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LaRusch, Jessica,Jung, Jinsei,General, Ignacio J.,Lewis, Michele D.,Park, Hyun Woo,Brand, Randall E.,Gelrud, Andres,Anderson, Michelle A.,Banks, Peter A.,Conwell, Darwin,Lawrence, Christopher,Romagnuo Public Library of Science 2014 PLoS genetics Vol.10 No.7
<▼1><P>CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (<I>CFTR<SUP>sev</SUP></I>) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those <I>CFTR</I> mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (<I>CFTR<SUP>BD</SUP></I>) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate <I>CFTR<SUP>BD</SUP></I> mutations from among 81 previously described <I>CFTR</I> variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined <I>CFTR<SUP>BD</SUP></I> variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (<I>CFTR</I> R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, <I>CFTR<SUP>BD</SUP></I> increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by <I>CFTR<SUP>BD</SUP></I> variants through multiple mechanisms. <I>CFTR<SUP>BD</SUP></I> variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.</P></▼1><▼2><P><B>Author Summary</B></P><P>Genetic disorders of ion channels can affect the body's ability to function properly in many ways. CFTR, an ion channel regulating movement of chloride and bicarbonate across cell membranes, is important for absorbing and secreting fluids. If the gene responsible for the CFTR channel is mutated severely, the result is cystic fibrosis, a hereditary disorder in which the patient develops thick mucus, especially in the lungs, as well as scarring (fibrosis) in the pancreas. Cystic fibrosis also affects the sweat glands, nasal sinuses, intestines, liver, and male reproductive system. Mutations to the CFTR gene that do not cause cystic fibrosis have been considered benign. However, we discovered 9 CFTR mutations that do not cause cystic fibrosis but do cause inflammation and scarring of the pancreas (chronic pancreatitis). These mutant CFTR channels secrete chloride, which is important in the sweat glands, lungs, and intestines, but not bicarbonate, which is important in the pancreas, sinuses, and male reproductive tract. We found patients with any of these 9 mutations had chronic pancreatitis, and often sinus infections, and male infertility, but not other symptoms of cystic fibrosis. Our computer models and data will help researchers develop better drugs and help physicians treating patients with chronic pancreatitis.</P></▼2>
Correlation of Early Outcomes and Intradiscal Interleukin-6 Expression in Lumbar Fusion Patients
John D. Koerner,Dessislava Z. Markova,Greg D. Schroeder,Christopher L. Antonacci,Joseph Mendelis,Alexander R. Vaccaro,D. Greg Anderson,Chris K. Kepler 대한척추신경외과학회 2020 Neurospine Vol.17 No.1
Objective: To determine if there is correlation between intradiscal levels of interleukin-6 (IL-6) and early outcome measures in patients undergoing lumbar fusion for painful disc degeneration. Methods: Intervertebral disc tissue was separated into annulus fibrosus/nucleus pulposus and cultured separately in vitro in serum-free medium (Opti-MEM). Conditioned media was collected after 48 hours. The concentration of IL-6 was quantified using enzyme-linked immunosorbent assay. Pearson correlation coefficients quantified relationships between IL-6 levels and pre- and postoperative visual analogue scale (VAS) back pain and Oswestry Disability Index (ODI), as well as change in VAS/ODI. Results: Sixteen discs were harvested from 9 patients undergoing anterior lumbar interbody fusion (mean age, 47.4 years; range, 21–70 years). Mean preoperative and 6-month postoperative VAS were 8.1 and 3.7, respectively. Mean preoperative and postoperative ODI were 56.2 and 25.6, respectively. There were significant positive correlations between IL-6 expression and postoperative VAS (ρ=0.38, p=0.048) and ODI (ρ=0.44, p=0.02). No significant correlations were found between intradiscal IL-6 expression and preoperative VAS (ρ=-0.12, p=0.54). Trends were seen associating IL-6 expression and change in VAS/ODI (ρ=-0.35 p=0.067; ρ=-0.34, p=0.08, respectively). A trend associated IL-6 and preoperative ODI (ρ=0.36, p=0.063). Conclusion: The direct association between IL-6 expression and VAS/ODI suggests patients with elevated intradiscal cytokine expression may have worse early outcomes than those with lower expression of IL-6 after surgery for symptomatic disc degeneration.
Bio-Frontier Symposia : Proteomics ; Advanced strategies for protein profiling using LC-FTICR/MS
( Ljiljana Pasa Toli ),( Gordon A. Anderson ),( Mary S. Lipton ),( David G. Camp II ),( Yu Feng Shen ),( Christophe Masselon ),( Richard D. Smith ) 한국생화학분자생물학회 (구 한국생화학회) 2005 62회 KSBMB Annual Meeting in 2005 Vol.- No.-
Bio-Frontier Symposia : Proteomics ; Advanced strategies for protein profiling using LC-FTICR/MS
( Ljiljana Pasa Tolic ),( Gordon A. Anderson ),( Mary S. Lipton ),( David G. Camp ),( Yu Feng Shen ),( Christophe Masselon ),( Richard D. Smith ) 한국생화학분자생물학회 (구 한국생화학회) 2005 생화학분자생물학회 춘계학술발표논문집 Vol.2005 No.-