephan J L
- Balcells Susana
- Balkau Beverley
- Ballantyne Christie M
- Balmforth Anthony J
- Bandinelli Stefania
- Barbalic Maja
- Barrett Amy
- Barroso Ines
- Barroso Inês
- Basart Hanneke
- Basart Hanneke V
- Bataille Veronique
- Baumert Jens
- Beckmann Jacques S
- Beekman Marian
- Been Latonya F
- Beilby John
- Beilby John P
- Bell Jordana T
- Bellis Claire
- Bennett Amanda J
- Bennett Franklyn
- Berenson Gerald S
- Bergman Richard N
- Bergmann Sven
- Berndt Sonja I
- Berne Christian
- Bidulescu Aurelian
- Bielak Lawrence F
- Bierut Laura J
- Biffar Reiner
- Bis Joshua C
- Blackburn Hannah
- Blangero John
- Blankenberg Stefan S
- Blüher Matthias
- Boban Mladen
- Bochud Murielle
- Boehm Bernhard O
- Boehnke Michael
- Boerwinkle Eric
- Boezen H Marike
- Bolton Jennifer L
- Bolton Judith A Hoffman
- Bonnet Fabrice
- Bonnycastle Lori L
- Boomsma Dorret I
- Borecki Ingrid
- Boright Andrew P
- Borja Judith B
- Bornstein Stefan R
- Boston Jonathan
- Bots Michiel L
- Bouatia-Naji Nabila
- Bouchard Claude
- Bovet Pascal
- Boyd Heather A
- Bragg-Gresham Jennifer L
- Brambilla Paolo
- Brand Eva
- Brand Stefan-Martin
- Brandi Maria Luisa
- Braund Peter S
- Brennan Eoin P
- Brismar Kerstin
- Brody Jennifer
- Broekmans Frank J
- Broer Linda
- Brown Matthew A
- Brown Morris J
- Brown-Gentry Kristin
- Bruinenberg Marcel
- Buchkovich Martin L
- Buckley Brendan M
- Buil Alfonso
- Bull Shelley B
- Burgdorf Christof
- Buring Julie E
- Burnett Mary S
- Burnier Michel
- Burri Andrea
- Burton Paul R
- Bush William S
- Busonero Fabio
- Buxbaum Sarah G
- Buyske Steve
- Buzkova Petra
- Byrne Enda M
- Böger Carsten A
- Böhringer Stefan
- Böttcher Yvonne
- Cambien Francois
- Campbell Harry
- Campbell Susan
- Carba Delia B
- Carlson Chris
- Carlson Olga D
- Carty Cara
- Casas Juan P
- Caspersen Ida H
- Castano-Betancourt Martha
- Cauchi Stéphane
- Cauley Jane A
- Caulfield Mark
- Cavalieri Margherita
- Cazier Jean-Baptiste
- Center Jacqueline R
- Cesana Giancarlo
- Chakravarti Aravinda
- Chambers John
- Chandak Giriraj R
- Chang Hsing-Yi
- Chang Yen-Pei C
- Chanock Stephen J
- Charchar Fadi J
- Chasman Dan
- Chaturvedi Nish
- Chen Constance
- Chen Han
- Chen Ida
- Chen Jin
- Chen Ming-Huei
- Chen Wei
- Chen Yii-Der Ida
- Cheng Iona
- Cheng Sulin
- Chines Peter S
- Cho Yoon Shin
- Choi Murim
- Chouraki Vincent
- Christiansen Claus
- Chu Audrey Y
- Cimponeriu Dan
- Ciullo Marina
- Clark Graeme R
- Clarke Robert
- Claudi-Boehm Simone
- Coassin Stefan
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- Collins Rory
- Connell John M
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- Cooper Jackie A
- Cooper Matthew N
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- Crawford Dana
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- Cucca Francesco
- Cummings Steven R
- Cupples Adrienne L
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- Curhan Gary
- d'Adamo Pio
- Dahgam Santosh
- Dailiana Zoe
- Danesh John
- Danoy Patrick
- Dastani Zari
- Davies Gail
- Daw E Warwick
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- Day Ian N M
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- de Boer Ian H
- de Boer Rudolf A
- de Faire Ulf
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- Demirkan Ayse
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- Denniff Matthew
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- Deshmukh Harshal
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- di Meglio Paola
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- Dominiczak Anna F
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- Donnelly Louise A
- Doumatey Ayo
- Dreisbach Albert W
- Drong Alexander W
- Duggan David
- Dumitrescu Logan
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- Dupuis Josee
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- El Mokhtari NourEddine
- Elks Cathy E
- Ellinghaus David
- Elliott Paul
- Elosua Roberto
- Emilsson Valur
- Endlich Karlhans
- Epstein Stephen E
- Erbel Raimund
- Erdmann Jeanette
- Erdos Michael R
- Eriksson Joel
- Eriksson Johan
- Eriksson Niclas
- Eriksson Per
- Ernst Florian
- Esko Tonu
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- Evangelou Evangelos
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- Eyjolfsson Gudmundur Ingi
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- Ferrannini Ele
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- Ferrucci Luigi
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- Folkersen Lasse
- Folsom Aaron R
- Fontanillas Pierre
- Ford Ian
- Fornage Myriam
- Foroud Tatiana
- Forouhi Nita G
- Forrester Terrence
- Forsblom Carol
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- Fowkes F Gerald R
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- Heikkilä Kauko
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- Helmer Catherine
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- Henderson Brian
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- Palsson Stefan Th
- Panduru Nicolae Mircea
- Pankow James
- Papamarkou Theodore
- Parish Sarah
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- Parving Hans-Henrik
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- Pechlivanis Sonali
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- Potter Simon
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- Power Chris
- Prabhakaran Dorairajan
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- Prentice Ross
- Prezelj Janez
- Price Jackie F
- Prince Richard L
- Prior Sarah
- Probst-Hensch Nicole M
- Prokopenko Inga
- Province Michael
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- Psaty Bruce
- Pérusse Louis
- Qi Lu
- Quertermous Thomas
- Quibrera Miguel
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- Rankinen Tuomo
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- Rao Madhumathi
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- Rasmussen-Torvik Laura J
- Rathmann Wolfgang
- Rauramaa Rainer
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- Rayner N William
- Rayner Nigel W
- Redline Susan
- Reeve Jonathan
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- Reppe Sjur
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- Rotimi Charles
- Rotter Jerome I
- Rousseau François
- Roussel Ronan
- Rubin Diana
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- Ruokonen Aimo
- Rybin Denis
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- Salumets Andres
- Samani Nilesh
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- Sandholm Niina
- Sandhu Manjinder S
- Sanghera Dharambir K
- Sanna Serena
- Saraheimo Markku
- Saramies Jouko
- Sarti Cinzia
- Sarzynski Mark A
- Sattar Naveed
- Savage David A
- Saxena Richa
- Schadt Eric
- Scharnagl Hubert
- Scherag André
- Schlessinger David
- Schmidt Ellen M
- Schmidt Helena
- Schmidt Reinhold
- Scholtens Salome
- Schork Nicholas J
- Schreiber Stefan
- Schumacher Fredrick
- Schunkert Heribert
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- Schäfer Arne
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- Scott James
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- Seeley Janet
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- Seielstad Mark
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- Semple Robert
- Sengupta Sebanti
- Sennblad Bengt
- Serafinceanu Cristian
- Service Susan K
- Seshadri Sudha
- Seufferlein Thomas
- Shah Sonia
- Shah Svati H
- Sham Pak Chung
- Sharma Pankaj
- Shaw-Hawkins Sue
- Sheu Wayne H-H
- Shi Gang
- Shin So-Youn
- Shlipak Michael G
- Shohet Ralph
- Shrine Nick R G
- Shriner Daniel
- Shuldiner Alan R
- Shungin Dmitry
- Sidore Carlo
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- Siggeirsdottir Kristin
- Sigurdsson Gunnar
- Sijbrands Eric J G
- Silander Kaisa
- Sim Xueling
- Singleton Andrew
- Sinisalo Juha
- Siscovick David S
- Sitlani Colleen M
- Sivananthan Mohan
- Sjögren Marketa
- Skorpen Frank
- Slaets Joris P
- Slagboom P Eline
- Small Kerrin
- Small Kerrin S
- Smit Johannes H
- Smith Albert
- Smith Erin N
- Smith George Davey
- Smith Jennifer A
- Smith Nicholas L
- Snider Harold
- Snieder Harold
- Soininen Pasi
- Song Ci
- Song Kijoung
- Soranzo Nicole
- Sorice Rossella
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- Sovio Ulla
- Spector Tim D
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- Speliotes Elizabeth K
- Spencer Kylee
- Srinivasan Sathanur R
- St Pourcain Beate
- Stacey Simon N
- Staessen Jan A
- Stanèáková Alena
- Stančáková Alena
- Stark Klaus
- Starr John M
- Stathopoulou Maria G
- Stavarachi Monica
- Stefansson Kari
- Steinle Nanette I
- Steinthorsdottir Valgerdur
- Stewart Alexandre F R
- Stirrups Kathleen
- Stolk Lisette
- Stolk Ronald P
- Strachan David P
- Stracke Sylvia
- Stram Daniel
- Strauch Konstantin
- Strawbridge Rona J
- Streeten Elizabeth A
- Stringham Heather M
- Struchalin Maksim
- Stumvoll Michael
- Styrkarsdottir Unnur
- Sulem Patrick
- Sun Yan V
- Sundström Johan
- Surakka Ida
- Surdulescu Gabriela
- Svensson Olle
- Swan Elizabeth J
- Swertz Morris A
- Swift Amy J
- Syreeni Anna
- Syvänen Ann-Christine
- Sõber Siim
- Söderlund Jenny
- Tabara Yasuharu
- Tai E Shyong
- Taliun Daniel
- Talmud Philippa J
- Tammesoo Mar-Liis
- Tan Sian-Tsung
- Tanaka Toshiko
- Tang Nelson L S
- Tarnow Lise
- Taylor Andrew
- Taylor Kira
- Tayo Bamidele
- Tenesa Albert
- Terzic Janos
- Teslovich Tanya M
- Teumer Alexander
- Thelle Dag S
- Thompson John R
- Thorand Barbara
- Thorgeirsson Gudmundur
- Thorleifsson Gudmar
- Thorn Lena M
- Thornton-Wells Tricia
- Thorsteinsdottir Unnur
- Thun Gian-Andri
- Tiirikainen Maarit
- Tikkanen Emmi
- Tikkanen Heikki
- Timpson Nicholas
- Timpson Nicholas J
- Tin Adrienne
- Tiret Laurence
- Tobin Martin
- Tobin Martin D
- Toenjes Anke
- Tolonen Nina
- Tomaschitz Andreas
- Tomaszewski Maciej
- Toniolo Daniela
- Townsend Raymond R
- Tracy Russell P
- Travers Mary E
- Tregouet David-Alexandre
- Treloar Susan A
- Tremblay Angelo
- Tremoli Elena
- Tripathy Vikal
- Troffa Chiara
- Trompet Stella
- Trummer Olivia
- Tryggvadottir Laufey
- Tryggvason Karl
- Trégouët David-Alexandre
- Tsaprouni Loukia
- Tsoka Sophia
- Tsui Kim
- Tukiainen Taru
- Tuomilehto Jaakko
- Turner Stephen T
- Tylavsky Frances A
- Tyrer Jonathon
- Tzoulaki Ioanna
- Tönjes Anke
- Uda Manuela
- Ueshima Hirotsugu
- Uh Hae-Won
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- Uitterlinden André G
- Ulivi Sheila
- Ulivi Shelia
- Umans Jason
- Umemura Satoshi
- Urreizti Roser
- Uusitupa Matti
- Vallejo Edgar E
- van Dam Rob M
- Van den Herik Evita G
- van der Harst Pim
- van der Klauw Melanie M
- van der Schoot C Ellen
- van der Schouw Yvonne T
- van Duijn Cornelia
- Van Duijn Cornelia
- van Gils Carla H
- van Gilst Wiek H
- van Heemst Diana
- Van Hul Wim
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- van Wingerden Sophie
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- Van Zuydam Natalie
- Vandenput Liesbeth
- Varga Tibor V
- Vartiainen Erkki
- Vasan Ramachandran S
- Vedantam Sailaja
- Veldre Gudrun
- Verlaan Dominique
- Vernon Smith Albert
- Veronesi Giovanni
- Verweij Niek
- Verwoert Germaine
- Verwoert Germaine C
- Viigimaa Margus
- Viikari Jorma
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- Virtamo Jarmo
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- Vitart Veronique
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- Voorhuis Marlies
- Völker Uwe
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- Wadén Johan
- Waeber Gerard
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- Waggott Daryl
- Wagner Peter J
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- Wainwright Nicholas
- Waite Lindsay L
- Walker Mark
- Wallace Leanne
- Wallaschofski Henri
- Wallentin Lars
- Wang Hansong
- Wang Jie Jin
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- Wang Xiaoling
- Wareham Nicholas
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- Waterworth Dawn
- Watkins Hugh
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- Wichmann H-Erich
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- Wijmenga Cisca
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- Willemsen Gonneke
- Willemsvan-vanDijk Ko
- Willenborg Christina
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- Williams Rasheeda
- Williams Winfred W
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- Wilsgaard Tom
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- Wilson James G
- Wilson Sarah
- Wilson Scott G
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- Witteman Jacqueline C
- Witteman Jacqueline C M
- Wojczynski Mary K
- Wolffenbuttel Bruce H R
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- Wong Tien Y
- Woo Jean
- Wood Andrew R
- Wood Andy
- Workalemahu Tsegaselassie
- Wright Alan F
- Wu Chunyuan
- Wu Joseph M W
- Wu Ying
- Würtz Peter
- Xiao Su-Mei
- Yajnik Chittaranjan S
- Yang Jian
- Yang Qiong
- Yang Tsun-Po
- Yao Jie
- Yengo Loïc
- Yerges-Armstrong Laura M
- Young Alicia
- Young Elizabeth H
- Young J H
- Young Lauren
- Yuan Xin
- Zaboli Ghazal
- Zalloua Pierre A
- Zarrabeitia María T
- Zelenika Diana
- Zemunik Tatijana
- Zerbini Gianpaolo
- Zgaga Lina
- Zhai Guangju
- Zhang Feng
- Zhang Qunyuan
- Zhang Weihua
- Zhao Jing Hua
- Zhao Wei
- Zheng Hou-Feng
- Zheng Wei
- Zhou Yanhua
- Zhu Haidong
- Zhu Kun
- Zhu Xiaofeng
- Zhuang Wei V
- Zhuang Wei Vivian
- Ziegler Andreas
- Zillikens M Carola
- Zimmermann Martina E
- Zitting Paavo
- Zondervan Krina T
- Zukowska-Szczechowska Ewa
- Zygmunt Marek
- Ärnlöv Johan
- Österholm Anne-May
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2015
- Field of study
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
Can learning health systems help organisations deliver personalised care?
- Author
- A Grant
- A Harvey
- A Muraro
- A Rehman
- AJ Avery
- AM Darcy
- Aziz Sheikh
- BI Nwaru
- BJ Powell
- Bright I. Nwaru
- British Thoracic Society and Scottish Intercollegiate Guidelines Network
- C Auffray
- C Friedman
- C Friedman
- Charles Friedman
- CP Friedman
- CP Friedman
- DA Chambers
- EA Ashley
- ED Green
- EM Antman
- ES Fisher
- ETG Kersten
- FS Collins
- G Blumenthal
- G Ginsburg
- GB Gomez
- GD Cleghorn
- HY King
- International HapMap Consortium
- J Mogensen
- JA Bernstein
- JA Leis
- JG Williams
- JJ Brewington
- JK Taitsman
- JL Jameson
- JNS Eisenberg
- John Halamka
- K Steilling
- L Borish
- L Hood
- L Hood
- L Hood
- L Hood
- LO Gostin
- M Flores
- MJ Khoury
- MJ Khoury
- MP Eccles
- National Research Council
- NI Lindeman
- PJ Pronovost
- RB Parikh
- RG Tabak
- SK Rostanski
- TL Bonfield
- TP Staa van
- VJ Dzau
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2017
- Field of study
There is increasing international policy and clinical interest in developing learning health systems and delivering precision medicine, which it is hoped will help reduce variation in the quality and safety of care, improve efficiency, and lead to increasing the personalisation of healthcare. Although reliant on similar policies, informatics tools, and data science and implementation research capabilities, these two major initiatives have thus far largely progressed in parallel. In this opinion piece, we argue that they should be considered as complementary, synergistic initiatives whereby the creation of learning health systems infrastructure can support and catalyse the delivery of precision medicine that maximises the benefits and minimises the risks associated with treatments for individual patients. We illustrate this synergy by considering the example of treatments for asthma, which is now recognised as an umbrella term for a heterogeneous group of related conditions
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
- Author
- Abassi Yama
- Abelin Jennifer G
- Abolhalaj Milad
- Abraham Tara S
- Adam Ammar
- Adams David
- Adams Homer
- Adams Sarah F
- Adamus Tomasz
- Addepalli Murali
- Addepalli Murali
- Adjei Alex A
- Agapova Larissa
- Agarwala Sanjiv
- Ager Casey
- Aggarwal Charu
- Agnello Giulia
- Agudo Judith
- Aguilar Ethan G
- Aguilera Todd
- Ahamadi Malidi
- Ahn Yong-Oon
- Ahrens Eric T
- Aizer Ayal
- Ajina Reham
- Akerley Wallace
- Al-Muftah Mariam
- Albershardt Tina C
- Albershardt Tina C
- Albrekt Ann-Sofie
- Alekar Shilpa
- Alemany Ramon
- Alemany Ramon
- Alexander Brian
- Allbritton Omaira
- Allen Clint T
- Alley Evan W
- Allison James
- Allison James
- Allison James
- Alston Tesha
- Alt Jürgen
- Alters Susan
- Amatulli Michael
- Anand Snjezana
- Anand Snjezana
- Anand Snjezana
- Anderson Clark
- Anderson Mark
- Andersson Bengt
- Andre Pascale
- Andtbacka Robert H I
- Andtbacka Robert H I
- Angiuoli Sam
- Ansari Tameem
- Anthony Scott
- Antonarakis Emmanuel S
- Antonia Scott J
- Anwar Firoz
- Aquino-Michaels Keston
- Archer Jacob F
- Arina Ainhoa
- Armand Philippe
- Armenta Paul
- Armet Caroline M
- Arnoux Thomas
- Ascarateil Stephane
- Askmyr David
- Atkins Michael
- Atkins Michael B
- Atkinson Victoria
- Au Katrina
- Autio Karen A
- Awad Mark
- Bagarazzi Mark
- Bai Dina
- Baia Gilson
- Baird Jason
- Bajaj Anshika
- Balatoni Timea
- Balboni Tracy
- Balch Leslie
- Bang Andrew
- Bao Riyue
- Bao Yangyi
- Bao Yangyi
- Barakat David
- Barberi Theresa
- Barker Christopher A
- Barnea Eytan
- Barras David
- Bartkowiak Todd
- Bartlett David
- Bartlett David
- Bartlett David
- Bartlett David
- Barton Sunjay M
- Barve Minal
- Bauer Todd
- Bauer Todd W
- Bauman Julie
- Baumgaertner Petra
- Bauml Joshua
- Beceren-Braun Figen
- Beck Kristen
- Becker Annette
- Beckers Johannes
- Beckett Michael A
- Bedognetti Davide
- Bedognetti Davide
- Bedognetti Davide
- Bell Bryan
- Bell Charles J M
- Bell Peter
- Beltran Pedro
- Bender Lewis H
- Bender Steven
- Bennett Mark K
- Benz Steven
- Bera Tapan
- Berglund Peter
- Berglund Peter
- Berkey Sara
- Bernatchez Chantale
- Berry John S
- Berzofsky Jay A
- Bhardwaj Nina
- Bian Zhen
- Bianco Alberto
- Biediger Ronald J
- Bifulco Carlo
- Bigley Alison
- Bingham Patrick
- Biniszkiewicz Detlev M
- Bischoff Helge
- Blake Zoe
- Blake Zoe
- Blakely Collin
- Blazar Bruce R
- Blogowski Wojciech
- Bloom Anja C
- Boehm Jesse
- Bokovanov Vladimir
- Bommareddy Praveen K
- Bommareddy Praveen K
- Bommareddy Praveen K
- Bommareddy Praveen K
- Booth Jamie
- Bornschlegl Svetlana
- Bose Nandita
- Bossenmaier Birgit
- Boughorbel Sabri
- Boyer Jean
- Bramante Simona
- Branstetter Daniel
- Brech Dorothee
- Brenin David
- Broaddus V. C
- Brockstedt Dirk G
- Brockstedt Dirk G
- Brody Joshua
- Bronson Roderick
- Brooks Alan
- Brooks Alan D
- Broucek Joseph
- Brown Alice
- Brown Brian
- Brown Brittany
- Brown Gail L
- Brown Sheila
- Bruce Jeffrey N
- Brunet Laura R
- Bruno Tullia C
- Bryan Jennifer
- Bryant Richard
- Buchbinder Elizabeth
- Bucsek Mark
- Budhu Sadna
- Budhu Sadna
- Budkowska Marta
- Bueno Raphael
- Buettner Florian
- Buettner Nico
- Bullock Kim
- Bullock Kim
- Burova Elena
- Burrill Joel
- Bussler Holm
- Butterfield Lisa H
- Butterfield Lisa H
- Byrne-Steele Miranda
- Cagney Daniel
- Calderon Hugo
- Callahan Margaret K
- Campesato Luis F
- Campogan Dwayne
- Cao Felicia
- Capasso Cristian
- Capasso Cristian
- Caplazi Patrick
- Cappuccini Federica
- Carcaboso Angel M
- Carlino Matteo S
- Carpi Sara
- Carrasco Ruben
- Carrera Diego A
- Carrero Rosa M S
- Carson Dennis A
- Castellini Laura
- Cathomas Richard
- Cauvin Annick
- Cauwenberghs Sandra
- Caux Christophe
- Cebon Jonathan S
- Ceccarelli Michele
- Celis Esteban
- Cerignoli Fabio
- Cerullo Vincenzo
- Cerullo Vincenzo
- Cervera-Carrascón Víctor
- Cesareni Gianni
- Cha John
- Cha John
- Cha John
- Champion Brian
- Chan Anissa S H
- Chan Chanty
- Chan Chanty
- Chan Ivan
- Chan Leo
- Chan Timothy A
- Chang Alfred E
- Chang Alfred E
- Chang Joe
- Chang Nancy N
- Chang Thomas
- Chanuc Fabien
- Chapelin Fanny
- Chaplin Jenny
- Chappel Scott C
- Charych Deborah H
- Charych Deborah H
- Chaudhuri Amitabha
- Chaussabel Damien
- Chen Ada
- Chen Ada
- Chen Gang
- Chen Jason
- Chen Jason
- Chen Xiaomu
- Chen Xin
- Chen Xiufen
- Chen Yu
- Chen Yu
- Chenchik Alex
- Chheda Zinal
- Chiang Eugene
- Chikina Maria
- Chittenden Thomas
- Chiu Hsiling
- Cho Charles
- Chongyung Fang
- Chou Margaret
- Choueiri Toni K
- Choy Carmen
- Clark Joseph I
- Clavijo Paul E
- Clifton Guy T
- Clynes Raphael
- Cobbold Mark
- Cobbold Mark
- Cobbold Mark
- Coder Brandon
- Coffman Robert L
- Cohen Cyrille
- Cohen Ezra E W
- Cohen Roger
- Colen Rivka
- Colevas A. D
- Collins Natalie
- Colrain Jillian
- Coltharp Carla
- Concha-Benavente Fernando
- Connolly Eileen P
- Conwell Darwin
- Conwell Darwin
- Corrales Leticia P
- Corrales Leticia P
- Coukos George
- Coukos George
- Coussens Lisa M
- Coussens Lisa M
- Craggs Graham
- Craig Andrew
- Crittenden Marka
- Cron Kyle R
- Cronstein Bruce N
- Crooks James
- Crosby Andrea
- Crosignani Stefano
- Crowder Robert
- Cruickshank Scott
- Csuka Orsolya
- Curbishley Stuart
- Curiel Tyler
- Curran Emily
- Curran Michael
- Curti Brendan
- Curti Brendan
- Da Costa Andre
- Dai Fu
- Dai Jie
- Dai Peihong
- Dalgleish Angus
- Dalvie Deepak
- Daniels Gregory A
- Daud Adil
- David Justin M
- Davies Bronwyn
- de Boisferon Marc H
- de Groot Patricia
- de Gruijl Tanja
- De Henau Olivier
- de Leon Laura
- De Maeseneire Coraline
- De Sanctis Francesco
- de Silva Suresh
- Deacon Donna
- Deacon Donna H
- DeBenedette Mark
- DeBenedette Mark
- Declerck Paul
- Decock Julie
- Decock Julie
- DeFalco Jeff
- Dela Cruz Filemon
- Delgoffe Greg
- Delgoffe Greg M
- Delgoffe Greg M
- Delgoffe Greg M
- Delogu Lucia
- Delorenzi Mauro
- Demaria Sandra
- Demaria Sandra
- Deng Liang
- Deng Weiwen
- Deng Wentao
- Denies Sofie
- Denis Caroline
- Desbien Anthony L
- deVries Michele
- Dhupkar Pooja
- Diab Adi
- Diab Adi
- Diab Adi
- Diaz Luis
- DiCostanzo AriCeli
- Diede Scott J
- Dietz Allan B
- Dillhoff Mary
- Dillon Patrick
- Dilworth Ryan
- Dimberg Anna
- Ding Yueyun
- Doberstein Stephen K
- Dobkin Julie
- Doener Fatma
- Dolegowska Barbara
- Doleschall Zoltan
- Doman Thompson
- Dominguez George
- Donahue Renee
- Donahue Renee
- Dorsey Frank C
- Dovedi Simon
- Downs-Canner Stephanie
- Drake Charles
- Drake Charles G
- Drake Charles G
- Driessens Gregory
- Driscoll Kyla
- Druker Brian J
- Dubensky Thomas W
- Dubensky Thomas W
- Dudimah Duafalia
- Duff Susan
- Dumontet Charles
- Dunai Cordelia
- Dunai Cordelia
- Dutcher Janice P
- Duttagupta Priyanka
- Duvvuri Uma
- Dyson Mike
- D’Apuzzo Massimo
- Ebner Peggy
- Edwards Robert
- Edwards Robert P
- Edwards Robert P
- Eickhoff Jens
- Eisenhower Mary
- El Alaoui Meddy
- El Alaoui Said
- Eles Klara
- Ellies Lesley
- Elnaggar Omar
- Elvecrog James
- Emberley Ethan
- Emerling Daniel
- Eng Charis
- Engelhard Victor H
- English Jessie
- Enstrom Amanda
- Eremeev Artem
- Eriksson Emma
- Eriksson Emma
- Eriksson Emma
- Ertelt Kathleen
- Eswarappa Rajesh
- Evans Elizabeth
- Evans Kathy
- Facciabene Andrea
- Facciabene Andrea
- Facciabene Andrea
- Facciponte John
- Facciponte John
- Falchook Gerald
- Fantini Massimo
- Fantini Massimo
- Fantini Massimo
- Farkas Emil
- Farren Matthew
- Faustman Denise
- Fa’ak Faisal
- Fa’ak Faisal
- Femel Julia
- Feng JunLi
- Feng Yan
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- Zhao Xingli
- Zheng Lianxing
- Zheng Wenxin
- Zheng Xianxian
- Zheng Yi
- Zhong Hong
- Zhou Li
- Zhou Xiangjun
- Zippelius Alfred
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zloza Andrew
- Zou Jun
- Zuba-Surma Ewa
- Zubkova Olga
- Zureikat Amer
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2016
- Field of study
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 31/01/2024
- Field of study
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
- Author
- Abbas M.
- Abdul Rasheed A.
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- Nature Publishing Group
- Publication date
- Field of study
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Audio Environment Design Applied To Long Duration Space Missions
- Author
- Publication venue
- Worcester Polytechnic Institute - Gordon Library
- Publication date
- 14/04/2009
- Field of study
In future space missions when distances and durations become longer, elements of space craft design, previously thought to be irrelevant, will carry extreme importance. Issues that may occur during a long term space mission are identified using research from analogue earth environments; locations on earth which have similar attributes to space, such as extreme climate or confinement. Music and sound research is than applied to these locales to show the positive changes that can result from the use of proper audio design, both in acoustics and generated sounds. Potential solutions are provided, as well as equipment options.
DSP Modulated Class D Audio Amplifier
- Publication venue
- Worcester Polytechnic Institute - Gordon Library
- Publication date
- 14/04/2009
- Field of study
The goal of this project was to create an 80W, 95% efficient Class D audio amplifier with less than 0.5% harmonic distortion and greater than 100 dB zero-input signal to noise ratio that accepts digital inputs. The amplifier that was built comprised of a three-state digital modulator, an H-bridge amplifier, and a passive filter and was capable of accepting both digital and analog audio inputs by means of the SPDIF protocol and an ADC. To allow the modulator design to be quickly altered, it was implemented on a DSP. Because the modulator could be easily changed, several different modulation schemes were simulated, designed and tested in order to achieve optimal audio quality and efficiency results
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