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in IPF?)Tj
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[(cohort using a Cox proportional hazard model,)11.1( )]TJ
-0.016 Tc -0.05 Tw 0 -1.222 TD
[(adjusted for age and sex, to generate a multivariable)-16( )]TJ
-0.017 Tc T*
[(risk predication signature. P)24.9(atients in the replication)-17( )]TJ
0 Tc 0.047 Tw 0 -1.222 TD
(cohort were divided into high risk \(above median )Tj
-0.048 Tw 0 -1.222 TD
(gene expression\) and low risk \(below median gene )Tj
0.044 Tw T*
(expression\) to determine prediction performance )Tj
-0.01 Tc -0.05 Tw T*
[(using log rank test. Survival analysis was performed)-10( )]TJ
0.03 Tc 0.422 Tw 0 -1.222 TD
[(with BAL prediction signature alone or in)30( )]TJ
0 Tc -0.025 Tw 0 -1.222 TD
(combination with the GAP score.)Tj
0.92 0.18 0.59 0.65 k
/GS0 gs
/T1_2 1 Tf
0.011 Tc -0.011 Tw 13 0 0 13 144.5669 614.7618 Tm
[(M)11.7(ai)-2.6(n)11( r)7.9(e)21.2(s)17.9(ul)28.5(t)-9.1(s)]TJ
0 0 0 1 k
/GS1 gs
/T1_1 1 Tf
0.027 Tc 0.151 Tw 9 0 0 9 144.5669 591.7618 Tm
[(This study examined the changes in BAL cell)27.1( )]TJ
0.015 Tc 0.05 Tw T*
[(transcriptomic across three separate cohorts of)15( )]TJ
-0.021 Tw T*
[(IPF patients \(total of 176 samples used, average)15.1( )]TJ
0.032 Tc 0.233 Tw 0 -1.222 TD
(age 68.1)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\035)Tj
/T1_1 1 Tf
0.032 Tc 0.233 Tw 4.885 0 Td
(9.5)Tj
/Span<>> BDC
( )Tj
EMC
1.825 0 Td
[(years and % predicted FVC of)32( )]TJ
0.023 Tc -0.023 Tw -6.709 -1.222 Td
(71)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\035)Tj
/T1_1 1 Tf
0.023 Tc 0.096 Tw 1.806 0 Td
[(21%\). A\027er adjustment for age and sex, a)23( )]TJ
0.015 Tc -0.033 Tw -1.806 -1.222 Td
[(total of 1582 genes were found to be associated)15( )]TJ
0.022 Tc 0.079 Tw 0 -1.222 TD
(with mortality in the derivation cohort \(n)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\037)Tj
/T1_1 1 Tf
0.022 Tc -0.022 Tw 19.467 0 Td
[(62\).)22( )]TJ
-0.005 Tc -0.05 Tw -19.467 -1.222 Td
[(Using component-wise likelihood-based boosting,)-5( )]TJ
0.002 Tc T*
[(a predic)0.5(tive sig)0.5(nature of )0.5(nine genes)0.5( was identi)0.5(\037ed)2( )]TJ
0.013 Tc T*
[(from this dataset and examined from predicative)13.1( )]TJ
0.031 Tc 0.215 Tw T*
[(performance in the replication cohorts. This)31( )]TJ
0.02 Tc 0.05 Tw T*
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-0.005 Tc -0.05 Tw 0 -1.222 TD
(expression of these genes )Tj
/T1_4 1 Tf
0.005 Tw (i.e.)Tj
/T1_1 1 Tf
-0.05 Tw [( high risk, had greater)-5( )]TJ
0.015 Tc -0.022 Tw 0 -1.222 TD
[(overall mortality than low-risk individuals \(Siena)15( )]TJ
0.023 Tc 0.09 Tw T*
(cohort p)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\034)Tj
/T1_1 1 Tf
0.023 Tc 0.09 Tw 4.441 0 Td
[(0.0032, c-index 0.66; CI 0.55\2260.76\))23( )]TJ
0.029 Tc 0.189 Tw -4.441 -1.222 Td
(and Leuven cohort \(p)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\037)Tj
/T1_1 1 Tf
0.029 Tc 0.189 Tw 10.811 0 Td
[(0.0033; c-index 0.63;)29.1( )]TJ
0.015 Tc -0.003 Tw -10.811 -1.222 Td
(CI)Tj
/Span<>> BDC
( )Tj
EMC
[(0.54\2260.72\). R)25(esampling and validation of the)15( )]TJ
0.027 Tc 0.158 Tw T*
[(signature with nCounter showed six of these)27( )]TJ
0.019 Tc 0.05 Tw T*
[(nine genes were reproducibly expressed across)19.1( )]TJ
0.022 Tc 0.08 Tw T*
(all cohorts \(n)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\037)Tj
/T1_1 1 Tf
0.022 Tc 0.08 Tw 6.633 0 Td
[(168\) and predictive of mortality)22( )]TJ
0.036 Tc -0.036 Tw -6.633 -1.222 Td
[(\()0.5(p)]TJ
/T1_3 1 Tf
0 Tc 0 Tw (\034)Tj
/T1_1 1 Tf
0.036 Tc 0.283 Tw 1.48 0 Td
[(0.)0.5(00)0.5(00)0.5(1, h)0.5(az)0.5(ar)0.5(d ra)0.5(ti)0.5(o 3)0.5(.95)0.5(1,)0.5( CI)0.5( 2)0.5(.1)0.5(32)0.5(\226)]TJ
0.031 Tc 0.21 Tw -1.48 -1.222 Td
[(7.323\). This signature also showed stronger)31.1( )]TJ
0.015 Tc -0.049 Tw T*
[(predictive ability of mortality than the GAP index)15.1( )]TJ
-0.009 Tw T*
[(\(c-index 0.63; 95% CI 0.58\2260.69\), and was able)15( )]TJ
0.026 Tc 0.137 Tw T*
[(to signi\037cantly reduce the rate of error when)26.1( )]TJ
0.031 Tc 0.211 Tw 0 -1.222 TD
[(combined with the GAP index. Interestingly)33.3(,)31( )]TJ
0.021 Tc 0.066 Tw 0 -1.222 TD
[(closer examination of the BAL signature found)21( )]TJ
0.025 Tc 0.129 Tw T*
[(921 of the genes identi\037ed in the microarray)25( )]TJ
0.024 Tc 0.116 Tw T*
[(were also upregulated in airway basal cells. A)24( )]TJ
0.003 Tc -0.05 Tw T*
[(gene si)0.5(gnature was then developed using iso)0.5(lated)3( )]TJ
0.015 Tc -0.044 Tw 0 -1.222 TD
[(ABC )0.5(from )0.5(healthy )0.5(controls, )0.5(compared )0.5(to alveolar)15( )]TJ
0.026 Tc 0.137 Tw 0 -1.222 TD
[(macrophages and bronchial epithelial cells. A)26( )]TJ
0.015 Tc 0.004 Tw T*
[(total of 165 genes from the ABC signature were)15( )]TJ
0.008 Tc -0.05 Tw T*
[(among the 1582 genes associated with mortality)8( )]TJ
0.022 Tc -0.022 Tw 0 -1.222 TD
(\(p)Tj
/T1_3 1 Tf
0 Tc 0 Tw (\034)Tj
/T1_1 1 Tf
0.022 Tc 0.08 Tw 1.439 0 Td
[(0.0001\). F)25(urther analysis of a signature for)22( )]TJ
0.015 Tc 0.011 Tw -1.439 -1.222 Td
[(ABC)31(-derived genes revealed that 16 genes were)15( )]TJ
-0.017 Tw 0 -1.222 TD
[(signi\037cantly associated )0.5(with )0.5(increased )0.5(mortality)15( )]TJ
0.013 Tc -0.05 Tw T*
[(across all three cohorts, with increased mortality)13( )]TJ
0.002 Tc T*
[(risk in those within the high-risk group \(F)25.2(riedberg:)2( )]TJ
0.006 Tc 0 -1.222 TD
[(c-index 0.73; 95% CI 0.68\2260.77; Leuven: c-index)6( )]TJ
-0.007 Tc -0.052 Tw 0 -1.222 TD
[(0.67; 95% CI 0.56\2260.76; Siena: c-index 0.66, 95%)-7( )]TJ
0.019 Tc 0.05 Tw T*
[(CI 0.57\2260.74\). F)25(urther investigation of the BAL)19.1( )]TJ
0.015 Tc -0.027 Tw T*
[(cellular composition in IPF patients revealed the)15( )]TJ
0.008 Tc -0.05 Tw 0 -1.222 TD
(presence of cytokeratin 5/6 and )Tj
/T1_3 1 Tf
0 Tc 0 Tw (\036)Tj
/T1_1 1 Tf
0.008 Tc -0.05 Tw 14.696 0 Td
[(NP63, markers)8( )]TJ
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[(c)0.5(o)0.6(m)0.5(p)0.6(a)0.5(r)0.6(t)0.5(m)0.5(e)0.6(n)0.5(t)0.6( o)0.6(f)0.6( I)0.6(P)0.5(F)0.5( )0.5(t)0.6(i)0.5(s)0.6(s)0.5(u)0.6(e)0.5(.)0.5( )0.5(T)0.6(h)0.5(e)0.6(s)0.5(e)0.5( )0.5(c)0.6(e)0.5(l)0.6(l)0.5(s)0.5( )0.5(w)0.6(e)0.5(r)0.6(e)29( )]TJ
0.015 Tc -0.013 Tw T*
[(rarely observed in healthy controls, nor COPD or)15( )]TJ
-0.025 Tw T*
(sacroidosis patients.)Tj
0.92 0.18 0.59 0.65 k
/GS0 gs
/T1_2 1 Tf
-0.012 Tc 0.012 Tw 13 0 0 13 347.2441 735.7618 Tm
[(C)-0.8(om)-31.6(m)-4.6(e)1.1(nt)-27.1(a)-22.6(r)-60.6(y)]TJ
0 0 0 1 k
/GS1 gs
/T1_1 1 Tf
-0.01 Tc 0.007 Tw 9 0 0 9 347.2441 712.7618 Tm
[(The clinical management of IPF is still signi\037cantly)-10( )]TJ
0.009 Tw T*
[(hindered by a lack of tools to help identify patients)-10( )]TJ
-0.016 Tc -0.05 Tw T*
[(at risk of disease progression. Therefore, there is still)-16( )]TJ
-0.008 Tc 0.05 Tw 0 -1.222 TD
[(an unmet need to identify useful and measurable)-8( )]TJ
0 Tc 0.131 Tw 0 -1.222 TD
[(biomarkers in )0.5(IPF )0.5(to assist in the )0.5(diagnosis and )]TJ
-0.005 Tc 0.054 Tw T*
[(prognosis of the disease [6]. In this study)32.8(, P)]TJ
0.005 Tw (\034\033\032\032\031)Tj
0 Tc 0 Tw 21.26 0 Td
( )Tj
/T1_4 1 Tf
-0.03 Tc -0.05 Tw -21.26 -1.222 Td
(et)Tj
/Span<>> BDC
( )Tj
EMC
(al)Tj
/T1_1 1 Tf
(.)Tj
/Span<>> BDC
( )Tj
EMC
[([5] looked for genetic changes present in the BAL)-30( )]TJ
-0.01 Tc 0.015 Tw 0 -1.222 TD
[(that could predict survival at diagnosis in IPF)98(. They)-9.9( )]TJ
-0.003 Tw 0 -1.222 TD
[(were able to identify a genetic signature in IPF BAL)-10( )]TJ
-0.015 Tc -0.05 Tw T*
[(t)0.5(h)0.5(a)0.5(t)0.5( )0.6(w)0.5(a)0.5(s)0.5( )0.5(p)0.5(r)0.5(e)0.5(d)0.5(i)0.6(c)0.5(t)0.5(i)0.5(v)0.5(e)0.5( )0.5(o)0.6(f)0.5( )0.5(m)0.5(o)0.5(r)0.5(t)0.5(a)0.6(l)0.5(i)0.5(t)0.5(y)33.5(,)0.5( )0.5(w)0.6(h)0.5(i)0.5(c)0.5(h)0.5( )0.5(w)0.5(a)0.6(s)0.5( )0.5(e)0.5(n)0.5(r)0.5(i)0.5(c)0.5(h)0.6(e)0.5(d)-15( )]TJ
-0.014 Tc T*
[(with genes from airway basal cells. Importantly)32.6(, this)-14( )]TJ
T*
[(signature and predictive performance was validated)-14( )]TJ
-0.006 Tc 0.05 Tw 0 -1.222 TD
[(in replication cohorts. F)24.6(urthermore, the signature)-6( )]TJ
-0.022 Tc -0.05 Tw 0 -1.222 TD
[(had a more robust estimation of poor prognosis than)-22( )]TJ
-0.006 Tc 0.05 Tw T*
[(the GAP index, which predicts mortality based on)-6( )]TJ
-0.01 Tc -0.025 Tw T*
(patient clinical characteristics [7].)Tj
0.011 Tc 0.146 Tw 1.26 -1.222 Td
[(BAL samples have o\027en been overlooked in)11( )]TJ
0.007 Tc 0.08 Tw -1.26 -1.222 Td
[(IPF)98(, and typically used as means of exclusion of)7.1( )]TJ
0.014 Tc 0.179 Tw T*
[(other potential alternative conditions, such as)14( )]TJ
0 Tc -0.05 Tw T*
[(hypersensitive pneumonia, nonspeci)0.5(\037c i)0.5(nt)0.5(erstitial )]TJ
0.03 Tc 0.421 Tw T*
(pneumonia, and connective-tissue disease-)Tj
0.016 Tc 0.218 Tw 0 -1.222 TD
[(associated interstitial lung disease [8]. Whilst)16( )]TJ
-0.014 Tc -0.05 Tw 0 -1.222 TD
[(peripheral blood is a noninvasive means to examine)-14( )]TJ
0.006 Tc 0.065 Tw T*
[(potential genetic and protein changes, potential)6( )]TJ
0.007 Tc 0.081 Tw T*
[(markers signi\037cant changes present in the lung)7( )]TJ
0.006 Tc 0.072 Tw 0 -1.222 TD
[(may )0.5(be )0.6(either )0.5(missed )0.6(or )0.5(confounded )0.6(with )0.5(other)6.1( )]TJ
0.004 Tc 0.05 Tw 0 -1.222 TD
[(changes in the body once in circulation. BAL, on)4( )]TJ
0.005 Tc 0.051 Tw T*
[(the other hand, enables access to cells from the)5.1( )]TJ
0.002 Tc 0.05 Tw T*
[(most distal regions of the lung. There have been)2( )]TJ
0.007 Tc 0.08 Tw T*
[(previous studies which have identi\037ed potential)7( )]TJ
0.011 Tc 0.146 Tw 0 -1.222 TD
[(biomarkers in BAL from IPF patients; however)32.6(,)11( )]TJ
0 Tc -0.034 Tw 0 -1.222 TD
[(these have been to either )0.5(validate results )0.5(found in )]TJ
-0.017 Tc -0.05 Tw T*
(peripheral blood)Tj
/Span<>> BDC
( )Tj
EMC
[([9] or focus on speci\037c cells such as)-17( )]TJ
-0.011 Tc T*
[(mac)0.5(ropha)0.5(ges [)0.5(10].)0.5( This)0.5( is )0.5(the \037r)0.5(st st)0.5(udy t)0.5(o un)0.5(dergo)-11( )]TJ
0 Tc -0.018 Tw 0 -1.222 TD
(a detailed transcriptomic analysis of the BAL from )Tj
-0.025 Tw 0 -1.222 TD
(IPF patients to identify potential biomarkers.)Tj
0.017 Tc 0.223 Tw 1.26 -1.222 Td
[(O)0.5(n)0.5(e )0.6(o)0.5(f )0.6(th)0.5(e)0.5( )0.5(m)0.5(o)0.5(st)0.5( )0.6(in)0.5(t)0.5(e)0.5(re)0.5(s)0.5(t)0.5(i)0.5(ng)0.5( )0.5(t)0.5(h)0.5(i)0.5(n)0.5(gs)0.5( )0.5(i)0.5(n)0.5( )0.5(t)0.5(h)0.5(i)0.5(s)17( )]TJ
0.009 Tc 0.103 Tw -1.26 -1.222 Td
[(st)0.5(udy i)0.5(s the)0.5( i)0.5(den)0.5(ti\037c)0.5(atio)0.5(n of)0.5( gene)0.5(s upr)0.5(egu)0.5(late)0.5(d)9( )]TJ
0.007 Tc 0.08 Tw T*
[(in ABCs within the set of genes associated with)7( )]TJ
0.022 Tc 0.309 Tw 0 -1.222 TD
[(mortality)32.7(. F)24.8(urthermore, cells expressing ABC)22( )]TJ
-0.015 Tc -0.05 Tw 0 -1.222 TD
[(markers were detected in both BAL and tissue of IPF)-15( )]TJ
0 Tc -0.043 Tw T*
(patients, whilst also not being observed in healthy )Tj
0.006 Tc 0.068 Tw T*
[(individuals, nor in COPD or sarcoidosis patients.)6.1( )]TJ
-0.005 Tc -0.05 Tw 0 -1.222 TD
[(T)0.5(he)0.5( )0.5(pr)0.5(e)0.5(se)0.5(n)0.5(ce)0.5( )0.5(o)0.5(f )0.5(ab)0.5(n)0.5(o)0.5(rm)0.5(a)0.5(l )0.5(e)0.5(pi)0.5(t)0.5(he)0.5(l)0.5(i)0.5(al)0.5( )0.5(ce)0.5(l)0.5(ls)0.5( )0.5(in)0.5( )0.5(th)0.5(e)0.5( )0.5(IP)0.5(F)-5( )]TJ
0 Tc 0.046 Tw 0 -1.222 TD
(lung has been recognised for some time, seen in )Tj
-0.016 Tw T*
(both early and late stages of IPF [11]. In advanced )Tj
0.005 Tw T*
(IPF lesions, bronchiolisation and the formation of )Tj
0.009 Tc 0.112 Tw T*
[(\223honeycomb\224 cysts are a typical feature, which)9( )]TJ
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[(consists of mucociliary epithelium within the)17( )]TJ
0.007 Tc 0.082 Tw 0 -1.222 TD
[(distorted )0.5(alveolar )0.5(region )0.5([12]. )0.5(ABCs are thought)7( )]TJ
0.004 Tc 0.05 Tw T*
[(to act as a regenerative cell type in the lung and)4( )]TJ
0 Tc -0.043 Tw T*
(accumulate in response to bronchiolar injury)Tj
/Span<>> BDC
( )Tj
EMC
([13]. )Tj
0.016 Tc 0.218 Tw 0 -1.222 TD
[(Abnormal )0.5(activation of )0.5(ABCs, which )0.5(reside )0.5(in)16.1( )]TJ
0.008 Tc 0.1 Tw 0 -1.222 TD
[(the conducting airways down to the respiratory)8( )]TJ
0.013 Tc 0.176 Tw T*
[(bronchioles and function as stem cells, might)13( )]TJ
-0.008 Tc -0.05 Tw T*
[(contribute to re-epithelisation of damaged alveolar)-7.9( )]TJ
-0.018 Tc T*
[(epi)0.5(theli)0.5(um an)0.5(d resu)0.5(lting)0.5( bro)0.5(nchio)0.5(lisa)0.5(tion )0.5(of al)0.5(veola)0.5(r)-18( )]TJ
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(spaces. The work by P)Tj
0 Tw (\034\033\032\032\031)Tj
( )Tj
/T1_4 1 Tf
0.003 Tw 12.11 0 Td
(et al.)Tj
/T1_1 1 Tf
( [5] supports the )Tj
0.001 Tc 0.05 Tw -12.11 -1.222 Td
[(concept that the cells may be re-programmed in)1( )]TJ
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[(December )275(2019)]TJ
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(Journal club: Could airway basal cells be a novel predictor of mortality\
in IPF?)Tj
-0.01 Tc -0.05 Tw 9 0 0 9 56.6929 738.7618 Tm
[(IPF)98.3(, resulting in the abnormal re-epithelialisation in)-10( )]TJ
-0.004 Tc 0 -1.222 TD
[(the IPF lung and may be a novel prognostic feature)-4( )]TJ
0 Tc -0.025 Tw T*
(of the disease.)Tj
0.008 Tc 0.098 Tw 1.26 -1.222 Td
[(One of the limitations of this study is that it)8( )]TJ
0 Tc 0.049 Tw -1.26 -1.222 Td
(only examined a singular time-point, rather than )Tj
-0.002 Tc -0.05 Tw T*
[(assessing whether the BAL signature also changes)-2( )]TJ
0.014 Tc 0.187 Tw T*
[(over time in correlation to mortality)32.9(. It would)14( )]TJ
0 -1.222 TD
[(be interesting to replicate these \037ndings with)14( )]TJ
0 Tc 0.046 Tw 0 -1.222 TD
(longitudinal samples and assess the dynamics of )Tj
-0.008 Tc -0.05 Tw T*
[(the gene signature in additional cohorts of patients)-7.9( )]TJ
-0.011 Tc T*
[(with IPF over time, with respect to both therapeutic)-11( )]TJ
0.019 Tc 0.267 Tw T*
[(response and clinical disease progression. In)19( )]TJ
-0.013 Tc -0.05 Tw 0 -1.222 TD
[(addition, further work examining the potential roles)-13( )]TJ
0 Tc -0.004 Tw 0 -1.222 TD
(of these genes and how the ABCs are functionally )Tj
0.004 Tc 0.05 Tw T*
[(altered is needed, as it is presently unclear what)4( )]TJ
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( 2015; 3: 462\226472.)Tj
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[(4)-17(.)]TJ
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[(Chilosi M, P)16(oletti V)82.1(, Murer B, )]TJ
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