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Fractal circuit sensors enable rapid quantification of biomarkers for donor lung assessment for transplantation.

Sage AT, Besant JD, Mahmoudian L, Poudineh M, Bai X, Zamel R, Hsin M, Sargent EH, Cypel M, Liu M, Keshavjee S, Kelley SO - Sci Adv (2015)

Bottom Line: Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies.A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung.This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.

ABSTRACT
Biomarker profiling is being rapidly incorporated in many areas of modern medical practice to improve the precision of clinical decision-making. This potential improvement, however, has not been transferred to the practice of organ assessment and transplantation because previously developed gene-profiling techniques require an extended period of time to perform, making them unsuitable in the time-sensitive organ assessment process. We sought to develop a novel class of chip-based sensors that would enable rapid analysis of tissue levels of preimplantation mRNA markers that correlate with the development of primary graft dysfunction (PGD) in recipients after transplant. Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies. A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung. Thus, the FraCS-based approach delivers a key predictive value test that could be applied to enhance transplant patient outcomes. This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation.

No MeSH data available.


Related in: MedlinePlus

Relative expression of LTx biomarkers.(A to D) Each circle represents the LTx biomarker signal normalized to GAPDH for an individual donor lung, and horizontal lines show the population means of PGD0/I (n = 23) and PGDIII+ (n = 16) donor lungs for (A) IL-6, (B) IL-10, (C) IL-6/IL-10, and (D) ATP11B. Data were analyzed by a two-tailed Mann-Whitney test. The P values of each comparison are as follows: IL-6, 0.0007; IL-10, 0.9833; IL-6/IL-10, 0.0027; and ATP11B, 0.0002.
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Figure 5: Relative expression of LTx biomarkers.(A to D) Each circle represents the LTx biomarker signal normalized to GAPDH for an individual donor lung, and horizontal lines show the population means of PGD0/I (n = 23) and PGDIII+ (n = 16) donor lungs for (A) IL-6, (B) IL-10, (C) IL-6/IL-10, and (D) ATP11B. Data were analyzed by a two-tailed Mann-Whitney test. The P values of each comparison are as follows: IL-6, 0.0007; IL-10, 0.9833; IL-6/IL-10, 0.0027; and ATP11B, 0.0002.

Mentions: We examined the expression profiles of IL-6, IL-10, IL-6/IL-10 ratio, and ATP11B in 39 distinct donor lungs that were not previously used in biomarker discovery with two objectives: (i) to confirm the predictive nature of these biomarkers and (ii) to determine whether the chip-based LTx assay could confirm the differential expression profiles of donor lungs in a set of patient samples. The population was separated on the basis of the outcome (PGD0/I and PGDIII+) (Fig. 5). We observed a significant difference between the two PGD populations for IL-6 (Fig. 5A), IL-6/IL-10 ratio (Fig. 5C), and ATP11B (Fig. 5D), but not IL-10 (Fig. 5B). To validate the ability of the LTx biomarkers to predict PGD in transplanted lungs, we performed receiver operating characteristic (ROC) curve analysis and determined a significant area under the curve (AUC) for IL-6 and ATP11B mRNA, and the IL-6/IL-10 ratio, but not IL-10 mRNA as a predictor alone (Table 1).


Fractal circuit sensors enable rapid quantification of biomarkers for donor lung assessment for transplantation.

Sage AT, Besant JD, Mahmoudian L, Poudineh M, Bai X, Zamel R, Hsin M, Sargent EH, Cypel M, Liu M, Keshavjee S, Kelley SO - Sci Adv (2015)

Relative expression of LTx biomarkers.(A to D) Each circle represents the LTx biomarker signal normalized to GAPDH for an individual donor lung, and horizontal lines show the population means of PGD0/I (n = 23) and PGDIII+ (n = 16) donor lungs for (A) IL-6, (B) IL-10, (C) IL-6/IL-10, and (D) ATP11B. Data were analyzed by a two-tailed Mann-Whitney test. The P values of each comparison are as follows: IL-6, 0.0007; IL-10, 0.9833; IL-6/IL-10, 0.0027; and ATP11B, 0.0002.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4643795&req=5

Figure 5: Relative expression of LTx biomarkers.(A to D) Each circle represents the LTx biomarker signal normalized to GAPDH for an individual donor lung, and horizontal lines show the population means of PGD0/I (n = 23) and PGDIII+ (n = 16) donor lungs for (A) IL-6, (B) IL-10, (C) IL-6/IL-10, and (D) ATP11B. Data were analyzed by a two-tailed Mann-Whitney test. The P values of each comparison are as follows: IL-6, 0.0007; IL-10, 0.9833; IL-6/IL-10, 0.0027; and ATP11B, 0.0002.
Mentions: We examined the expression profiles of IL-6, IL-10, IL-6/IL-10 ratio, and ATP11B in 39 distinct donor lungs that were not previously used in biomarker discovery with two objectives: (i) to confirm the predictive nature of these biomarkers and (ii) to determine whether the chip-based LTx assay could confirm the differential expression profiles of donor lungs in a set of patient samples. The population was separated on the basis of the outcome (PGD0/I and PGDIII+) (Fig. 5). We observed a significant difference between the two PGD populations for IL-6 (Fig. 5A), IL-6/IL-10 ratio (Fig. 5C), and ATP11B (Fig. 5D), but not IL-10 (Fig. 5B). To validate the ability of the LTx biomarkers to predict PGD in transplanted lungs, we performed receiver operating characteristic (ROC) curve analysis and determined a significant area under the curve (AUC) for IL-6 and ATP11B mRNA, and the IL-6/IL-10 ratio, but not IL-10 mRNA as a predictor alone (Table 1).

Bottom Line: Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies.A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung.This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.

ABSTRACT
Biomarker profiling is being rapidly incorporated in many areas of modern medical practice to improve the precision of clinical decision-making. This potential improvement, however, has not been transferred to the practice of organ assessment and transplantation because previously developed gene-profiling techniques require an extended period of time to perform, making them unsuitable in the time-sensitive organ assessment process. We sought to develop a novel class of chip-based sensors that would enable rapid analysis of tissue levels of preimplantation mRNA markers that correlate with the development of primary graft dysfunction (PGD) in recipients after transplant. Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies. A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung. Thus, the FraCS-based approach delivers a key predictive value test that could be applied to enhance transplant patient outcomes. This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation.

No MeSH data available.


Related in: MedlinePlus