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Philip N. Hawkins - One of the best experts on this subject based on the ideXlab platform.
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Use of cAnAkinumAb in the cryopyrin-AssociAted periodic syndrome.
New England Journal of Medicine, 2009Co-Authors: Helen J Lachmann, Pierre Quartier, Jasmin B. Kuemmerle-deschner, Isabelle Koné-paut, Kieron S. Leslie, Eric Hachulla, Xavier Gitton, A Widmer, N Patel, Philip N. HawkinsAbstract:BAckground The cryopyrin-AssociAted periodic syndrome (CAPS) is A rAre inherited inflAmmAtory diseAse AssociAted with overproduction of interleukin-1. CAnAkinumAb is A humAn Anti–interleukin-1β monoclonAl Antibody. Methods We performed A three-pArt, 48-week, double-blind, plAcebo-controlled, rAndomized withdrAwAl study of cAnAkinumAb in pAtients with CAPS. In pArt 1, 35 pAtients received 150 mg of cAnAkinumAb subcutAneously. Those with A complete response to treAtment entered pArt 2 And were rAndomly Assigned to receive either 150 mg of cAnAkinumAb or plAcebo every 8 weeks for up to 24 weeks. After the completion of pArt 2 or At the time of relApse, whichever occurred first, pAtients proceeded to pArt 3 And received At leAst two more doses of cAnAkinumAb. We evAluAted therApeutic responses using diseAse-Activity scores And AnAlysis of levels of C-reActive Protein (CRP) And serum Amyloid A Protein (SAA). Results In pArt 1 of the study, 34 of the 35 pAtients (97%) hAd A complete response to cAnAkinumAb. Of ...
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Use of AnAkinrA (Kineret) in the treAtment of fAmiliAl cold AutoinflAmmAtory syndrome with A 16-month follow-up.
Journal of Cutaneous Medicine and Surgery, 2008Co-Authors: J. Barrie Ross, Laura Finlayson, P. Jennifer Klotz, Richard G. Langley, Roxanne Gaudet, Kara Thompson, Sarah M. Churchman, Michael F. Mcdermott, Philip N. HawkinsAbstract:BAckground: The susceptibility gene for fAmiliAl cold AutoinflAmmAtory syndrome (FCAS) hAs been mApped to chromosome 1q44 And A point mutAtion determined to be present in All Affected members of A lArge CAnAdiAn kindred. AnAkinrA (Kineret) is known to block the tumor necrosis fActor receptor And in the few pAtients with FCAS in whom it hAs been used, it hAs been shown to provide relief for this lifelong disAbility. Objective: To demonstrAte the efficAcy And sAfety of AnAkinrA (Kineret) in FCAS. Methods: Eight Affected fAmily members Aged 29 to 77 yeArs received AnAkinrA 100 mg subcutAneously dAily for 4 weeks preceded And followed by A 2-week control period. Results: The treAtment wAs rApidly effective pArAlleled by the immediAte fAll of the C-reActive Protein And serum Amyloid A Protein. The only significAnt side effect wAs An injection-site reAction in 50%, which declined in the follow-up period. The effect wAs sustAined in All who continued to use the treAtment At 4 And 16 months of follow-up.
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NAturAl history And outcome in systemic AA Amyloidosis.
The New England journal of medicine, 2007Co-Authors: Helen J Lachmann, Julian D. Gillmore, Janet A. Gilbertson, Hugh J. B. Goodman, J. Ruth Gallimore, Caroline A. Sabin, Philip N. HawkinsAbstract:BAckground Deposition of Amyloid fibrils derived from circulAting Acute-phAse reActAnt serum Amyloid A Protein (SAA) cAuses systemic AA Amyloidosis, A serious complicAtion of mAny chronic inflAmmAtory disorders. Little is known About the nAturAl history of AA Amyloidosis or its response to treAtment. Methods We evAluAted clinicAl feAtures, orgAn function, And survivAl Among 374 pAtients with AA Amyloidosis who were followed for A mediAn of 86 months. The SAA concentrAtion wAs meAsured seriAlly, And the Amyloid burden wAs estimAted with the use of whole-body serum Amyloid P component scintigrAphy. TherApy for inflAmmAtory diseAses wAs Administered to suppress the production of SAA. Results MediAn survivAl After diAgnosis wAs 133 months; renAl dysfunction wAs the predominAnt diseAse mAnifestAtion. MortAlity, Amyloid burden, And renAl prognosis All significAntly correlAted with the SAA concentrAtion during follow-up. The risk of deAth wAs 17.7 times As high Among pAtients with SAA concentrAtions in the highe...
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diAgnostic performAnce of Amyloid A Protein quAntificAtion in fAt tissue of pAtients with clinicAl AA Amyloidosis
Amyloid, 2007Co-Authors: Bouke P C Hazenberg, Philip N. Hawkins, Johan Bijzet, Pieter C Limburg, Martha Skinner, Irena Butrimiene, Avi Livneh, Olga Lesnyak, Evgeney L Nasonov, Anna FilipowiczsosnowskaAbstract:Objective. Amyloid A Protein quAntificAtion in fAt tissue is A new immunochemicAl method for detecting AA Amyloidosis, A rAre but serious diseAse. The objective wAs to Assess diAgnostic performAnce in clinicAl AA Amyloidosis.Methods. AbdominAl subcutAneous fAt tissue of pAtients with AA Amyloidosis wAs studied At the stArt of An internAtionAl clinicAl triAl with eprodisAte (NC-503; 1,3-propAnedisulfonAte; KiActA™), An AntiAmyloid compound. All pAtients hAd renAl findings, i.e. ProteinuriA (≥1 g/dAy) or reduced creAtinine cleArAnce (20 – 60 ml/min). Controls were pAtients with other types of Amyloidosis And Arthritic pAtients without Amyloidosis. Amyloid A Protein wAs quAntified by ELISA using monoclonAl AntihumAn serum Amyloid A Antibodies. Congo red stAined slides were scored by light microscopy in A semiquAntitAtive wAy (0 to 4+).Results. Ample fAt tissue (>50 mg) wAs AvAilAble for AnAlysis in 154 of 183 pAtients with AA Amyloidosis And in 354 controls. The sensitivity of Amyloid A Protein quAntificAtio...
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Amyloid loAd And clinicAl outcome in AA Amyloidosis in relAtion to circulAting concentrAtion of serum Amyloid A Protein
The Lancet, 2001Co-Authors: Julian D. Gillmore, M B Pepys, Laurence Lovat, Malcolm R Persey, Philip N. HawkinsAbstract:SummAry BAckground ReActive systemic (AA, secondAry) Amyloidosis occurs in chronic inflAmmAtory diseAses, And most pAtients present with nephropAthy. The Amyloid fibrils Are derived from the circulAting Acute-phAse reActAnt serum Amyloid A Protein (SAA), but the relAtion between production of fibril precursor Protein, Amyloid loAd, And clinicAl outcome in AA And other types of Amyloidosis is uncleAr. Methods We studied Amyloidotic orgAn function And survivAl prospectively for 12–117 months in 80 pAtients with systemic AA Amyloidosis in whom serum SAA concentrAtion wAs meAsured monthly And viscerAl Amyloid deposits were Assessed AnnuAlly by serum Amyloid P component scintigrAphy. Underlying inflAmmAtory diseAses were treAted As vigorously As possible. Findings Amyloid deposits regressed in 25 of 42 pAtients whose mediAn SAA vAlues were within the reference rAnge ( InterpretAtion Although isolAted Amyloid fibrils Are stAble in vitro, AA Amyloid deposits exist in A stAte of dynAmic turnover, And outcome is fAvourAble in AA Amyloidosis when the SAA concentrAtion is mAintAined below 10 mg/L. The potentiAl for Amyloid to regress And for the function of Amyloidotic orgAns to recover support therApeutic strAtegies to decreAse the supply of Amyloid fibril precursor Proteins in Amyloidosis generAlly.
Alexander S. Whitehead - One of the best experts on this subject based on the ideXlab platform.
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regulAtion of serum Amyloid A Protein expression during the Acute phAse response
Biochemical Journal, 1998Co-Authors: Liselotte E Jensen, Alexander S. WhiteheadAbstract:The Acute-phAse (AP) serum Amyloid A Proteins (A-SAA) Are multifunctionAl ApolipoProteins which Are involved in cholesterol trAnsport And metAbolism, And in modulAting numerous immunologicAl responses during inflAmmAtion And the AP response to infection, trAumA or stress. During the AP response the hepAtic biosynthesis of A-SAA is up-regulAted by pro-inflAmmAtory cytokines, And circulAting concentrAtions cAn increAse by up to 1000-fold. ChronicAlly elevAted A-SAA concentrAtions Are A prerequisite for the pAthogenesis of secondAry Amyloidosis, A progressive And fAtAl diseAse chArActerized by the deposition in mAjor orgAns of insoluble plAques composed principAlly of proteolyticAlly cleAved A-SAA, And mAy Also contribute to physiologicAl processes thAt leAd to Atherosclerosis. There is therefore A requirement for both positive And negAtive control mechAnisms thAt permit the rApid induction of A-SAA expression until it hAs fulfilled its host-protective function(s) And subsequently ensure thAt its expression cAn be rApidly returned to bAseline. These mechAnisms include modulAtion of promoter Activity involving, for exAmple, the inducer nucleAr fActor kAppAB (NF-kAppAB) And its inhibitor IkAppAB, up-regulAtory trAnscription fActors of the nucleAr fActor for interleukin-6 (NF-IL6) fAmily And trAnscriptionAl repressors such As yin And yAng 1 (YY1). Post-trAnscriptionAl modulAtion involving chAnges in mRNA stAbility And trAnslAtion efficiency permit further up- And down-regulAtory control of A-SAA Protein synthesis to be Achieved. In the lAter stAges of the AP response, A-SAA expression is effectively down-regulAted viA the increAsed production of cytokine AntAgonists such As the interleukin-1 receptor AntAgonist (IL-1RA) And of soluble cytokine receptors, resulting in less signAl trAnsduction driven by pro-inflAmmAtory cytokines.
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OrgAnizAtion of the region encompAssing the humAn serum Amyloid A (SAA) gene fAmily on chromosome 11p15.1.
Genomics, 1994Co-Authors: Grant C Sellar, Kathy Oghene, Shelagh Boyle, Wendy A. Bickmore, Alexander S. WhiteheadAbstract:The four members of the humAn serum Amyloid A Protein (SAA) gene fAmily Are clustered on humAn chromosome 11p15.1. Three genes Are differentiAlly expressed And encode smAll ApolipoProteins of M(r) 12-19 kDA: SAA1 And SAA2 encode the Acute phAse SAAs (A-SAAs), And SAA4 encodes the constitutively expressed SAA (C-SAA). A fourth locus, SAA3, is A pseudogene. The humAn SAA gene fAmily encompAsses ApproximAtely 150 kb contAined on A 900-kb yeAst ArtificiAl chromosome contig. SAA1 And SAA2 Are 15-20 kb ApArt And Are ArrAnged in divergent trAnscriptionAl orientAtions. SAA4 is 9 kb downstreAm of SAA2 And in the sAme orientAtion. SAA3 is 110 kb downstreAm of SAA4, And its relAtive orientAtion could not be determined. All genes known to be in the sAme humAn And mouse syntenic linkAge group As SAA were mApped within the contig. InterphAse FISH wAs used to orientAte the region relAtive to the centromere: cen-LDHC-LDHA-SAA1-SAA2-SAA4-SAA3-TP H-D11S18- KCNC1-MYOD1-pter.
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the mAjor Acute phAse reActAnts c reActive Protein serum Amyloid p component And serum Amyloid A Protein
Immunology Today, 1994Co-Authors: Diana M Steel, Alexander S. WhiteheadAbstract:AbstrAct Following An Acute phAse stimulus, such As infection or physicAl injury, mAny liver-derived plAsmA Proteins Are increAsed in concentrAtion. These provide enhAnced protection AgAinst invAding micro-orgAnisms, limit tissue dAmAge And promote A rApid return to homeostAsis. DiAnA Steel And AlexAnder WhiteheAd discuss the gene structure, regulAtion And possible clinicAl significAnce of the most drAmAticAlly induced Acute phAse reActAnts.
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The humAn serum Amyloid A Protein (SAA) superfAmily gene cluster: mApping to chromosome 11p15.1 by physicAl And genetic linkAge AnAlysis.
Genomics, 1994Co-Authors: Grant C Sellar, Wendy A. Bickmore, S.a. Jordan, Judy Fantes, Veronica Van Heyningen, Alexander S. WhiteheadAbstract:AbstrAct The humAn serum Amyloid A Protein (SAA) fAmily comprises A number of smAll, hepAticAlly produced, differentiAlly expressed ApolipoProteins encoded by genes locAlized on the short Arm of chromosome 11. SAA1 And SAA2 Are highly relAted genes thAt together encode the Acute-phAse SAAs; SAA3 is A pseudogene; And SAA4 is A low-level constitutively expressed gene encoding constitutive SAA. We hAve used A combinAtion of physicAl And genetic mApping techniques to provide evidence thAt the SAA gene superfAmily comprises A cluster of closely linked genes locAlized to 11p15.1. Pulsed-field gel electrophoresis plAced SAA1 to within 350 kb of the previously linked SAA2 And SAA4 genes. SAA locus-specific polymerAse chAin reAction AmplificAtion from A pAnel of somAtic cell hybrids cArrying defined regions of chromosome 11p mApped All four loci to 11p15.1-pter. Fluorescence in situ hybridizAtion AnAlysis using A cosmid probe cArrying the SAA2 And SAA4 genes refined the locAlizAtion of these genes (And SAA1 ) to 11p15.1. To order SAA3 on the genetic mAp, A highly polymorphic (CA) n dinucleotide repeAt within SAA3 wAs typed through the CEPH reference fAmilies. In AccordAnce with the physicAl locAlizAtion of SAAs 1, 2 , And 4, SAA3 mAps to the 11p15.1 region proximAl to the pArAthyroid hormone ( PTH ) locus (θ = 0.02; lod = 12.020) And distAl to D11S455 (θ = 0.058, lod = 8.274). To provide further evidence of An SAA superfAmily gene cluster, An Nco I restriction frAgment length polymorphism in the SAA2 gene wAs Also typed through the CEPH reference pAnel, Two-point lod score AnAlysis gAve θ = 0.001, with lod = 10.82 between SAA3 And SAA2 , thereby firmly confirming close linkAge between All known SAA superfAmily members on chromosome 11p15.1.
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A constitutively expressed serum Amyloid A Protein gene (SAA4) is closely linked to, And shAres structurAl similArities with, An Acute-phAse serum Amyloid A Protein gene (SAA2).
Genomics, 1993Co-Authors: Diana M. Steel, Grant C Sellar, Clarissa M. Uhlar, Susan Simon, Fred C. Debeer, Alexander S. WhiteheadAbstract:The Acute-phAse reActAnt serum Amyloid A (SAA) is A polymorphic ApolipoProtein encoded by A fAmily of highly homologous And closely linked genes: SAA1, SAA2, And SAA3. We hAve isolAted A humAn genomic cosmid clone contAining the gene encoding A fourth, constitutively expressed member of the humAn SAA superfAmily, C-SAA, together with An SAA2*2 (SAA2 betA) gene. The gene encoding C-SAA shAres the sAme 5' to 3' orientAtion As SAA2*2 And hAs the chArActeristic four-exon structure of the other members of the SAA superfAmily. The exons of the gene encoding C-SAA shAre only limited sequence identity with those of SAA1, SAA2, And SAA3; they specify An mRNA, represented by the CS-1 cDNA reported previously by us, which is expressed At low levels (relAtive to the Acute-phAse SAAs) in normAl And Acute-phAse liver. The gene encoding C-SAA is locAted 9 kb downstreAm of SAA2*2 And therefore occupies the locus thAt hAs been identified As contAining the SAA4 gene.
Helen J Lachmann - One of the best experts on this subject based on the ideXlab platform.
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SecondAry, AA, Amyloidosis
Rheumatic diseases clinics of North America, 2018Co-Authors: Riccardo Papa, Helen J LachmannAbstract:AA Amyloidosis, otherwise known As secondAry Amyloidosis, is A complicAtion of chronic inflAmmAtion. The Amyloid fibrils Are derived from the hepAtic Acute phAse reActAnt, serum Amyloid A Protein. ClinicAlly AA Amyloidosis hAs A predominAntly renAl presentAtion with ProteinuriA And renAl impAirment. UntreAted diseAse will progress to end-stAge renAl fAilure. TreAtment depends on complete control of the underlying chronic inflAmmAtory condition, And if this cAn be Achieved long-term outcomes Are fAvourAble. MediAn survivAl in pAtients with AA Amyloidosis now exceeds 12 yeArs Although renAl fAilure eventuAlly develops in more thAn 40%.
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Use of cAnAkinumAb in the cryopyrin-AssociAted periodic syndrome.
New England Journal of Medicine, 2009Co-Authors: Helen J Lachmann, Pierre Quartier, Jasmin B. Kuemmerle-deschner, Isabelle Koné-paut, Kieron S. Leslie, Eric Hachulla, Xavier Gitton, A Widmer, N Patel, Philip N. HawkinsAbstract:BAckground The cryopyrin-AssociAted periodic syndrome (CAPS) is A rAre inherited inflAmmAtory diseAse AssociAted with overproduction of interleukin-1. CAnAkinumAb is A humAn Anti–interleukin-1β monoclonAl Antibody. Methods We performed A three-pArt, 48-week, double-blind, plAcebo-controlled, rAndomized withdrAwAl study of cAnAkinumAb in pAtients with CAPS. In pArt 1, 35 pAtients received 150 mg of cAnAkinumAb subcutAneously. Those with A complete response to treAtment entered pArt 2 And were rAndomly Assigned to receive either 150 mg of cAnAkinumAb or plAcebo every 8 weeks for up to 24 weeks. After the completion of pArt 2 or At the time of relApse, whichever occurred first, pAtients proceeded to pArt 3 And received At leAst two more doses of cAnAkinumAb. We evAluAted therApeutic responses using diseAse-Activity scores And AnAlysis of levels of C-reActive Protein (CRP) And serum Amyloid A Protein (SAA). Results In pArt 1 of the study, 34 of the 35 pAtients (97%) hAd A complete response to cAnAkinumAb. Of ...
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NAturAl history And outcome in systemic AA Amyloidosis.
The New England journal of medicine, 2007Co-Authors: Helen J Lachmann, Julian D. Gillmore, Janet A. Gilbertson, Hugh J. B. Goodman, J. Ruth Gallimore, Caroline A. Sabin, Philip N. HawkinsAbstract:BAckground Deposition of Amyloid fibrils derived from circulAting Acute-phAse reActAnt serum Amyloid A Protein (SAA) cAuses systemic AA Amyloidosis, A serious complicAtion of mAny chronic inflAmmAtory disorders. Little is known About the nAturAl history of AA Amyloidosis or its response to treAtment. Methods We evAluAted clinicAl feAtures, orgAn function, And survivAl Among 374 pAtients with AA Amyloidosis who were followed for A mediAn of 86 months. The SAA concentrAtion wAs meAsured seriAlly, And the Amyloid burden wAs estimAted with the use of whole-body serum Amyloid P component scintigrAphy. TherApy for inflAmmAtory diseAses wAs Administered to suppress the production of SAA. Results MediAn survivAl After diAgnosis wAs 133 months; renAl dysfunction wAs the predominAnt diseAse mAnifestAtion. MortAlity, Amyloid burden, And renAl prognosis All significAntly correlAted with the SAA concentrAtion during follow-up. The risk of deAth wAs 17.7 times As high Among pAtients with SAA concentrAtions in the highe...
Jicheng Li - One of the best experts on this subject based on the ideXlab platform.
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serum Amyloid A Protein z And c4b binding Protein β chAin As new potentiAl biomArkers for pulmonAry tuberculosis
PLOS ONE, 2017Co-Authors: Tingting Jiang, Xiang Li, Su Yang, Chong Wang, Zhongliang Chen, Huihui Tu, Zhongjie Li, Jicheng LiAbstract:: The Aim of this study wAs to discover novel biomArkers for pulmonAry tuberculosis (TB). DifferentiAlly expressed Proteins in the serum of pAtients with TB were screened And identified by iTRAQ-two dimensionAl liquid chromAtogrAphy tAndem mAss spectrometry AnAlysis. A totAl of 79 AbnormAl Proteins were discovered in pAtients with TB compAred with heAlthy controls. Of these, significAnt differences were observed in 47 AbnormAlly expressed Proteins between pAtients with TB or pneumoniA And chronic obstructive pulmonAry diseAse (COPD). PAtients with TB (n = 136) exhibited significAntly higher levels of serum Amyloid A (SAA), vitAmin K-dependent Protein Z (PROZ), And C4b-binding Protein β chAin (C4BPB) thAn those in heAlthy controls (n = 66) (P<0.0001 for eAch) Albeit significAntly lower levels compAred with those in pAtients with pneumoniA (n = 72) (P<0.0001 for eAch) or COPD (n = 72) (P<0.0001, P<0.0001, P = 0.0016, respectively). After 6 months of treAtment, the levels of SAA And PROZ were significAntly increAsed (P = 0.022, P<0.0001, respectively), whereAs the level of C4BPB wAs significAntly decreAsed (P = 0.0038) in treAted TB cAses (n = 72). ClinicAl AnAlysis showed thAt there were significAnt differences in blood clotting And lipid indices in pAtients with TB compAred with heAlthy controls, pAtients with pneumoniA or COPD, And treAted TB cAses (P<0.05). CorrelAtion AnAlysis reveAled significAnt correlAtions between PROZ And INR (rs = 0.414, P = 0.044), And between C4BPB And FIB (rs = 0.617, P = 0.0002) in pAtients with TB. Receiver operAting chArActeristic curve AnAlysis reveAled thAt the AreA under the curve vAlue of the diAgnostic model combining SAA, PROZ, And C4BPB to discriminAte the TB group from the heAlthy control, pneumoniA, COPD, And cured TB groups wAs 0.972, 0.928, 0.957, And 0.969, respectively. Together, these results suggested thAt SAA, PROZ, And C4BPB mAy serve As new potentiAl biomArkers for TB. Our study mAy thus provide experimentAl dAtA for the differentiAl diAgnosis of TB.
Tania Siahanidou - One of the best experts on this subject based on the ideXlab platform.
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clinicAl vAlue of serum Amyloid A Protein high density lipoProtein cholesterol And ApolipoProtein A1 in the diAgnosis And follow up of neonAtAl sepsis
Pediatric Infectious Disease Journal, 2020Co-Authors: Vasiliki Bourika, Eugenia Hantzi, Athanasios Michos, Alexandra Margeli, Ioannis Papassotiriou, Tania SiahanidouAbstract:BACKGROUND: To evAluAte the performAnce of serum Amyloid-A (SAA), high-density lipoProtein cholesterol (HDL-C) And ApolipoProtein-A1 (Apo-A1) levels in the identificAtion And monitoring of neonAtAl sepsis. METHODS: This prospective study included 113 full-term septic neonAtes (postnAtAl Age 4-28 dAys) Admitted to the SpeciAl CAre NeonAtAl Unit of A University HospitAl from JAnuAry 1, 2016, to April 30, 2019, And 68 heAlthy neonAtes (controls). Blood sAmples were drAwn seriAlly in septic neonAtes At enrollment And on dAys 1, 3 And 7, And once in controls, for SAA, HDL-C And Apo-A1 determinAtion. RESULTS: At enrollment, SAA levels were significAntly higher in septic neonAtes in compArison with controls (mediAn 50.7 vs. 3.5 mg/L; P < 0.0001); HDL-C And Apo-A1 levels were significAntly lower in pAtients thAn in controls (P < 0.001 And P < 0.006, respectively). SAA levels were higher in culture-positive compAred with culture-negAtive sepsis (mediAn 202.0 vs. 14.2 mg/L; P < 0.0001). HDL-C And Apo-A1 levels did not differ significAntly between culture-positive And culture-negAtive sepsis. Receiver operAting chArActeristic curve AnAlysis of SAA levels At enrollment resulted in significAnt AreAs under the curve (AUC) for detecting sepsis {AUC = 0.929 [95% confidence intervAl: 0.885-0.973]; P < 0.0001} And Also for discriminAting between culture-positive And culture-negAtive sepsis [AUC = 0.933 (95% confidence intervAl: 0.882-0.984); P < 0.0001]. The combinAtion of HDL-C And Apo-A1 with SAA increAsed its diAgnostic performAnce. Furthermore, seriAl SAA levels following enrollment could indicAte clinicAl response in septic neonAtes. CONCLUSIONS: SAA seems to be A useful biomArker for identificAtion And monitoring of neonAtAl sepsis, And Also for discriminAting between culture-positive And culture-negAtive sepsis. HDL-C And Apo-A1 could be used As complementAry mArkers.