PMID- 22223479
OWN - NLM
STAT- MEDLINE
DCOM- 20121220
LR  - 20181201
IS  - 1536-4844 (Electronic)
IS  - 1078-0998 (Linking)
VI  - 18
IP  - 8
DP  - 2012 Aug
TI  - Genes associated with intestinal permeability in ulcerative colitis: changes in 
      expression following infliximab therapy.
PG  - 1399-410
LID - 10.1002/ibd.22853 [doi]
AB  - BACKGROUND: Alterations in intestinal permeability have been implicated in 
      ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor 
      alpha (TNFalpha) antibody, can induce clinical response in UC. Gene expression in 
      colonic biopsies taken from responders and nonresponders to infliximab can 
      provide insight into the mechanisms of the altered intestinal permeability at a 
      molecular level. METHODS: Colonic biopsies (n = 18 anti-TNFalpha naive UC patients; n 
      = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) 
      were analyzed for mRNA expression using gene expression microarrays. 
      Computational reverse causal reasoning was applied to build causal network models 
      of UC and response and nonresponse of UC to treatment. Quantitative 
      reverse-transcription polymerase chain reaction (qPCR) was used to confirm 
      differentially expressed genes. RESULTS: Reverse causal reasoning on mRNA 
      expression data from anti-TNFalpha-naive UC and normal samples provided a mechanistic 
      disease model of the biology of gene expression observed in UC. mRNA expression 
      data from the ACT 1 study enabled construction of a mechanistic model describing 
      the biology of nonresponders to infliximab, including evidence for increased 
      intestinal permeability compared with normal and responder samples. Gene 
      expression changes identified as central to intestinal permeability dysregulation 
      were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. 
      Gene expression returned toward normal levels in infliximab responders, but not 
      in nonresponders. CONCLUSION: Gene expression analysis and causal network 
      modeling in combination showed that aberrant mRNA expression of genes involved in 
      intestinal epithelial permeability for infliximab responders was restored toward 
      levels observed in normal samples. Infliximab nonresponders showed no equivalent 
      restoration in the expression of these genes.
CI  - Copyright (c) 2012 Crohn's & Colitis Foundation of America, Inc.
FAU - Toedter, Gary
AU  - Toedter G
AD  - Biomarkers, Centocor Research & Development, Malvern, Pennsylvania, USA. 
      gtoedter@its.jnj.com
FAU - Li, Katherine
AU  - Li K
FAU - Sague, Sarah
AU  - Sague S
FAU - Ma, Keying
AU  - Ma K
FAU - Marano, Colleen
AU  - Marano C
FAU - Macoritto, Michael
AU  - Macoritto M
FAU - Park, Jennifer
AU  - Park J
FAU - Deehan, Renee
AU  - Deehan R
FAU - Matthews, Andrea
AU  - Matthews A
FAU - Wu, Gary D
AU  - Wu GD
FAU - Lewis, James D
AU  - Lewis JD
FAU - Arijs, Ingrid
AU  - Arijs I
FAU - Rutgeerts, Paul
AU  - Rutgeerts P
FAU - Baribaud, Frederic
AU  - Baribaud F
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120104
PL  - England
TA  - Inflamm Bowel Dis
JT  - Inflammatory bowel diseases
JID - 9508162
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Biomarkers)
RN  - 0 (Gastrointestinal Agents)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - B72HH48FLU (Infliximab)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Biomarkers/*metabolism
MH  - Case-Control Studies
MH  - Cell Membrane Permeability/*drug effects
MH  - Colitis, Ulcerative/*drug therapy/*genetics
MH  - Drug Resistance/genetics
MH  - Female
MH  - Gastrointestinal Agents/*therapeutic use
MH  - Gene Expression Profiling
MH  - Humans
MH  - Infliximab
MH  - Intestinal Mucosa/metabolism
MH  - Intestines/*drug effects
MH  - Male
MH  - Middle Aged
MH  - Oligonucleotide Array Sequence Analysis
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors
EDAT- 2012/01/10 06:00
MHDA- 2012/12/21 06:00
CRDT- 2012/01/07 06:00
PHST- 2011/11/10 00:00 [received]
PHST- 2011/11/15 00:00 [accepted]
PHST- 2012/01/07 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/12/21 06:00 [medline]
AID - 10.1002/ibd.22853 [doi]
PST - ppublish
SO  - Inflamm Bowel Dis. 2012 Aug;18(8):1399-410. doi: 10.1002/ibd.22853. Epub 2012 Jan 
      4.