Detecting b-ISOX precipitates as biofluid biomarkers for diagnosis and monitoring of prediabetes, diabetes and cancers

Abstract

Described herein are detecting methods for conformational disease, aging and proteinopathies, by measuring the presence of b-isox-precipitates and the levels of b-isox-captured proteins in biofluids of healthy individuals and patients. Research identified additional biomarkers, which made it possible to detect, diagnose or treat, a human disease in a human subject by, with or without adding an isoxazole to an obtained biofluid sample, detecting the biomarker. Use of b-iso and / or biomarkers for diagnosing the disease are made possible.

Description

Docket No. 378-003PCTMETHODS FOR DETECTING B-ISOX PRECIPITATES OR CAPTURED PROTEINS AS BIOFLUID BIOMARKERS FOR DIFFERENTIAL DIAGNOSTIC, PATHOPHYSIOLOGY MONITORING OR PRESYMPTOMATIC DIAGNOSTIC OF PREDIABETES, DIABETES AND CANCERSCROSS REFERENCE

[0001] The present application claims priority benefit to US provisional application no. 63 / 682,115, filed 12 August 2024, and US provisional application no. 63 / 716,876 filed 6 November 2024, each application of which is hereby incorporated herein by reference in its entirety.TECHNOLOGY FIELD

[0002] A method detects, and makes it possible to diagnose or treat, a human disease in a human subject by adding an isoxazole to an obtained biofluid sample to form a biofluid isoxazole composition in the biofluid sample, and detecting a presence of the biofluid isoxazole composition. Research identified additional biomarkers, which made it possible to detect, diagnose or treat, a human disease in a human subject by, with or without adding an isoxazole to an obtained biofluid sample, detecting the biomarker.

[0003] Although usable for other purposes, the methods relate to methods for differential diagnostics, real-time pathophysiology monitoring, presymptomatic diagnostics, and pharmacoresponse measurement of conformational diseases and proteinopathies, such as neurodegenerative diseases, diabetes, cancer, psychiatric disorders, and even aging.INTRODUCTION

[0004] Conformational diseases include more than 50 disorders caused by the accumulation of unfolded or misfolded proteins. Improper protein folding can lead to deposit amorphous aggregates, such as p-TDP-43 aggregates, or ordered amyloid fibrils, such as synuclein and tau inclusions (1).

[0005] Proteinopathies refer to pathologies caused by certain misfolded aggregation-prone proteins, such as synuclein, TDP-43 and tau. For example, synucleinopathies and tauopathy.

[0006] In patients with Type 2 diabetes (T2D), pancreatic islet amyloid deposits, primarily composed of misfolded Insulin-degrading enzyme-Associated Peptide (IAPP), are frequently observed (2). These aggregates contribute to the reduction of 0 cell mass and exacerbate insulinDocket No. 378-003PCT secretion defects (3). Both in vitro and in vivo studies, including isolated islet cultures and transgenic mouse models overexpressing human IAPP, have demonstrated the prion-like properties of IAPP aggregates (4). When pancreatic tissue homogenates containing preformed IAPP aggregates are administered, they induce IAPP aggregation and diabetic pathology in both ex vivo and in vivo models (5). Notably, the pathological changes are absent when these aggregates are neutralized with antibodies specific to IAPP (6, 7).

[0007] Cancer research has revealed prion-like properties in certain tumor suppressor proteins, notably p53. In tumor tissues, mutant forms of p53 have been observed forming amyloid aggregates that compromise its functionality, potentially accelerating cancer progression (8). A promising therapeutic strategy involves reactivating mutant p53 to restore its essential downstream functions. Development is underway for small molecules designed to stabilize the native conformation of mutant p53, thereby preventing its misfolding and aggregation (9). However, extensive research is still required to optimize these molecules for specific p53 mutations and to assess their long-term safety and efficacy.

[0008] b-isox, biotinylated isoxazole (6-(5-(Thiophen-2-yl) isoxazole-3-carboxamido) hexyl 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl) pentanoate), is a small molecule known to precipitate RNA-binding proteins enriched in stress granules and RNA granules. Most of the proteins precipitated by b-isox contained low-complexity (LC) domain, which is responsible for the interaction with b-isox. The LC domains are intrinsic disordered structure and self-interactions. This novel type of self-interaction domain transiently forms a cross-0 polymeric condensed phase to perform crucial biological processes, including DNA transcription and replication, chromatin remodeling, nuclear pore passage, signal transduction, synaptic transmission, and cytoskeleton regulation by homotypic- or heterotypic cross-0 multimeric interactions. In contrast to pathological cross-0 aggregate stacked inregister, the physiological cross-0 multimers are loose and reversible (10, 11, 12, 13).

[0009] Currently, the cost-effective biomarker testing and noninvasive diagnostic techniques for detection of pathophysiology in clinical and asymptomatic stage of conformational diseases and proteinopathies, particularly prediabetes and early lung cancer, are unmet medical need. The present invention addresses this need and other needs.BRIEF SUMMARY

[0010] Methods for advances made in the differential diagnostics, real-time monitoring pathophysiology, and asymptomatic diagnostics of diabetes and cancers by detecting theDocket No. 378-003PCT presence of b-isox or its analogs precipitates or the level of b-isox or its analogs-captured proteins from plasma and CSF of patients. Example of neurodegenerative diseases includes, but not limited to, prediabetes, diabetes, lung cancer, pancreatic cancer, Alzheimer’s disease (AD), Parkinson’s disease (PD) and dementia with Lewy body (DLB).

[0011] Example of b-isox precipitated proteins for prediabetes diagnosis includes, but not limited to, IAPP, p-TDP-43, a-synuclein, amyloid p and KRT1.

[0012] Example of b-isox precipitated proteins for diabetes diagnosis includes, but not limited to, IAPP, p-TDP-43, a-synuclein, amyloid [3 and KRT1.

[0013] Example of b-isox precipitated proteins for lung cancer diagnosis includes, but not limited to, Rb, CD36, LGALS3BP, LEI, PPP1CB and SAAL

[0014] Example of b-isox precipitated proteins for pancreatic cancer diagnosis includes, but not limited to, p53, CD36, LGALS3BP, LEI, PPP1CB and SAAL

[0015] A method for detecting a human disease in a subject, comprises detecting a presence of biofluid isoxazole- precipitates in a biofluid sample of the subject. In some embodiments, the method of Claim 1 , wherein the isoxazole in the isoxazole-precipitates is biotin-isoxazole, (6-(5-(Thiophen-2-yl)isoxazole-3-carboxamido)hexyl 5-((3a.S',4.S',6a / ?)-2-oxohexahydro- 1 W- thieno[3,4-d]imidazol-4-yl)pentanoate) or its salt or an analog, specifically OG3 or OG4, thereof. OG3 (6-(5-(5-chlorothiophen-2-yl)isoxazole-3-carboxamido)hexyl 5-((3aS,4S,6aR)- 2-oxohexahydro-l H-thieno[3,4-d]imidazol-4-yl)pentanoate) and OG4 (6-(5- (benzo[b]thiophen-2-yl)isoxazole-3-carboxamido)hexyl5-((3aS,4S,6aR)-2-oxohexahydro- lH-thieno[3,4-d]imidazol-4-yl)pentanoate).

[0016] In some embodiments, the human disease is prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD or DLB.

[0017] In some embodiments, the biofluid is cerebrospinal fluid (CSF) or plasma.

[0018] A method for detecting a human conformational disease in a subject, comprises detecting a presence of biofluid isoxazole- captured proteins in a biofluid sample of the subject.

[0019] In some embodiments, the isoxazole is biotin-isoxazole (6-(5-(Thiophen-2- yl)isoxazole-3-carboxamido)hexyl 5-((3alS’,4lS',6aR)-2-oxohexahydro-177-thieno[3,4- d]imidazol-4-yl)pentanoate) or its analogous, specifically OG3 or OG4. OG3 (6-(5-(5- chlorothiophen-2-yl)isoxazole-3-carboxamido)hexyl 5-((3aS,4S,6aR)-2-oxohexahydro-lH- thieno[3,4-d]imidazol-4-yl)pentanoate) and OG4 (6-(5-(benzo[b]thiophen-2-yl)isoxazole-3-Docket No. 378-003PCT carboxamido)hexyl5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4- yl)pentanoate).

[0020] In some embodiments, the human conformational disease is prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD or DLB.

[0021] In some embodiments, the isoxazole-captured proteins are detected by a polypeptide.

[0022] In some embodiments, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the isoxazole-captured proteins. In some embodiments, the human diseases is prediabetes, and wherein polypeptide for detecting prediabetes is an antibody against IAPP, phospho-TDP-43, a-synuclein, amyloid , IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B. In some embodiments, the human diseases is diabetes, and wherein polypeptide for detecting diabetes is an antibody against IAPP, phospho-TDP-43, a-synuclein, amyloid p, PLEK, KRT1, IGA2, LBP, IGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE. In some embodiments, the human diseases is lung cancer, and wherein polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1. In some embodiments, the human diseases is pancreatic cancer, and wherein polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB 1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA1A, or TGFB1. In some embodiments, the human diseases is AD, and wherein polypeptide for detecting AD is an antibody against FN1, LTBP4, PLXNB2, SNED1,Docket No. 378-003PCTAFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, AP0L1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, LI CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7; In some embodiments, the human diseases is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR,Docket No. 378-003PCTNRXN3, VAT1, MEGF8, BMP6, HRNR, N0TCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB 10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1 , H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3 A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT IL, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B 1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7. In some embodiments, the human diseases is DLB, and wherein the polypeptide for detecting DLB is an antibody against IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1 , HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, IGHM, APOA2, KRT9, SERPINA7, or YWHAE. In some embodiments, the biofluid is plasma and CSF.

[0023] A method for detecting conformational disease in a subject, comprises the step of detecting the biofluid level of proteins with cross-P structure in the sample of the subject.

[0024] In some embodiments, the biofluid is plasma and CSF. In some embodiments, the proteins with cross-P structure is detected by a combination of a cross-P recognized probe and a polypeptide. In some embodiments, the conformational disease is prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD or DLB.

[0025] The use of a reagent for detecting a b-isox captured complex in the manufacture of a kit to evaluate the risks of developing conformational disease or the progression of conformational diseases.Docket No. 378-003PCT

[0026] A method for detecting aging and conformational disease in a subject, comprises the step of detecting the presence of low complexity protein’ complex in the sample of the subject.

[0027] In one aspect, a method for detecting a human disease in a human subject, comprising,

[0028] optionally obtaining a biofluid sample from the subject,

[0029] adding an isoxazole to the obtained biofluid sample to form a biofluid isoxazole composition in the biofluid sample, and

[0030] detecting a presence of the biofluid isoxazole composition.

[0031] In one embodiment, the isoxazole is biotin-isoxazole, (6-(5-(Thiophen-2- yl)isoxazole-3-carboxamido)hexyl 5-((3a.S',4.S\6af )-2-oxohexahydro- 1 / / -thieno|3,4- |imidazol-4-yl jpenlanoaie), or its salt or an analog thereof, especially biotin-isoxazole and very especially biotin-isoxazole, such as OG3 6-(5-(5-chlorothiophen-2-yl)isoxazole-3- carboxamidojhexyl 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4- yljpentanoate) and OG4 (6-(5-(benzo[b]thiophen-2-yl)isoxazole-3-carboxamido)hexyl5- ((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)pentanoate).

[0032] In one embodiment, the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

[0033] In one embodiment, the human disease is prediabetes, diabetes, lung cancer, and pancreatic cancer, Alzheimer’s disease (AD), parkinson disease dementia (PD), and dementia with Lewy body (DLB).

[0034] In one embodiment, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0035] In one embodiment, the concentration of isoxazole ranges from 0.075mM to 0.225 mM, preferably from 0.100 mM to 0.200mM, in the biofluid sample.Docket No. 378-003PCT

[0036] In one embodiment, the biofluid isoxazole composition is in a precipitate.

[0037] In one embodiment, the human disease is prediabetes, diabetes, lung cancer, and pancreatic cancer, Alzheimer’s disease (AD), parkinson disease dementia (PD), and dementia with Lewy body (DLB).

[0038] In one embodiment, further comprising adding a polypeptide to biofluid isoxazole composition in the biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0039] In one embodiment, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biofluid isoxazole composition.

[0040] In one embodiment, the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against IAPP, p-TDP-43, amyloid [3, a- synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1 , IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B.

[0041] In one embodiment, the human diseases is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against IAPP, p-TDP-43, amyloid [3, a-synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-3O, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE.

[0042] In one embodiment, the human diseases is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, mHl, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE,Docket No. 378-003PCTAPOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1.

[0043] In one embodiment, the human diseases is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS 1, HLA-B, TPM1, IGHV1-3, TUBA1A, or TGFB1.

[0044] In one embodiment, the human diseases is AD, and wherein polypeptide for detecting AD is an antibody against FN1 , LTBP4, PLXNB2, SNED1 , AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC,Docket No. 378-003PCTRPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAAO319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL1O, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7.

[0045] In one embodiment, the human disease is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPTNE1 , ANXA2, OMG, APLP2, GPLD1 , NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, N API LI, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2,Docket No. 378-003PCTCALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

[0046] In one embodiment, the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against KRT1, IAPP, IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, Fl 3 Al, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

[0047] In one embodiment, the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

[0048] In one embodiment, the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0049] Use of an isoxazole to detect a human disease in any method disclosed herein.

[0050] In one aspect, a method for detecting a human disease in a human subject, comprising,

[0051] detecting a presence of a biomarker from an obtained biofluid sample, and

[0052] optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample, and

[0053] wherein the human disease is selected from prediabetes, diabetes, lung cancer, pancreatic cancer, Alzheimer’s disease (AD), Parkinson disease dementia (PD), and dementia with Lewy body (DLB).

[0054] wherein, for prediabetes, the biomarker is selected from IAPP, p-TDP-43, amyloid , a-synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B;

[0055] wherein, for diabetes, the biomarker is selected from IAPP, p-TDP-43, amyloid 3, a-synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-Docket No. 378-003PCT30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE;

[0056] wherein, for lung cancer, the biomarker is selected from Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, TGKV3D-11 , GPX3, FCN3, SERPINC1 , CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1;

[0057] wherein, for pancreatic cancer, the biomarker is selected from p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA1A, or TGFBl;

[0058] wherein, for AD, the biomarker is selected from FN1, LTBP4, PLXNB2,SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1- 5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70,Docket No. 378-003PCTPGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1 , FUS, YBX1, RPL18A, TARSI , YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7;

[0059] wherein, for PD, the biomarker is selected from FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY,Docket No. 378-003PCTEIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, G0T1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7, and

[0060] wherein for DLB, the biomarker is selected from KRT1, IAPP, IGHG4, IGHV5- 10-1 , TGHA1 , IGA2, FN 1 , LBP, TGHV4-28, AMBP, IGHV3-48, HLA-A, F10, TGKV1 -27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

[0061] In one embodiment, the obtained biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

[0062] In one embodiment, the human disease is prediabetes.

[0063] In one embodiment, the human disease is diabetes.

[0064] In one embodiment, the human disease is lung cancer.

[0065] In one embodiment, the human disease is pancreatic cancer.

[0066] In one embodiment, the human disease is AD.

[0067] In one embodiment, the human disease is PD.

[0068] In one embodiment, the human disease is DLB.

[0069] In one embodiment, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, suchDocket No. 378-003PCT as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0070] In one embodiment, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0071] In one embodiment, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

[0072] In one embodiment, the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against IAPP, p-TDP-43, amyloid [3, a- synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B.

[0073] In one embodiment, the human diseases is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against IAPP, p-TDP-43, amyloid (3, oc-synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-3O, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE.

[0074] In one embodiment, the human disease is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1.Docket No. 378-003PCT

[0075] In one embodiment, the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA 1 A, or TGFB1.

[0076] In one embodiment, the human disease is AD, and wherein polypeptide for detecting AD is an antibody against FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1 , SERPINE1 , ANXA2, OMG, ACTN1, CD5L, GPLD1 , NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10,Docket No. 378-003PCTSF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7.

[0077] In one embodiment, the human disease is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

[0078] In one embodiment, the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against KRT1, IAPP, IGHG4, IGHV5-10-1, IGHA1, IGA2,Docket No. 378-003PCTFN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, Fl 3 Al, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

[0079] In one embodiment, the biofluid is plasma or CSF.

[0080] In one embodiment, the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0081] In one embodiment, use of the biomarker to detect the human disease in any method disclosed herein.

[0082] In one aspect, a method for detecting conformational disease in a human subject, comprising,

[0083] detecting a presence of amyloid oligomers from an obtained biofluid sample, and

[0084] optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

[0085] In one embodiment, the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

[0086] In one embodiment, the amyloid oligomer is selected from Al l recognized oligomers.

[0087] In one embodiment, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0088] In one embodiment, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a lightDocket No. 378-003PCT scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0089] In one embodiment, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

[0090] In one embodiment, the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against Al l.

[0091] In one embodiment, the human disease is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against Al l.

[0092] In one embodiment, the human diseases is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Al l.

[0093] In one embodiment, the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against Al l.

[0094] In one embodiment, the human disease is AD, and wherein the polypeptide for detecting AD is an antibody against Al l.

[0095] In one embodiment, the human disease is PD, and wherein the polypeptide for detecting PD is an antibody against Al l.

[0096] In one embodiment, the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against Al l.

[0097] In one embodiment, the human disease is ALS, and wherein the polypeptide for detecting ALS is an antibody against Al l.

[0098] In one embodiment, the biofluid is plasma or CSF.

[0099] In one embodiment, the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0100] In one embodiment, use of Al 1 recognized oligomers to detect conformational diseases in any method disclosed herein.Docket No. 378-003PCT

[0101] In one aspect, a method for detecting conformational disease in a human subject at the asymptomatic and prodromal stage, comprising,

[0102] detecting a presence of cross p-, amyloid oligomers from an obtained biofluid sample, and

[0103] optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

[0104] In one embodiment, the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

[0105] In one embodiment, the cross 0-, amyloid oligomer is Al 1 recognized proteins.

[0106] In one embodiment, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0107] In one embodiment, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0108] In one embodiment, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

[0109] In one embodiment, the polypeptide for detecting sporadic or SOD 1 inheritedALS is an antibody against amyloid oligomers.

[0110] In one embodiment, the biofluid is plasma or CSF.Docket No. 378-003PCT

[0111] In one embodiment, the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0112] In one embodiment, use of Al 1 recognized protein to detect sporadic or SOD1 inherited ALS in any method disclosed herein.

[0113] In one embodiment, use of any described substance or composition for diagnosing a human disease disclosed herein.

[0114] In one aspect, a method for detecting conformational disease in a human subject, comprising,

[0115] detecting a presence of LBP from an obtained biofluid sample, and

[0116] optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

[0117] In one embodiment, the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

[0118] In one embodiment, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0119] In one embodiment, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0120] In one embodiment, the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which hinds to the biomarker.Docket No. 378-003PCT

[0121] In one embodiment, the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against LBP.

[0122] In one embodiment, the human disease is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against LBP.

[0123] In one embodiment, the human disease is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against LBP.

[0124] In one embodiment, the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against LBP.

[0125] In one embodiment, the human disease is AD, and wherein the polypeptide for detecting AD is an antibody against LBP.

[0126] In one embodiment, the human disease is PD, and wherein the polypeptide for detecting PD is an antibody against LBP.

[0127] In one embodiment, the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against LBP.

[0128] In one embodiment, the human disease is ALS, and wherein the polypeptide for detecting ALS is an antibody against LBP.

[0129] In one embodiment, the biofluid is plasma or urine.

[0130] In one embodiment, the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0131] In one embodiment, use of LBP to detect conformational diseases in any method disclosed herein.

[0132] The terms “invention,” “the invention,” “this invention” and “the present invention” used in this patent are intended to refer broadly to all of the subject matter of this patent and the patent claims below. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the patent claims below. Embodiments of the invention covered by this patent are defined by the claims below, not thisDocket No. 378-003PCT summary. This summary is a high-level overview of various aspects of the invention and introduces some of the concepts that are further described in the Detailed Description section below. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all drawings and each claim.

[0133] The invention will become more apparent when read with the accompanying figures and detailed description which follow.

[0134] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0135] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiment(s) of the invention and together with the description, serve to explain the principles of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Illustrative embodiments of the present invention are described in detail below with reference to the following Figures:

[0137] Fig. 1 comprises a series of images that illustrate the analysis of chemical precipitates, specifically b-isox and its analogs, extracted from the plasma of healthy controls, prediabetic patients, diabetic and cancer patients. Panel (a) analyzes the size of chemical precipitates isolated from the plasma of healthy, prediabetic, and diabetic individuals using b-isox. Panel (b) analyzes the size of chemical precipitates isolated from the plasma of healthy, prediabetic, and diabetic individuals using OG3. Panel (c) analyzes the size of chemical precipitates isolated from the plasma of healthy, prediabetic, and diabetic individuals using OG4. Panel (d) analyzes the size of chemical precipitates isolated from the plasma of healthy and patients with lung cancer using b-isox. Panel (e) analyzes the size of chemical precipitates isolated from the plasma of healthy and patients with NSCL and pancreatic cancer using OG3. Panel (f) analyzes the size of chemical precipitates isolated from the plasma of healthy and patients with lung cancer using OG4. Panel (g) analyzes the size of chemical precipitates isolated from the plasma of healthy and patients with DLB using b-isox, OG3 and OG4. Panel (h) shows the size of b- isox precipitates exhibited a progressive decrease with disease advancement.Docket No. 378-003PCT

[0138] Fig. 2 is an assembly of images illustrating a validation of known and newly identified prediabetes and diabetes biomarkers by b-isox-ELISA. Panel (a) contains an assembly of images illustrating plasma levels of IAPP in healthy individuals (H) and patients with prediabetes and diabetes. Panel (b) contains an assembly of images illustrating plasma levels of p-TDP-43, a-synuclein, and amyloid P in healthy individuals (H) and patients with prediabetes and diabetes. Panel (c) contains an assembly of images illustrating plasma levels of KRT1 in healthy individuals (H) and patients with prediabetes and diabetes.

[0139] Fig. 3 is an assembly of images illustrating a validation of known and newly identified biomarkers of lung cancer and pancreatic cancer by b-isox-ELISA. Panel (a) contains an assembly of images illustrating plasma levels of Rb in healthy individuals (H) and patients with cancer (NSCLC). Panel (b) contains an assembly of images illustrating plasma levels of p53 in healthy individuals (H) and patients with cancer. Panel (c) contains an assembly of images illustrating plasma levels of CD36, LGALS3BP, LEI, PPP1CB and SAA1 in healthy individuals (H) and patients with cancer.

[0140] Fig. 4 is an assembly of images illustrating a validation of known and newly identified biomarkers of DLB by b-isox-ELISA. Panel (a) contains an assembly of images illustrating plasma levels of b-isox captured proteins, including a-synuclein (aSYN), CHL1, RUVBL1, BGN, NCAM, ANXA5, ANK1, DISCI, TDP-43, pTDP-43, Poly(GR), CD14, CAI, STOM, NONO, and PRDX2 in healthy individuals (H) and patients with DLB. Panel (b) contains an assembly of images illustrating plasma levels of IAPP and KRT1 in healthy individuals (H) and patients with DLB.

[0141] Fig. 5 is an assembly of images illustrating a validation of Al 1 recognized oligomers in diabetic and cancer patients by b-isox-ELISA. Panel (a) contains an assembly of images illustrating plasma levels of Al 1 recognized oligomers in healthy individuals (H), and patients with prediabetes or diabetes. Panel (b) contains an assembly of images illustrating plasma levels of Al l recognized oligomers in healthy individuals (H) and patients with lung or pancreatic cancer. Panel (c) contains an assembly of images illustrating plasma levels of Al 1 recognized oligomers in healthy individuals (H) and patients with DLB. Panel (d) presents a series of images illustrating the immunodepletion of plasma amyloid oligomers in patients with DLB using Al l antibodies, followed by b-isox ELISA detection of Amyloid oligomers of a- synuclein and p-TDP-43. After the immunodepletion process, a-synuclein and p-TDP-43 levels were reduced to those typical of healthy individuals. Panel (e) presents an analysisDocket No. 378-003PCT illustrating elevated Al l levels were noted in both a patient with S0D1 -mutated ALS (son) and a carrier of the inherited SOD1 mutation (asymptomatic mother), but not in a non- mutated individual (patient's brother) and health.

[0142] Fig. 6 is an assembly of images illustrating a validation of LBP level in prediabetes, diabetes, cancer and ALS patients by b-isox-ELISA (panel a, c, and d) or OG3-ELISA (panel b). Panel (a) contains an assembly of images illustrating plasma levels of LBP in healthy individuals (H) and patients with prediabetes and diabetes. Panel (b) contains an assembly of images illustrating plasma levels of LBP in healthy individuals (H) and patients with cancer. Panel (c) contains an assembly of images illustrating CSF, plasma and urine levels of SOD1 in a SOD 1 -mutated ALS patient treating with tofersen. Panel (d) contains an assembly of images illustrating urine levels of LBP in a SOD 1 -mutated ALS patient treating with tofersen.DESCRIPTION OF EMBODIMENTS

[0143] Reference will now be made in detail to the present embodiment(s) (exemplary embodiments) of the invention, an example(s) of which is (are) illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

[0144] The present application is related to International Application no. PCT / US2023 / 025073, filed 12 June 2024, and United States Provisional Application no. 63 / 351,813, filed 13 June 2022, the entire contents of each of which application is hereby incorporated herein by reference in its entirety.

[0145] Table 1. Differential expression of plasma proteins precipitated from healthy and prediabetic subjects using b-isox and analyzed by proteomics.

[0146] Table 2. Differential expression of plasma proteins precipitated from healthy, and diabetic patients using b-isox and analyzed by proteomics.

[0147] Table 3. Differential expression of plasma proteins precipitated from healthy and patients with lung cancer using b-isox and analyzed by proteomics.

[0148] Table 4. Differential expression of plasma proteins precipitated from healthy and patients with pancreatic cancer using b-isox and analyzed by proteomics.

[0149] Table 5. Differential expression of plasma proteins precipitated from healthy and AD patient using b-isox and analyzed by proteomics.Docket No. 378-003PCT

[0150] Table 6. Differential expression of plasma proteins precipitated from healthy and PD patient using b-isox and analyzed by proteomics.

[0151] Table 7. Differential expression of plasma proteins precipitated from healthy and DLB patient using b-isox and analyzed by proteomics.

[0152] Methods for the detection of conformational diseases and proteinopathies, such as prediabetes, diabetes, lung cancer, and pancreatic cancer, are described herein by using a smallmolecule to generate visual precipitates.

[0153] In addition, applicants identified novel and specific biofluid biomarkers for differential diagnosis and monitoring pathophysiology in patients with prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD and DLB.

[0154] Also described are novel methods for the plasma diagnosis of conformational diseases. The novel method named b-isox-ELISA, is combination of b-isox chemicalprecipitation and immunoassay with specific biomarkers of prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD and DLB. b-isox ELISA can be used to screen the risks of prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD and DLB. This invention can be used for real-time readout of pharmacoresponse, and monitoring the relief of pathological burden of misfolded disease proteins in clinical trial, preclinical diagnosis and clinical practice.Definitions

[0155] As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0156] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise.Representative Embodiments

[0157] Embodiment 1. A method for detecting a human disease in a human subject, comprises, optionally obtaining a biofluid sample from the subject, adding an isoxazole to the obtained biofluid sample to form a biofluid isoxazole composition in the biofluid sample, and detecting a presence of the biofluid isoxazole composition.

[0158] Embodiment 2. The method of Embodiment 1, wherein the isoxazole is biotin- isoxazole, (6-(5-(Thiophen-2-yl)isoxazole-3-carboxamido)hexyl 5-((3aS,4S,6aR)-2- oxohexahydro- 177-thieno[3,4-d]imidazol-4-yl)pentanoate), or its salt or an analog thereof, especially biotin-isoxazole or its salt and very especially biotin-isoxazole.Docket No. 378-003PCT

[0159] Embodiment 3. The method of Embodiments 1-2, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma. In some embodiments, the biofluid sample is in the form of a biological fluid such as urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, and optionally, the biofluid sample is further processed, e.g., to remove some components, e.g., by techniques to enrich components such as proteins by chemical precipitation. In some embodiments, the biofluid sample is blood, plasma, or serum, CSF, urine or saliva. In some embodiments, the biofluid sample is plasma or CSF.

[0160] Embodiment 4. The method of Embodiments 1-3, wherein the human disease is dementia with Lewy body (DLB), prediabetes, diabetes, cancer, or protienopathies.

[0161] Embodiment 5. The method of Embodiments 1-4, further comprises thereafter treating the human disease or thereafter changing an existing treatment based on the detecting the presence of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease. In some embodiments, the method further comprises diagnosing the human disease.

[0162] Embodiment 6. The method of Embodiments 1-5, wherein the concentration of isoxazole ranges from 0.075mM to 0.225 mM, preferably from 0.100 mM to 0.200mM, in the biofluid sample.

[0163] Embodiment 7. The method of Embodiments 1-6, wherein the biofluid isoxazole composition is in a precipitate.

[0164] Embodiments 8. The method of Embodiment 7, wherein the human disease is DLB, prediabetes, diabetes, lung cancer or pancreatic cancer.

[0165] Embodiment 9. The method of Embodiments 1-6, further comprises adding a polypeptide to biofluid isoxazole composition in the biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0166] Embodiment 10. The method of Embodiment 12, wherein the human conformational disease is prediabetes, diabetes, lung cancer, pancreatic cancer, AD, PD, or DLB.Docket No. 378-003PCT

[0167] Embodiment 11. The method of Embodiments 9-10, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biofluid isoxazole composition.

[0168] Embodiment 12. The method of Embodiment 11, wherein the human diseases is prediabetes, and wherein polypeptide for detecting prediabetes is an antibody against IAPP, phospho-TDP-43, a-synuclein, amyloid 0, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B.

[0169] Embodiment 13. The method of Embodiment 11, wherein the human diseases is diabetes, and wherein polypeptide for detecting diabetes is an antibody against IAPP, phospho- TDP-43, a-synuclein, amyloid £, PLEK, KRT1 , TGA2, LBP, TGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3- 23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5- 10-1, or YWHAE.

[0170] Embodiment 14. The method of Embodiment 11, wherein the human diseases is lung cancer, and wherein polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI , SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-30, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1.

[0171] Embodiment 15. The method of Embodiment 11, wherein the human diseases is pancreatic cancer, and wherein polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA 1 A, or TGFB1.Docket No. 378-003PCT

[0172] Embodiment 16. The method of Embodiment 11, wherein the human diseases is AD, and wherein polypeptide for detecting AD is an antibody against FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D- 15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1 , B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO 1 , NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7.

[0173] Embodiment 17. The method of Embodiment 11, wherein the human diseases is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1,Docket No. 378-003PCTMEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1 , API Bl , SNRPD3, RPL12, CAPZA1 , ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

[0174] Embodiments 18. The method of Embodiment 11, wherein the human diseases is DLB, and wherein the polypeptide for detecting DLB is an antibody against IGHG4, IGHV5- 10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

[0175] Embodiment 19. The method of Embodiments 9-18, wherein biofluid is plasma or CSF.

[0176] Embodiment 20. The method of Embodiments 9-19, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.Docket No. 378-003PCT

[0177] Embodiment 21. Use of an isoxazole to detect a human disease in any method of Embodiments 1-20.

[0178] Embodiment 22. A method for detecting a human disease in a human subject, comprises, detecting a presence of a biomarker from an obtained biofluid sample, and optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample, and wherein the human disease is selected from prediabetes, diabetes, lung cancer, and pancreatic cancer, AD, PD or DLB; wherein, for prediabetes, the biomarker is selected from IAPP, phospho-TDP-43, a-synuclein, amyloid p, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B; wherein, for diabetes, the biomarker is selected from a-synuclein, IAPP, phospho-TDP-43, amyloid , PLEK, KRT1, IGA2, LBP, IGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE; wherein for lung cancer, the biomarker is selected from Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1; wherein for pancreatic cancer, the biomarker is selected from p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1 , HLA-C, CPN1 , IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA1A, or TGFB1 ; wherein for AD, the biomarker is selected from FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9,Docket No. 378-003PCTCFHR3, CTSO, LTBP1, LRRC4B, LING01, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDT2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7 ; wherein for PD, the biomarker is selected from FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9,Docket No. 378-003PCTANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB 1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARS I, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1 , HNRNPD, NAP1 L1 , AP2B1 , HNRNPDL, RPS8, RPL36, TUBA IB, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7; and wherein for DLB, the biomarker is selected from IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1 , LBP, IGHV4- 28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, 1GHM, APOA2, KRT9, SERP1NA7, or YWHAE;.

[0179] Embodiment 23. The method of Embodiment 20, wherein the obtained biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma. The biofluid sample includes those in Embodiment 3.

[0180] Embodiment 24. The method of Embodiments s 22-23, wherein the human disease is prediabetes and diabetes.

[0181] Embodiment 25. The method of Embodiments 22-23, wherein the human disease is lung cancer and pancreatic cancer.

[0182] Embodiment 26. The method of Embodiments 22-23, wherein the human disease is DLB, AD and PD.

[0183] Embodiment 27. The method of Embodiments 22-26, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.Docket No. 378-003PCT

[0184] Embodiment 28. The method of Embodiments 22-27, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0185] Embodiment 29. The method of Embodiment 28, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

[0186] Embodiment 30. The method of Embodiment 29, wherein the human diseases is diabetes, and wherein the polypeptide for detecting prediabetes is an antibody against IAPP, phospho-TDP-43, a-synuclein, amyloid 0, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B; and diabetes is an antibody a-synuclein, IAPP, phospho-TDP-43, amyloid p, PLEK, KRT1, IGA2, LBP, IGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE.

[0187] Embodiment 31. The method of Embodiment 29, wherein the human diseases is cancer, and wherein polypeptide for detecting lung cancer is an antibody against Rb, IGHV5- 10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-30, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB 1 ; and pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1 , IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS 1, HLA-B, TPM1, IGHV1-3, TUBA1A, or TGFBl.Docket No. 378-003PCT

[0188] Embodiment 32. The method of Embodiment 29, wherein the human diseases is neurodegenerative disease, and wherein polypeptide for detecting DLB is an antibody against IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, IGHM, APOA2, KRT9, SERPINA7, or YWHAE; AD is an antibody against FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1 , NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7 ; and PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2,Docket No. 378-003PCTBGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QS0X2, PL0D1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1 , RPL4, TPI1 , KRT6B, RPL14, HNRNPA2B1 , NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT IL, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, E1F5A, E1F4A1, 1GLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

[0189] Embodiment 33. The method of Embodiments 30-32, wherein biofluid is plasma or CSF.

[0190] Embodiment 34. The method of Embodiment 28-33, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0191] Embodiment 35. Use of the biomarker to detect the human disease in any method of Embodiments 22-34.

[0192] Embodiment 36. A method for detecting proteinopathies in a human subject, comprises, detecting total amyloid oligomers from an obtained biofluid sample, and optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.Docket No. 378-003PCT

[0193] Embodiment 37. The method of Embodiment 34, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

[0194] Embodiment 38. The method of Embodiments 36-37, wherein the total amyloid oligomers are those that bind to the Al l antibody.

[0195] Embodiment 39. The method of Embodiments 36-38, further comprises thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

[0196] Embodiment 40. The method of Embodiments 36-39, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

[0197] Embodiment 41. The method of Embodiment 38, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

[0198] Embodiment 42. The method of Embodiment 40, wherein the human diseases is proteinopathies, and wherein Al 1 antibody for detecting proteinopathy is an antibody against amyloid oligomers.

[0199] Embodiment 43. The method of Embodiment 39-42, wherein biofluid is plasma or CSF.

[0200] Embodiment 44. The method of Embodiments 39-42, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

[0201] Embodiment 45. Use of total amyloid oligomers to detect proteinopathies in any method of Embodiments 36-44.Methods for Diagnosing Prediabetes, Diabetes, Lung Cancer, Pancreatic Cancer, and Dementia with Lewy Bodies (DLB) by Detecting b-isox or Its Analogs Precipitates from Plasma SamplesDocket No. 378-003PCT

[0202] Applicants uses a small-molecule compound, b-isox to generate precipitates, which can be visually observed in samples from patients with prediabetes and diabetes, but not in samples from healthy people (Fig. la), b-isox precipitates accurately discriminated healthy individuals from prediabetes and diabetes patients.

[0203] Applicants uses a small-molecule compound, OG3 to generate precipitates, which can be visually observed in samples from patients with prediabetes and diabetes, but not in samples from healthy people (Fig. lb). OG3 precipitates accurately discriminated healthy individuals from prediabetes and diabetes patients.

[0204] Applicants uses a small-molecule compound, OG4 to generate precipitates, which can be visually observed in samples from patients with prediabetes and diabetes, but not in samples from healthy people (Fig. 1c). OG4 precipitates accurately discriminated healthy individuals from prediabetes and diabetes patients.

[0205] Applicants uses a small-molecule compound, b-isox to generate precipitates, which can be visually observed in samples from patients with lung cancer, but not in samples from healthy people (Fig. Id), b-isox precipitates accurately discriminated healthy individuals from lung cancer patients.

[0206] Applicants uses a small-molecule compound, OG3 to generate precipitates, which can be visually observed in samples from patients with lung cancer, but not in samples from healthy people (Fig. le). OG3 precipitates accurately discriminated healthy individuals from lung cancer patients.

[0207] Applicants uses a small-molecule compound, OG4 to generate precipitates, which can be visually observed in samples from patients with lung cancer and pancreatic cancer, but not in samples from healthy people (Fig. If). OG4 precipitates accurately discriminated healthy individuals from lung cancer and pancreatic cancer patients.

[0208] Applicants uses a small-molecule compound, b-isox to generate precipitates, which can be visually observed in samples from patients with DLB, but not in samples from healthy people (Fig. 1g). b-isox precipitates accurately discriminated healthy individuals from DLB patients. These levels progressively decreased as the disease advanced, as illustrated in Fig. Ih.Methods for Prediabetes and Diabetes Diagnostic by Detecting Plasma b-isox-captured ProteinsDocket No. 378-003PCT

[0209] Applicants found b-isox ELISA detected the levels of IAPP tested in plasma, and significantly differed between prediabetes and diabetes groups and HCs (Fig 2a).

[0210] Applicants further identified novel biofluid biomarkers of PD by proteomics analysis of b-isox precipitates and further replicated and validated the identified biomarker candidates, including p-TDP-43, amyloid [3, a-synuclein and KRT1 in another cohort of patients (Fig. 2b and c, and Table 1, 2). The levels of these novel biomarkers tested in the plasma significantly differed between the disease groups and healthy individuals.Methods for Lung and Pancreatic Cancers Diagnostic by Detecting Plasma b-isox- captured Proteins

[0211] Applicants found tb-isox ELISA detected the levels of Rb and p53 tested in plasma, and significantly differed between cancer groups, including lung cancer and pancreatic cancer, and HCs (Fig. 3a and b).

[0212] Applicants further identified novel biofluid biomarkers of cancer by proteomics analysis of b-isox precipitates and further replicated and validated the identified biomarker candidates, including CD36, LGALS3BP, LEI, PPP1CB and SAA1 in another cohort of patients (Fig. 3c and Table 3, 4). The levels of these novel biomarkers tested in the plasma significantly differed between the disease groups and healthy individuals.Methods for AD, PD or DLB Diagnostic by Detecting Plasma b-isox-captured Proteins

[0213] Applicants further identified novel biofluid biomarkers of AD, PD and DLB by proteomics analysis of b-isox precipitates (Table 5, 6, 7).

[0214] Applicants found b-isox ELISA detected the levels of a-synuclein (aSYN), CHL1, RUVBL1, BGN, NCAM, ANXA5, ANK1, DISCI, TDP-43, pTDP-43, Poly(GR), CD14, CAI, STOM, NONO, PRDX2, and IAPP, KRT1 tested in plasma, and significantly differed between DLB groups and HCs (Fig. 4).Methods for Diagnostic of Proteinopathies by Detecting Plasma b-isox-captured All Recognized Amyloid Oligomers

[0215] Applicants found the b-isox ELISA detected the levels of Al l specific- captured amyloid oligomers tested in plasma, and significantly differed between proteinopathies, including diabetes, cancers, and neurodegenerative disease, and health controls (Fig. 5a-e).

[0216] Significantly, plasma levels of Al l antibody-recognized proteins were quantitatively assessed in individuals with and without SOD1 mutations using the b-isox -Docket No. 378-003PCTELISA method. Elevated Al l levels were noted in both a patient with SOD 1 -mutated ALS (son) and a carrier of the inherited SOD1 mutation (asymptomatic mother), but not in a nonmutated individual (patient's brother) and health, as shown in Fig. 5e. Thus, Al l proteins serve as not only for differential diagnostic of ALS, but also asymptomatic biomarkers for ALS risk assessment.

[0217] All of applicants’ data suggested plasma b-isox-captured, Al l recognized proteins can act as sensitive indicators of pathophysiological changes during the pathogenesis of diabetes, cancers, and neurodegenerative diseases, and enable a precision medicine approach for proteinopathies.Methods for Diagnostic of Proteinopathies by Detecting plasma or urine levels of LBP

[0218] Applicants found the levels of LBP tested in plasma and urine, and significantly differed between proteinopathies, including neurodegenerative disease, cancers, prediabetes, and diabetes, and health controls (Fig. 6a-d).

[0219] All of applicants’ data suggested plasma or urine LBP can act as sensitive indicators of pathophysiological changes during the pathogenesis of diabetes, cancers, and neurodegenerative diseases, and enable a precision medicine approach for proteinopathies.Description of Materials and Methods Used in the Examples

[0220] The following materials and methods were used in the Examples described below.

[0221] Reagents and Antibodies: b-isox was purchased from Sigma and Dalton dissolved in dimethyl sulfoxide (DMSO). The primary antibodies against SERPINB1 (MBS2025872) were purchased from Mybiosource. The primary antibodies against Rb (#17218-1-AP), p53 (#21891-1-AP), alpha-synuclein (#10842-l-AP phospho-TDP-43 (Ser 409 / 410) (#22309-1- AP), KRT1 (#16848-1-AP), Galectin- 3 -binding protein (#10281-l-AP), Nucleosome assembly protein 1-like 1 (#14898-1-AP), SAA1 (#16721-1-AP), CD36 (#18836-1-AP) and CD5L (#17224-1-AP) were purchased from Proteintech. Al l antibody (#AB9234) were purchased from MERCK MILIPORE. IAPP antibody (#PA5-98309) were purchased from Invitrogen.

[0222] b-isox Precipitation: 10 mM biotinylated isoxazole was added to the human blood plasma or CSF to a final concentration of 100 to 200 pM. The mixtures were then incubated at 4°C for 60 min, centrifuged at 15000 rpm for 15 min at 4°C, and the supernatant was discarded. The diameters of b-isox precipitates were measured.Docket No. 378-003PCT

[0223] b-isox precipitation and Enzyme-linked immunosorbent assay (ELISA) Blood samples from patients and healthy control were firstly collected through Blood Collection Tubes. Centrifugation of the tubes for 15 min at 2,200 'g. The resulting supernatant (upper layer) as the plasma sample. Before immunoassay, gently mixed 50-100mL plasma (or CSF) with 0.5-lmL b-isox through pipetting and rotated for Ih at 4°C. Wash each streptavidin-coated microwell 3 times by 200mL wash buffer (WB / (25mM Tris, 150mM NaCl; pH 7.2), 0.1% BSA, 0.05% Tween®-20) (do not allow wells to dry). Add lOOpL of the reaction mixtures to each well and incubate for 2h with shaking (-60 rpm) at room temperature (RT). Wash 3 times with 200pL WB when reaction finished. Add lOOmL primary antibody diluent (appropriate primary antibody dilution in WB), incubating for Ih at RT with shaking. At this step, a no primary antibody control should be included (Add antibody diluent alone in a sample well). Wash 3 times with 200, uL WB. Add lOOpL antibody diluent with appropriately diluted HRP- conjugated secondary antibody, incubating for Ih at RT with shaking. Equilibrate the TMB substrate solution to RT at this step. Wash 3 times with 200pL WB. Add I OO,uL of the TMB Substrate Solution to each microplate well, incubating for 15-30 min until the color develops. Stop the reaction by adding lOOpL 2M sulfuric acid (or 2N HC1). Measure the optical density of at 450 nm by a microplate reader.EXAMPLESExample 1: Analysis of b-isox, OG3, and OG4 precipitates in plasma from healthy controls and patients with prediabetes, diabetes, and cancers.

[0224] 100 ul of blood plasma from normal individuals and patients with prediabetes and diabetes was incubated with b-isox, and then centrifuged to pull down binding proteins. The statistical analysis of the size of b-isox precipitates is shown in Fig. la and d. The cut-off value is set at 1.2 mm. Values below 1.2 mm are considered within normal limits and suggest an absence of the significant pathological elevations typically associated with prediabetes, diabetes, and cancers. In our analysis, we employed a cut-off value of 1.2 mm for b-isox precipitates measured in plasma samples. This threshold was determined based on prior validation studies that identified it as critical for distinguishing pathological conditions from normal states.

[0225] The statistical analysis of the size of OG3 precipitates is shown in Fig. lb and e. The cut-off value is set at 1.5 mm. Values below 1.5 mm are considered within normal limits andDocket No. 378-003PCT suggest an absence of the significant pathological elevations typically associated with prediabetes, diabetes, and cancers.

[0226] The statistical analysis of the size of OG4 precipitates from the plasma of prediabetes, diabetes, and cancers is shown in Fig. 1c and f. Values above 2. 1 mm are considered as healthy.

[0227] The statistical analysis of the size of precipitates from the plasma of patient with DLB using b-isox, OG3 and OG4 is shown in Fig. 1g. These levels gradually decreased with the progression of the disease, as illustrated in Fig. Ih.Example 2: Identification and validation of novel plasma biomarkers of prediabetes and diabetes by b-isox ELISA

[0228] The plasma levels of IAPP in patients with prediabetes and diabetes were quantitatively analyzed using the b-isox-ELISA method. Significant differences in IAPP concentrations were observed between these patients and healthy individuals, as illustrated in Fig. 2a.

[0229] Furthermore, an examination of other proteins associated with conformational diseases revealed that plasma levels of p-TDP-43, amyloid 0, and a-synuclein exhibit a slight increase in patients with prediabetes and a significant increase in those with diabetes, as shown in Fig. 2b.

[0230] Proteomic analysis was employed to comprehensively investigate the precipitates isolated from the plasma of patients with prediabetes and diabetes. This analysis yielded se veral biomarker candidates for prediabetes and diabetes, as detailed in Table 1 and 2.

[0231] Subsequent validation of the identified biomarker candidates was conducted in an additional cohort of patients, confirming KRT1 as a biomarker of pathophysiology in prediabetes and diabetes. Significant differences in plasma levels of KRT1 between the disease groups and healthy individuals were observed, as depicted in Fig. 2c.Example 3: Identification and validation of novel plasma biomarkers of lung and pancreatic cancers by b-isox ELISA

[0232] Plasma levels of Rb in patients with lung cancer were quantitatively assessed using the b-isox-ELISA method. A significant increase in the plasma levels of Rb was observed at the la stage of lung cancer compared to healthy individuals. These levels gradually decreased with the progression of the disease, as illustrated in Fig. 3a.Docket No. 378-003PCT

[0233] Plasma levels of p53 in patients with pancreatic cancer were quantitatively analyzed using the b-isox-ELISA method. Significant differences in the protein concentrations of p53 were observed between these patients and healthy individuals, as depicted in Fig. 3b.

[0234] Proteomic analysis was employed to comprehensively investigate the precipitates isolated from the plasma of patients with lung and pancreatic cancers. This analysis yielded several biomarker candidates for lung and pancreatic cancers, as detailed in Table 3 and 4.

[0235] Subsequent validation of the identified biomarker candidates was conducted in an additional cohort of patients, confirming CD36, LGALS3BP, LEI, PPP1CB and SAA1 as a biomarker of pathophysiology in lung and pancreatic cancers. Significant differences in plasma levels of CD36, LGALS3BP, LEI, PPP1CB and SAA1 between the disease groups and healthy individuals were observed, as depicted in Fig. 3c.Example 4: Identification and validation of novel plasma biomarkers of DLB by b-isox ELISA

[0236] Plasma levels of b-isox captured proteins in a patient with DLB were quantitatively assessed using the b-isox-ELISA method. A significant increase in the plasma levels of b-isox captured proteins was observed in a patient with DLB compared to healthy individuals (Fig 4a). These biomarkers include a-synuclein (cxSYN), CHL1, RUVBL1, BGN, NCAM, ANXA5, ANK1, DISCI, TDP-43, pTDP-43, Poly(GR), CD14, CAI, STOM, NONO, and PRDX2.

[0237] Plasma levels of newly identified proteins, including IAPP and KRT1, in patients with DLB were quantitatively assessed using the b-isox-ELISA method. A significant increase in the plasma levels of IAPP and KRT1 was observed in a patient with DLB compared to healthy individuals (Fig 4b).Example 5: All recognized oligomers is a diagnostic and asymptomatic biomarker for diabetes, cancers, DLB and ALS

[0238] Plasma levels of Al l antibody-recognized proteins in patients with prediabetes and diabetes were quantitatively analyzed using the b-isox-ELISA method. Significant differences in the concentrations of Al l -positive oligomers were observed between these patients and healthy individuals, as depicted in Fig. 5a.

[0239] Plasma levels of Al l antibody -recognized proteins in patients with cancers were quantitatively analyzed using the b-isox-ELISA method. Significant differences in theDocket No. 378-003PCT concentrations of Al l -positive oligomers were observed between these patients and healthy individuals, as depicted in Fig. 5b.

[0240] Plasma levels of Al l antibody -recognized proteins in patients with DLB were quantitatively analyzed using the b-isox-ELISA method. Significant differences in the concentrations of Al l -positive oligomers were observed between these patients and healthy individuals, as depicted in Fig. 5c.

[0241] Fig. 5d displays images showing the use of Al 1 antibodies to immunodeplete plasma amyloid oligomers in DLB patients, followed by b-isox ELISA detection of a-synuclein and p-TDP-43. Post-depletion, a-synuclein and p-TDP-43 levels decreased to those typical in healthy individuals.

[0242] Plasma levels of Al 1 antibody-recognized proteins were quantitatively analyzed in patients with SODl-mutated ALS, and individuals with and without inherited SOD1 mutations, using the b-isox-ELISA method. Increased levels of Al l were observed in both the SODl- mutated ALS patient (son) and the individual with an inherited SOD1 mutation (asymptomatic mother). However, the individual without the SOD1 mutation (patient's brother) and health group did not show increased Al l levels, as depicted in Fig. 5e. Thus, Al l antibody- recognized proteins serve as asymptomatic biomarkers of ALS and can be used to assess whether subjects are at risk.Example 6: plasma and urine LBP is a diagnostic and asymptomatic biomarker for prediabetes, diabetes, cancers, DLB and ALS

[0243] Plasma levels of LBP in patients with prediabetes and diabetes were quantitatively analyzed using the b-isox-ELISA method. Significant differences in the concentrations of LBP were observed between these patients and healthy individuals, as depicted in Fig. 6a.

[0244] Plasma levels of LBP in patients with cancers were quantitatively analyzed using the b-isox-ELISA method. Significant differences in the concentrations of LBP were observed between these patients and healthy individuals, as depicted in Fig. 6b.

[0245] Urine levels of SOD1 and LBP in patients with ALS were quantitatively analyzed using the b-isox-ELISA method with b-isox and OG3. Significant differences in the concentrations of SOD1 and LBP in urine were observed after tofersen treatment, as depicted in Fig. 6c and d.Example 7: Identification of novel plasma biomarkers of AD, PD and DLBDocket No. 378-003PCT

[0246] Proteomic analysis was utilized to comprehensively investigate the precipitates isolated from the plasma of patients with AD. This analysis identified several biomarker candidates for AD, as detailed in Table 5.

[0247] Proteomic analysis was utilized to comprehensively investigate the precipitates isolated from the cerebrospinal fluid (CSF) of patients with PD. This analysis identified several biomarker candidates for PD, as detailed in Table 6.

[0248] Proteomic analysis was utilized to comprehensively investigate the precipitates isolated from the cerebrospinal fluid (CSF) of patients with DLB. This analysis identified several biomarker candidates for DLB, as detailed in Table 7.

[0249] Tables are as follows:

[0250] Table 1. Differential Expression Analysis of Plasma Proteins in Prediabetes People Compared to Healthy Controls.Accession Gene name Normalized ratio TrendP01602 IGKV1 -5 2.17421671 19016504 up-regulatedQ9UK55 SERPINA10 8.4566966623946006E-3A0A0B4J1X5 IGHV3-74 8.4566966623946006E-3P02656 APOC3 8.4566966623946006E-3Q9HBI1 PARVB 8.4566966623946006E-3P01764 IGHV3-23 0.21564576489106216P23528 CFL1 0.24017018521200645. down-regulatedPODOY2 IGLC2 0.35264425082185458P02766 TTR 0.37124898347912272P35542 SAA4 0.40084742179750371P69905 HBA1 0.41268679712485612P68871 HBB 0.41437813645733523P05452 CLEC3B 0.44735925344067407

[0251] Table 2. Differential Expression Analysis of Plasma Proteins in Diabetes Patients Compared to Healthy Controls.Accession Gene name Normalized ratio TrendP08567 PLEK 3.1614754178244442 up-regulatedP04264 KRT1 3.0594923398301068 up-regulatedImmunoglobulinPODOX2 alpha-2 heavy 2.0477554549656536 up-regulated chainDocket No. 378-003PCTP18428 LBP 2.4848257892270977 up-regulatedP01768 IGHV3-30 2.8603825208887832 up-regulatedA0A0C4DH34 IGHV4-28 2.0267113277604731 up-regulatedP0C0L5 C4B 3.2901683495792033 up-regulatedP04114 APOB 2.0930812674075812 up-regulatedP02760 AMBP 2.63699101671071 16 up-regulatedP07437 TUBB 2.0339958333314971 up-regulatedP04406 GAPDH 2.0145704851420998 up-regulatedP35908 KRT2 80.938950789156266 up-regulatedP13645 KRT10 80.938950789156266 up-regulatedQ9UK55 SERPINA10 8.093895078915626E-3 down-regulatedA0A0B4J1X5 IGHV3-74 8.093895078915626E-3 down-regulatedP02656 APOC3 8.093895078915626E-3 down -regulatedP01764 IGHV3-23 0.34884687790126362 down-regulatedPODOY2 IGLC2 0.322137024140842 down-regulatedP05452 CLEC3B 8.093895078915626E-3 down-regulatedA0A075B6H7 IGKV3-7 0.40145719591421519 down-regulatedA0A0C4DH25 IGKV3D-20 0.4581 1446146662455 down-regulatedA0A0C4DH72 IGKV1 -6 0.4734928621 1656422 down-regulated043866 CD5L 0.45568629294294982 down-regulatedP01871 IGHM 0.47430225162445583 down-regulatedP01599 IGKV1 -17 0.46863652506921483 down-regulatedA0A0J9YXX1 IGHV5-10-1 5.2610318012951574E-2 down-regulatedP62258 YWHAE 8.093895078915626E-3 down-regulated

[0252] Table 3. Differential Expression Analysis of Plasma Proteins in Lung Cancer Patients Compared to Healthy Controls.Accession Gene name Normalized ratio TrendA0A0J9YXX1 IGHV5-10-1 2.002129075 up-regulatedQ13011 ECH1 2.14582255 up-regulatedP12931 SRC 2.167110472 up-regulatedP40197 GP5 2.174029047 up-regulatedQ71 U36 TUBA1A 2.341 139235 up-regulatedQ15942 ZYX 2.407663992 up-regulatedP18428 LBP 2.440128073 up-regulatedQ14247 CTTN 2.453965222 up-regulatedP00488 F13A1 2.486961502 up-regulatedP04792 HSPB1 2.54497109 up-regulatedQ14697 GANAB 2.574241982 up-regulatedDocket No. 378-003PCTP16671 CD36 3.002129217 up-regulatedP07900 HSP90AA1 3.357637516 up-regulatedP01 137 TGFB1 3.484300653 up-regulatedP31 150 GDI1 3.621075553 up-regulatedP50148 GNAQ 5.309207777 up-regulatedP0DJI8 SAA1 1 1.31346621 up-regulatedP02741 GRP 17.72219517 up-regulatedP0DJI9 SAA2 53.2198053 up-regulated043294 TGFB1 I1 53.2198053 up-regulatedP06744 GPI 53.2198053 up-regulated015143 ARPC1 B 53.2198053 up-regulatedP55209 NAP1 L1 53.2198053 up-regulatedQ9Y251 HPSE 53.2198053 up-regulatedQ8N0Y7 PGAM4 53.2198053 up-regulatedP19367 HK1 53.2198053 up-regulatedQ15833 STXBP2 53.2198053 up-regulatedQ27J81 INF2 53.2198053 up-regulatedP40227 CCT6A 53.2198053 up-regulatedQ06187 BTK 53.2198053 up-regulatedP30740 SERPINB1 53.2198053 up-regulatedA0A0A0MT36 IGKV6D-21 0.005321981 down-regulatedP02655 APOC2 0.005321981 down-regulatedP35858 IGFALS 0.005321981 down-regulatedP02656 APOC3 0.149547653 down-regulatedP04114 APOB 0.163384802 down-regulatedP02652 APOA2 0.195848884 down-regulatedP19827 ITIH1 0.221926588 down-regulatedP19823 ITIH2 0.222458786 down-regulatedP02766 TTR 0.234699341 down-regulatedP08519 LPA 0.253326273 down-regulatedP27169 PON1 0.25705166 down-regulatedP04439 HLA-A 0.263438036 down-regulatedP05090 APOD 0.271953205 down-regulatedP02647 APOA1 0.27621079 down-regulatedP35542 SAA4 0.288451345 down-regulatedP05452 CLEC3B 0.292708929 down-regulatedP02765 AHSG 0.312400257 down-regulatedP29622 SERPINA4 0.325705208 down-regulatedP2531 1 AZGP1 0.354443903 down-regulatedDocket No. 378-003PCTP04278 SHBG 0.364023468 down-regulatedP05154 SERPINA5 0.365620062 down-regulatedQ06033 ITIH3 0.367748855 down-regulatedP02787 TF 0.377860618 down-regulatedP00739 HPR 0.381053806 down-regulatedP02649 APOE 0.386375786 down-regulated095445 APOM 0.391 165569 down-regulatedA0A0A0MRZ8 IGKV3D-11 0.398616342 down-regulatedP22352 GPX3 0.402873926 down-regulated075636 FCN3 0.411921293 down-regulatedP01008 SERPINC1 0.415646679 down-regulatedQ96IY4 CPB2 0.418839868 down-regulatedP01602 IGKV1 -5 0.426822839 down-regulatedP02753 RBP4 0.430548225 down-regulatedP06727 APOA4 0.432677017 down-regulatedQ96PD5 PGLYRP2 0.434805809 down-regulatedP01768 IGHV3-30 0.450239553 down-regulatedP02768 ALB 0.455561533 down-regulatedP20851 C4BPB 0.469930881 down-regulatedP43652 AFM 0.470463079 down-regulatedP02774 GC 0.477381654 down-regulatedP01861 IGHG4 0.480574842 down-regulatedP69905 HBA2 0.48376803 down-regulatedP08185 SERPINA6 0.486961219 down-regulatedP08697 SERPINF2 0.492815397 down-regulatedP10909 CLU 0.496008585 down-regulatedQ08380 LGALS3BP 0.49760518 down-regulatedP03952 KLKB1 0.498137378 down-regulated

[0253] Table 4. Differential Expression Analysis of Plasma Proteins in Pancreatic Cancer Patients Compared to Healthy Controls.Accession Gene name Normalized ratio TrendP10643 C7 2.279126038 up-regulatedP02748 C9 2.167857162 up-regulatedP05160 F13B 3.339952183 up-regulatedP27824 CANX 2.105622028 up-regulatedQ14697 GANAB 2.314958388 up-regulatedP50148 GNAQ 2.159370553 up-regulatedP0DJI8 SAA1 2.333817519 up-regulatedDocket No. 378-003PCTP02741 CRP 6.163164164 up-regulatedP0DJI9 SAA2 94.29565734 up-regulated043294 TGFB1 I1 94.29565734 up-regulatedP06744 GPI 94.29565734 up-regulated015143 ARPC1 B 94.29565734 up-regulatedP55209 NAP1 L1 94.29565734 up-regulatedQ9Y251 HPSE 94.29565734 up-regulatedQ8N0Y7 PGAM4 94.29565734 up-regulatedP55058 PLTP 94.29565734 up-regulatedA0A0A0MT36 IGKV6D-21 0.009429566 down-regulatedP02655 APOC2 0.297974277 down-regulatedP35858 IGFALS 0.410186109 down-regulatedP02656 APOC3 0.346065062 down-regulatedP04114 APOB 0.395098804 down-regulatedP02652 APOA2 0.303632017 down-regulatedP27169 PON1 0.44036072 down-regulatedP02647 APOA1 0.479021939 down-regulatedP05452 CLEC3B 0.449790286 down-regulatedP04278 SHBG 0.359266454 down-regulatedP05154 SERPINA5 0.388498108 down-regulated075636 FCN3 0.291373581 down-regulatedQ96IY4 CPB2 0.009429566 down-regulatedP01768 IGHV3-30 0.093352701 down-regulatedQ08380 LGALS3BP 0.466763504 down-regulatedImmunoglobulinP0DOX5 gamma-1 heavy 0.454505068 down-regulated chainP01597 IGKV1 -39 0.358323498 down-regulatedP10720 PF4V1 0.361 152368 down-regulatedP01593 IGKV1 D-33 0.488451505 down-regulatedP06310 IGKV2-30 0.354551672 down-regulatedP62873 GNB1 0.009429566 down-regulatedP31946 YWHAB 0.009429566 down-regulatedQ9H0U4 RAB1 B 0.009429566 down-regulatedQ9UK55 SERPINA10 0.497881071 down-regulatedP10809 HSPD1 0.009429566 down-regulatedP10321 HLA-C 0.468649417 down-regulatedP15169 CPN1 0.497881071 down-regulatedA0A075B6R2 IGHV4-4 0.009429566 down-regulatedP04632 CAPNS1 0.009429566 down-regulatedDocket No. 378-003PCTP01889 HLA-B 0.207450446 down-regulatedP09493 TPM1 0.009429566 down-regulatedA0A0C4DH29 IGHV1 -3 0.009429566 down-regulatedQ71 U36 TUBA1A 0.4733642 down-regulatedP01 137 TGFB1 0.009429566 down-regulated

[0254] Table 5. Differential Expression Analysis of Plasma Proteins in DLB Patient Compared to Healthy Controls.Accession Gene name Normalized ratio TrendP01861 IGHG4 2.517046607 Up-regulatedA0A0J9YXX1 IGHV5-10-1 2.44438575 Up-regulatedP01876 IGHA1 2.301858685 Up-regulatedImmunoglobulinPODOX2 alpha-2 heavy 2.476058431 Up-regulated chainP02751 FN1 2.672615365 Up-regulatedP18428 LBP 3.002383869 Up-regulatedA0A0C4DH34 IGHV4-28 2.295337838 Up-regulatedP02760 AMBP 3.375003648 Up-regulatedP01763 IGHV3-48 93.15494474 Up-regulatedP04439 HLA-A 93.15494474 Up-regulatedP00742 F10 93.15494474 Up-regulatedA0A075B6S5 IGKV1 -27 93.15494474 Up-regulatedQ9UK55 SERPINA10 0.365167383 Down-regulatedQ9HBI1 PARVB 9.32E-03 Down-regulatedPODOY2 IGLC2 0.436896691 Down-regulatedP02766 TTR 0.292506526 Down-regulatedP69905 HBA1 0.425718097 Down-regulatedP68871 HBB 0.359578087 Down-regulatedP05452 CLEC3B 9.32E-03 Down-regulatedP00915 CA1 0.466706273 Down-regulatedP02647 APOA1 0.418265702 Down-regulatedP27105 STOM 9.32E-03 Down-regulatedP02745 C1 QA 9.32E-03 Down-regulated043866 CD5L 0.363304284 Down-regulatedP40197 GP5 9.32E-03 Down-regulatedP35858 IGFALS 0.439691339 Down-regulatedP15169 CPN1 0.251518351 Down-regulatedA0A0C4DH69 IGKV1 -9 9.32E-03 Down-regulatedP00488 F13A1 9.32E-03 Down-regulatedDocket No. 378-003PCTP01871 IGHM 0.354920339 Down-regulatedP02652 APOA2 9.32E-03 Down-regulatedP35527 KRT9 9.32E-03 Down-regulatedP05543 SERPINA7 0.48906346 Down-regulatedP62258 YWHAE 9.32E-03 Down-regulated

[0255] Table 6. Differential Expression Analysis of Plasma Proteins in AD Patient Compared to HealthyControls.Accession Gene name Normalized ratio TrendP02751 FN1 15.44026846 up-regulatedQ8N2S1 LTBP4 18.3100671 1 up-regulated015031 PLXNB2 134.2281879 up-regulatedQ8TER0 SNED1 134.2281879 up regulatedP43652 A M 134.2281879 up-regulatedP16157 ANK1 134.2281879 up-regulatedP1 1277 SPTB 134.2281879 up-regulatedQ92876 KLK6 134.2281879 up-regulatedP35442 THBS2 134.2281879 up-regulatedQ562R1 ACTBL2 134.2281879 up-regulated014791 APOL1 134.2281879 up-regulatedP05121 SERPINE1 134.2281879 up-regulatedP07355 ANXA2 134.2281879 up-regulatedP23515 OMG 134.2281879 up-regulatedP12814 ACTN1 57.99194631 up-regulated043866 CD5L 134.2281879 up-regulatedP80108 GPLD1 134.2281879 up-regulatedQ92823 NRCAM 134.2281879 up-regulatedQ14767 LTBP2 134.2281879 up-regulatedQ14520 HABP2 134.2281879 up-regulatedP21810 BGN 20.18657718 up-regulatedP43251 BTD 134.2281879 up-regulatedP04114 APOB 134.2281879 up-regulatedQ9H2X0 CHRD 134.2281879 up-regulatedA0A087WSY6 IGKV3D-15 134.2281879 up-regulatedP20851 C4BPB 134.2281879 up-regulatedA0A0J9YXX1 IGHV5-10-1 134.2281879 up-regulatedP02042 HBD 134.2281879 up-regulatedQ6YHK3 CD109 134.2281879 up-regulatedQ6ZRP7 QSOX2 134.2281879 up-regulatedDocket No. 378-003PCTQ02809 PLOD1 134.2281879 up-regulatedQ96KG7 MEGF10 134.2281879 up-regulatedP1 1362 FGFR1 134.2281879 up-regulatedP49257 LMAN1 134.2281879 up-regulatedP00915 CA1 134.2281879 up-regulatedQ9C0A0 CNTNAP4 134.2281879 up-regulatedP49641 MAN2A2 134.2281879 up-regulatedQ8IV08 PLD3 134.2281879 up-regulatedQ9UBG0 MRC2 134.2281879 up-regulatedP02533 KRT14 134.2281879 up-regulatedP35052 GPC1 134.2281879 up-regulatedP60033 CD81 26.24026846 up regulatedP27105 STOM 134.2281879 up-regulatedP12277 CKB 134.2281879 up-regulated014594 NCAN 134.2281879 up-regulatedQ99972 MYOC 134.2281879 up-regulatedQ9NPR2 SEMA4B 134.2281879 up-regulatedP47972 NPTX2 134.2281879 up-regulatedP02461 C0L3A1 134.2281879 up-regulatedQ8IXL6 FAM20C 134.2281879 up-regulatedP07942 LAMB1 134.2281879 up-regulatedQ06033 ITIH3 134.2281879 up-regulatedQ7Z3B1 NEGR1 134.2281879 up-regulatedP01602 IGKV1 -5 16.91946309 up-regulatedP1 1047 LAMC1 134.2281879 up-regulatedQ53RD9 FBLN7 134.2281879 up-regulatedP12110 COL6A2 134.2281879 up-regulatedP02549 SPTA1 134.2281879 up-regulatedQ6UX72 B3GNT9 134.2281879 up-regulatedQ02985 CFHR3 134.2281879 up-regulatedP43234 CTSO 134.2281879 up-regulatedQ14766 LTBP1 134.2281879 up-regulatedQ9NT99 LRRC4B 134.2281879 up-regulatedQ96FE5 LINGO1 134.2281879 up-regulatedQ9ULB1 NRXN1 134.2281879 up-regulatedP23468 PTPRD 134.2281879 up-regulatedP04070 PROC 134.2281879 up-regulatedP08779 KRT16 134.2281879 up-regulatedQ6UWH4 GASK1 B 134.2281879 up-regulatedDocket No. 378-003PCTQ13751 LAMB3 134.2281879 up-regulatedA0A0C4DH38 IGHV5-51 134.2281879 up-regulatedQ8N475 FSTL5 134.2281879 up-regulatedQ96PX8 SLITRK1 134.2281879 up-regulatedQ9Y6N7 ROBO1 134.2281879 up-regulatedP48740 MASP1 134.2281879 up-regulatedP22105 TNXB 134.2281879 up-regulatedP32004 L1 CAM 134.2281879 up-regulatedQ6UXD5 SEZ6L2 134.2281879 up-regulatedQ8N436 CPXM2 134.2281879 up-regulatedP00749 PLAU 134.2281879 up-regulatedQ92752 TNR 134.2281879 up regulatedQ9HDB5 NRXN3 134.2281879 up-regulatedQ99536 VAT1 134.2281879 up-regulatedQ7Z7M0 MEGF8 134.2281879 up-regulatedP22004 BMP6 134.2281879 up-regulatedQ86YZ3 HRNR 134.2281879 up-regulatedQ9UM47 NOTCH3 134.2281879 up-regulatedQ24JP5 TMEM132A 134.2281879 up-regulatedP62805 H4C1 0.013422819 down-regulatedP09651 HNRNPA1 0.013422819 down-regulatedP63104 YWHAZ 0.017449664 down-regulatedP22626 HNRNPA2B1 0.013422819 down-regulatedP51991 HNRNPA3 0.017449664 down-regulatedQ99729 HNRNPAB 0.013422819 down-regulatedP08865 RPSA 0.013422819 down-regulatedP40925 MDH1 0.013422819 down-regulatedQ10567 AP1 B1 0.013422819 down-regulatedP62318 SNRPD3 0.013422819 down-regulatedP30050 RPL12 0.013422819 down-regulatedP52907 CAPZA1 0.013422819 down-regulatedP21281 ATP6V1 B2 0.013422819 down-regulatedQ9Y2X3 NOP58 0.013422819 down-regulatedQ13148 TARDBP 0.013422819 down-regulatedP50991 CCT4 0.013422819 down-regulatedQ14195 DPYSL3 0.013422819 down-regulatedP47756 CAPZB 0.013422819 down-regulatedP26641 EEF1 G 0.013422819 down-regulated015145 ARPC3 0.013422819 down-regulatedDocket No. 378-003PCTQ14974 KPNB1 0.013422819 down-regulatedQ92520 FAM3C 0.013422819 down-regulatedP63244 RACK1 0.013422819 down-regulatedQ13509 TUBBS 0.013422819 down-regulatedP37802 TAGLN2 0.013422819 down-regulatedP27348 YWHAQ 0.013422819 down-regulatedP52272 HNRNPM 0.013422819 down-regulatedQ99832 CCT7 0.013422819 down-regulatedP08621 SNRNP70 0.013422819 down-regulatedP18669 PGAM 1 0.013422819 down-regulatedQ1 KMD3 HNRNPUL2 0.013422819 down-regulatedP63261 ACTG1 0.013422819 down-regulatedP49368 CCT3 0.013422819 down-regulatedP41250 GARS1 0.013422819 down-regulatedP1 1940 PABPC1 0.013422819 down-regulatedQ7KZF4 SND1 0.013422819 down-regulatedQ0821 1 DHX9 0.013422819 down-regulatedP08758 ANXA5 0.013422819 down-regulatedQ15029 EFTUD2 0.013422819 down-regulatedQ12906 ILF3 0.013422819 down-regulatedQ13838 DDX39B 0.013422819 down-regulatedP50395 GD 0.013422819 down-regulatedQ15063 POSTN 0.013422819 down-regulatedP61026 RAB10 0.013422819 down-regulatedP68371 TUBB4B 0.013422819 down-regulatedQ01 105 SET 0.013422819 down-regulatedP05388 RPLPO 0.013422819 down-regulatedP55795 HNRNPH2 0.013422819 down-regulatedQ8TAG5 VSTM2A 0.013422819 down-regulatedP22087 FBL 0.013422819 down-regulatedP62995 TRA2B 0.013422819 down-regulatedQ86VP6 CAND1 0.013422819 down-regulatedP04908 H2AC4 0.013422819 down-regulatedP07437 TUBE 0.013422819 down-regulatedQ96DA2 RAB39B 0.013422819 down-regulatedP06753 TPMS 0.013422819 down-regulatedQ96IY4 CPB2 0.013422819 down-regulatedP62826 RAN 0.013422819 down-regulatedP84243 H3-3A 0.013422819 down-regulatedDocket No. 378-003PCTP55072 VCP 0.013422819 down-regulatedQ15717 ELAVL1 0.013422819 down-regulatedQ9BQE3 TUBA1 C 0.013422819 down-regulated060814 H2BC12 0.013422819 down-regulatedP10809 HSPD1 0.013422819 down-regulatedQ15185 PTGES3 0.013422819 down-regulatedP62873 GNB1 0.013422819 down-regulatedP07814 EPRS 0.013422819 down-regulatedA0A0C4DH69 IGKV1 -9 0.013422819 down-regulatedP61224 RAP1 B 0.013422819 down-regulatedQ9ULV4 CORO1 C 0.013422819 down-regulatedQ8N2Q7 NLGN1 0.013422819 down-regulatedP45973 CBX5 0.013422819 down-regulatedQ9HCJ6 VATI L 0.013422819 down-regulatedP62424 RPL7A 0.013422819 down-regulatedP26599 PTBP1 0.013422819 down-regulatedP26378 ELAVL4 0.013422819 down-regulatedP29401 TKT 0.013422819 down-regulatedP61978 HNRNPK 0.013422819 down-regulatedP54136 RARS 0.013422819 down-regulatedP05141 SLC25A5 0.013422819 down-regulatedP57721 PCBP3 0.013422819 down-regulatedP18621 RPL17 0.013422819 down-regulatedP40926 MDH2 0.013422819 down-regulatedP53396 ACLY 0.013422819 down-regulatedP63241 EIF5A 0.013422819 down-regulatedP60842 EIF4A1 0.013422819 down-regulatedA0M8Q6 IGLC7 0.013422819 down-regulatedQ9Y265 RUVBL1 0.013422819 down-regulatedQ09328 MGAT5 0.013422819 down-regulatedP15311 EZR 0.013422819 down-regulated060506 SYNCRIP 0.013422819 down-regulatedP17174 GOT1 0.013422819 down-regulatedQ71 U36 TUBA1A 0.013422819 down-regulatedP68104 EEF1A1 0.013422819 down-regulatedQ15366 PCBP2 0.013422819 down-regulatedQ00839 HNRNPU 0.013422819 down-regulated014980 XPO1 0.013422819 down-regulatedP50990 CCT8 0.013422819 down-regulatedDocket No. 378-003PCTP31943 HNRNPH1 0.013422819 down-regulatedP21796 VDAC1 0.013422819 down-regulatedP52597 HNRNPF 0.013422819 down-regulatedQ08945 SSRP1 0.013422819 down-regulatedP12235 SLC25A4 0.013422819 down-regulatedP00558 PGK1 0.013422819 down-regulatedP35637 FUS 0.013422819 down-regulatedP67809 YBX1 0.013422819 down-regulatedQ02543 RPL18A 0.013422819 down-regulatedP26639 TARS1 0.013422819 down-regulatedP61981 YWHAG 0.013422819 down-regulatedQ12905 ILF2 0.013422819 down-regulatedQ16643 DBN1 0.013422819 down-regulatedP07910 HNRNPC 0.013422819 down-regulatedP62913 RPL1 1 0.013422819 down-regulatedP23396 RPS3 0.013422819 down-regulatedP62937 PPIA 0.013422819 down-regulatedP06576 ATP5F1 B 0.013422819 down-regulatedP68431 H3C1 0.013422819 down-regulatedQ14103 HNRNPD 0.013422819 down-regulatedP55209 NAP1 L1 0.013422819 down-regulatedP63010 AP2B1 0.013422819 down-regulatedP46781 RPS9 0.013422819 down-regulated014979 HNRNPDL 0.013422819 down-regulatedP62241 RPS8 0.013422819 down-regulatedQ9Y3U8 RPL36 0.013422819 down-regulatedP68363 TUBA1 B 0.013422819 down-regulatedP54577 YARS 0.013422819 down-regulatedP35580 MYH10 0.013422819 down-regulatedP38159 RBMX 0.013422819 down-regulatedP41219 PRPH 0.013422819 down-regulatedQ8TC07 TBC1 D15 0.013422819 down-regulatedQ00610 CLTC 0.013422819 down-regulatedQ8IZA0 KIAA0319L 0.013422819 down-regulatedP19022 CDH2 0.013422819 down-regulatedP04350 TUBB4A 0.013422819 down-regulatedQ16629 SRSF7 0.013422819 down-regulatedQ6FHJ7 SFRP4 0.013422819 down-regulatedP84103 SRSF3 0.013422819 down-regulatedDocket No. 378-003PCTP61313 RPL15 0.013422819 down-regulatedP46783 RPS10 0.013422819 down-regulatedP18124 RPL7 0.013422819 down-regulatedP17844 DDX5 0.013422819 down-regulatedQ14194 CRMP1 0.013422819 down-regulatedQ71 DI3 HIST2H3A 0.013422819 down-regulatedP0DN76 U2AF1 L5 0.013422819 down-regulatedP61247 RPS3A 0.013422819 down-regulatedQ9UQ80 PA2G4 0.013422819 down-regulatedP16402 H1 -3 0.013422819 down-regulatedQ99623 PHB2 0.013422819 down-regulatedP07237 P4HB 0.013422819 down-regulatedP14866 HNRNPL 0.013422819 down-regulated075367 H2AFY 0.013422819 down-regulatedP27635 RPL10 0.013422819 down-regulated075533 SF3B1 0.013422819 down-regulatedP78371 CCT2 0.013422819 down-regulatedP0DP23 CALM 1 0.013422819 down-regulatedP46777 RPL5 0.013422819 down-regulatedP16104 H2AFX 0.013422819 down-regulatedP62701 RPS4X 0.013422819 down-regulatedP40227 CCT6A 0.013422819 down-regulatedQ5EB52 MEST 0.013422819 down-regulatedP83731 RPL24 0.013422819 down-regulatedP55884 EIF3B 0.013422819 down-regulatedP49588 AARS 0.013422819 down-regulatedQ5JXB2 UBE2NL 0.013422819 down-regulatedP19338 NCL 0.013422819 down-regulatedP17987 TCP1 0.013422819 down-regulatedP62847 RPS24 0.013422819 down-regulatedP60660 MYL6 0.013422819 down-regulatedP1 1413 G6PD 0.013422819 down-regulatedP62081 RPS7 0.013422819 down-regulated

[0256] Table 7. Differential Expression Analysis of Plasma Proteins in PD Patient Compared to HealthyControls.Accession Gene name Normalized ratio TrendP02751 FN1 13.67028494 up-regulatedP01023 A2M 14.52917232 up-regulatedDocket No. 378-003PCTP00450 CP 15.68928087 up-regulatedQ14515 SPARCL1 23.24694708 up-regulated000533 CHL1 31.20624152 up-regulatedP78509 RELN 18.90502035 up-regulatedQ8N2S1 LTBP4 14.40976934 up-regulated015031 PLXNB2 135.6852103 up-regulatedQ8TER0 SNED1 135.6852103 up-regulatedP05060 CHGB 13.85345997 up-regulatedP43652 AFM 135.6852103 up-regulatedP16157 ANK1 135.6852103 up-regulatedQ92876 KLK6 135.6852103 up-regulatedP35442 THBS2 135.6852103 up regulatedQ562R1 ACTBL2 135.6852103 up-regulatedQ53EL9 SEZ6 24.49253731 up-regulated014791 AP0L1 135.6852103 up-regulatedP05121 SERPINE1 135.6852103 up-regulatedP07355 ANXA2 135.6852103 up-regulatedP23515 OMG 135.6852103 up-regulatedQ06481 APLP2 34.34871099 up-regulatedP80108 GPLD1 135.6852103 up-regulatedQ92823 NRCAM 135.6852103 up-regulatedQ14767 LTBP2 135.6852103 up-regulatedQ14520 HABP2 135.6852103 up-regulatedQ99435 NELL2 14.16824966 up-regulatedP21810 BGN 17.48032564 up-regulatedP43251 BTD 135.6852103 up-regulatedQ9H2X0 CHRD 135.6852103 up-regulatedA0A087WSY6 IGKV3D-15 135.6852103 up-regulatedA0A0J9YXX1 IGHV5-10-1 135.6852103 up-regulatedQ6YHK3 CD109 135.6852103 up-regulatedQ6ZRP7 QSOX2 135.6852103 up-regulatedQ02809 PL0D1 135.6852103 up-regulatedQ96KG7 MEGF10 135.6852103 up-regulatedP1 1362 FGFR1 135.6852103 up-regulatedP49257 LMAN1 135.6852103 up-regulatedQ9C0A0 CNTNAP4 135.6852103 up-regulatedP49641 MAN2A2 135.6852103 up-regulatedQ8IV08 PLD3 135.6852103 up-regulatedQ9UBG0 MRC2 135.6852103 up-regulatedDocket No. 378-003PCTP02533 KRT14 135.6852103 up-regulatedP35052 GPC1 135.6852103 up-regulatedP12277 CKB 135.6852103 up-regulated014594 NCAN 135.6852103 up-regulatedQ99972 MYOC 135.6852103 up-regulatedQ9NPR2 SEMA4B 135.6852103 up-regulatedP47972 NPTX2 135.6852103 up-regulatedP02461 COL3A1 135.6852103 up-regulatedQ8IXL6 FAM20C 135.6852103 up-regulatedP07942 LAMB1 135.6852103 up-regulatedQ9BYH1 SEZ6L 15.35142469 up-regulatedQ7Z3B1 NEGR1 135.6852103 up regulatedP1 1047 LAMC1 135.6852103 up-regulatedQ53RD9 FBLN7 135.6852103 up-regulatedP12110 COL6A2 135.6852103 up-regulatedQ6UX72 B3GNT9 135.6852103 up-regulatedQ02985 CFHR3 135.6852103 up-regulatedP43234 CTSO 135.6852103 up-regulatedQ14766 LTBP1 135.6852103 up-regulatedQ9NT99 LRRC4B 135.6852103 up-regulatedQ96FE5 LINGO1 135.6852103 up-regulatedQ9ULB1 NRXN1 135.6852103 up-regulatedP23468 PTPRD 135.6852103 up-regulatedP04070 PROC 135.6852103 up-regulatedP08779 KRT16 135.6852103 up-regulatedA0A0C4DH38 IGHV5-51 135.6852103 up-regulatedQ96PX8 SLITRK1 135.6852103 up-regulatedQ9Y6N7 ROBO1 135.6852103 up-regulatedP48740 MASP1 135.6852103 up-regulatedP32004 L1 CAM 135.6852103 up-regulatedQ6UXD5 SEZ6L2 135.6852103 up-regulatedQ8N436 CPXM2 135.6852103 up-regulatedP00749 PLAU 135.6852103 up-regulatedQ92752 TNR 135.6852103 up-regulatedQ9HDB5 NRXN3 135.6852103 up-regulatedQ99536 VAT1 135.6852103 up-regulatedQ7Z7M0 MEGF8 135.6852103 up-regulatedP22004 BMP6 135.6852103 up-regulatedQ86YZ3 HRNR 135.6852103 up-regulatedDocket No. 378-003PCTQ9UM47 NOTCH3 135.6852103 up-regulatedQ24JP5 TMEM132A 135.6852103 up-regulatedP10586 PTPRF 135.6852103 up-regulatedP55268 LAMB2 135.6852103 up-regulatedQ16706 MAN2A1 135.6852103 up-regulatedP12814 ACTN1 0.013568521 down-regulatedP00739 HPR 0.013568521 down-regulatedP01782 IGHV3-9 0.013568521 down-regulated043143 DHX15 0.013568521 down-regulatedP60900 PSMA6 0.013568521 down-regulatedP50502 ST13 0.013568521 down-regulatedP23528 CFL1 0.013568521 down-regulatedP00338 LDHA 0.013568521 down-regulatedP62805 H4C1 0.013568521 down-regulatedP11142 HSPA8 0.013568521 down-regulatedP68400 CSNK2A1 0.013568521 down-regulatedP36578 RPL4 0.013568521 down-regulatedP60174 TPI1 0.013568521 down-regulatedP04259 KRT6B 0.013568521 down-regulatedP50914 RPL14 0.013568521 down-regulatedP22626 HNRNPA2B1 0.013568521 down-regulated000567 NOP56 0.013568521 down-regulatedP51991 HNRNPA3 0.013568521 down-regulatedP13639 EEF2 0.013568521 down-regulatedQ99729 HNRNPAB 0.013568521 down-regulatedP08865 RPSA 0.013568521 down-regulatedP40925 MDH1 0.013568521 down-regulatedQ10567 AP1 B1 0.013568521 down-regulatedP62318 SNRPD3 0.013568521 down-regulatedP30050 RPL12 0.013568521 down-regulatedP52907 CAPZA1 0.013568521 down-regulatedP21281 ATP6V1 B2 0.013568521 down-regulatedQ9Y2X3 NOP58 0.013568521 down-regulatedQ13148 TARDBP 0.013568521 down-regulatedP50991 CCT4 0.013568521 down-regulatedQ14195 DPYSL3 0.013568521 down-regulatedP26641 EEF1 G 0.013568521 down-regulated015145 ARPC3 0.013568521 down-regulatedQ14974 KPNB1 0.013568521 down-regulatedDocket No. 378-003PCTQ92520 FAM3C 0.013568521 down-regulatedQ13509 TUBB3 0.013568521 down-regulatedP37802 TAGLN2 0.013568521 down-regulatedP27348 YWHAQ 0.013568521 down-regulatedP52272 HNRNPM 0.013568521 down-regulatedQ99832 CCT7 0.013568521 down-regulatedP08621 SNRNP70 0.013568521 down-regulatedP18669 PGAM 1 0.013568521 down-regulatedQ1 KMD3 HNRNPUL2 0.013568521 down-regulatedP63261 ACTG1 0.013568521 down-regulatedP49368 CCT3 0.013568521 down-regulatedP41250 GARS1 0.013568521 down-regulatedQ7KZF4 SND1 0.013568521 down-regulatedQ0821 1 DHX9 0.013568521 down-regulatedP08758 ANXA5 0.013568521 down-regulatedQ15029 EFTUD2 0.013568521 down-regulatedQ12906 ILF3 0.013568521 down-regulatedQ13838 DDX39B 0.013568521 down-regulatedP50395 GDI2 0.013568521 down-regulatedQ15063 POSTN 0.013568521 down-regulatedP61026 RAB10 0.013568521 down-regulatedP68371 TUBB4B 0.013568521 down-regulatedQ01 105 SET 0.013568521 down-regulatedP05388 RPLPO 0.013568521 down-regulatedP55795 HNRNPH2 0.013568521 down-regulatedP22087 FBL 0.013568521 down-regulatedP62995 TRA2B 0.013568521 down-regulatedQ86VP6 CAND1 0.013568521 down-regulatedP04908 H2AC4 0.013568521 down-regulatedP07437 TUBB 0.013568521 down-regulatedQ96DA2 RAB39B 0.013568521 down-regulatedP06753 TPMS 0.013568521 down-regulatedQ96IY4 CPB2 0.013568521 down-regulatedP62826 RAN 0.013568521 down-regulatedP84243 H3-3A 0.013568521 down-regulatedP55072 VCP 0.013568521 down-regulatedQ15717 ELAVL1 0.013568521 down-regulatedQ9BQE3 TUBA1 C 0.013568521 down-regulated060814 H2BC12 0.013568521 down-regulatedDocket No. 378-003PCTQ15185 PTGES3 0.013568521 down-regulatedP62873 GNB1 0.013568521 down-regulatedP07814 EPRS 0.013568521 down-regulatedA0A0C4DH69 IGKV1 -9 0.013568521 down-regulatedP61224 RAP1 B 0.013568521 down-regulatedQ9ULV4 CORO1 C 0.013568521 down-regulatedQ8N2Q7 NLGN1 0.013568521 down-regulatedP45973 CBX5 0.013568521 down-regulatedQ9HCJ6 VATI L 0.013568521 down-regulatedP62424 RPL7A 0.013568521 down-regulatedP26599 PTBP1 0.013568521 down-regulatedP29401 TKT 0.013568521 down-regulatedP61978 HNRNPK 0.013568521 down-regulatedP54136 RARS 0.013568521 down-regulatedP05141 SLC25A5 0.013568521 down-regulatedP57721 PCBP3 0.013568521 down-regulatedP18621 RPL17 0.013568521 down-regulatedP40926 MDH2 0.013568521 down-regulatedP53396 ACLY 0.013568521 down-regulatedP63241 EIF5A 0.013568521 down-regulatedP60842 EIF4A1 0.013568521 down-regulatedA0M8Q6 IGLC7 0.013568521 down-regulatedQ9Y265 RUVBL1 0.013568521 down-regulatedQ09328 MGAT5 0.013568521 down-regulatedP1531 1 EZR 0.013568521 down-regulated060506 SYNCRIP 0.013568521 down-regulatedP17174 GOT1 0.013568521 down-regulatedQ71 U36 TUBA1A 0.013568521 down-regulatedP68104 EEF1A1 0.013568521 down-regulatedQ15366 PCBP2 0.013568521 down-regulated014980 XPO1 0.013568521 down-regulatedP31943 HNRNPH1 0.013568521 down-regulatedP21796 VDAC1 0.013568521 down-regulatedP52597 HNRNPF 0.013568521 down-regulatedP12235 SLC25A4 0.013568521 down-regulatedP00558 PGK1 0.013568521 down-regulatedP35637 FUS 0.013568521 down-regulatedP67809 YBX1 0.013568521 down-regulatedQ02543 RPL18A 0.013568521 down-regulatedDocket No. 378-003PCTP26639 TARS1 0.013568521 down-regulatedP61981 YWHAG 0.013568521 down-regulatedQ12905 ILF2 0.013568521 down-regulatedQ16643 DBN1 0.013568521 down-regulatedP07910 HNRNPC 0.013568521 down-regulatedP62913 RPL1 1 0.013568521 down-regulatedP23396 RPS3 0.013568521 down-regulatedP06576 ATP5F1 B 0.013568521 down-regulatedP68431 H3C1 0.013568521 down-regulatedQ14103 HNRNPD 0.013568521 down-regulatedP55209 NAP1 L1 0.013568521 down-regulatedP63010 AP2B1 0.013568521 down-regulated014979 HNRNPDL 0.013568521 down-regulatedP62241 RPS8 0.013568521 down-regulatedQ9Y3U8 RPL36 0.013568521 down-regulatedP68363 TUBA1 B 0.013568521 down-regulatedP54577 YARS 0.013568521 down-regulatedP35580 MYH10 0.013568521 down-regulatedP38159 RBMX 0.013568521 down-regulatedP41219 PRPH 0.013568521 down-regulatedQ8TC07 TBC1 D15 0.013568521 down-regulatedQ00610 CLTC 0.013568521 down-regulatedQ8IZA0 KIAA0319L 0.013568521 down-regulatedP04350 TUBB4A 0.013568521 down-regulatedQ16629 SRSF7 0.013568521 down-regulatedQ6FHJ7 SFRP4 0.013568521 down-regulatedP84103 SRSF3 0.013568521 down-regulatedP61313 RPL15 0.013568521 down-regulatedP46783 RPS10 0.013568521 down-regulatedP18124 RPL7 0.013568521 down-regulatedP17844 DDX5 0.013568521 down-regulatedQ14194 CRMP1 0.013568521 down-regulatedQ71 DI3 HIST2H3A 0.013568521 down-regulatedP0DN76 U2AF1 L5 0.013568521 down-regulatedP61247 RPS3A 0.013568521 down-regulatedQ9UQ80 PA2G4 0.013568521 down-regulatedP16402 H1 -3 0.013568521 down-regulatedQ99623 PHB2 0.013568521 down-regulatedP07237 P4HB 0.013568521 down-regulatedDocket No. 378-003PCTP14866 HNRNPL 0.013568521 down-regulated075367 H2AFY 0.013568521 down-regulatedP27635 RPL10 0.013568521 down-regulated075533 SF3B1 0.013568521 down-regulatedP78371 CCT2 0.013568521 down-regulatedP0DP23 CALM 1 0.013568521 down-regulatedP46777 RPL5 0.013568521 down-regulatedP16104 H2AFX 0.013568521 down-regulatedP62701 RPS4X 0.013568521 down-regulatedP40227 CCT6A 0.013568521 down-regulatedQ5EB52 MEST 0.013568521 down-regulatedP83731 RPL24 0.013568521 down-regulatedP55884 EIF3B 0.013568521 down-regulatedP49588 AARS 0.013568521 down-regulatedQ5JXB2 UBE2NL 0.013568521 down-regulatedP19338 NCL 0.013568521 down-regulatedP62847 RPS24 0.013568521 down-regulatedP60660 MYL6 0.013568521 down-regulatedP1 1413 G6PD 0.013568521 down-regulatedP62081 RPS7 0.013568521 down-regulated

[0257] References1. Prof et al. Conformational disease, 1997, The Lancet, vol. 350, pp.134-138.2. Westermark et al. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus, 2011, Physiol Rev. vol. 91, pp.795-826.3. Hull et al. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes, 2004, 1. Clin. Endocrinol. Metab. vol. 89, pp.3629-3643.4. Janson et al. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide, 1996, Proc Natl Acad Sci U S A. vol. 93, pp. 7283-7288.5. Jurgens et al. P-cell loss and P-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition, 2011, Am J Pathol, vol. 178, pp. 2632-4260.6. Vogt et al. Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes, 2021, Vaccines (Basel), vol. 9, pp. 1316.7. Raimundo et al. Islet Amyloid Polypeptide: A Partner in Crime With Ap in the Pathology of Alzheimer's Disease, 2020, Front Mol Neurosci. vol. 13, pp. 35.Docket No. 378-003PCT8. Soragni et al. A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. 2016, Cancer Cell. vol. 9, pp. 90-103.9. Bykov et al. Restoration of the tumor suppressor function to mutant p53 by a low- molecular-weight compound. 2002, Nat Med. vol.8, p. 282-288.10. Wang et al. The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies, 2012, Nature Commun., vol. 3, pp. 766.11. Kato et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels, 2012, Cell, vol. 149, pp. 753-767.12. Han et al. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies, 2012, Cell, vol. 149, pp. 768-779.13. Brangwynne et al. Germline P granules are liquid droplets that localize by controlled dissolution / condensation, 2009, Science vol. 324, pp. 1729-1732.

[0258] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only.

Claims

Docket No. 378-003PCTWHAT IS CLAIMED IS:

1. A method for detecting a human disease in a human subject, comprising, optionally obtaining a biofluid sample from the subject, adding an isoxazole to the obtained biofluid sample to form a biofluid isoxazole composition in the biofluid sample, and detecting a presence of the biofluid isoxazole composition.

2. The method of claim 1, wherein the isoxazole is biotin-isoxazole, (6-(5-(Thiophen-2- yl)isoxazole-3-carboxamido)hexyl 5-((3a5,4S,6aR)-2-oxohexahydro-177-thieno[3,4-<7]imidazol-4-yl)pentanoate), or its salt or an analog thereof, especially biotin-isoxazole and very especially biotin-isoxazole, such as OG3 6-(5-(5-chlorothiophen-2-yl)isoxazole-3- carboxamidojhexyl 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4- yljpentanoate) and OG4 (6-(5-(benzo[b]thiophen-2-yl)isoxazole-3-carboxamido)hexyl5- ((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)pentanoate).

3. The method of Claims 1-2, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

4. The method of Claims 1-3, wherein the human disease is prediabetes, diabetes, lung cancer, and pancreatic cancer, Alzheimer’s disease (AD), parkinson disease dementia (PD), and dementia with Lewy body (DLB).

5. The method of claims 1-4, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.Docket No. 378-003PCT6. The method of claims 1-5, wherein the concentration of isoxazole ranges from 0.075mM to 0.225 mM, preferably from 0.100 mM to 0.200mM, in the biofluid sample.

7. The method of claims 1-6, wherein the biofluid isoxazole composition is in a precipitate.

8. The method of claim 7, wherein the human disease is prediabetes, diabetes, lung cancer, and pancreatic cancer, Alzheimer’s disease (AD), parkinson disease dementia (PD), and dementia with Lewy body (DLB).9.The method of claims 1-6, further comprising adding a polypeptide to biofluid isoxazole composition in the biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

10. The method of claim 9, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biofluid isoxazole composition.

11. The method of claim 9, wherein the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against IAPP, p-TDP-43, amyloid P, a- synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA 1 , HBB, or CLEC3B.

12. The method of Claim 9, wherein the human diseases is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against IAPP, p-TDP-43, amyloid [3, a- synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE.Docket No. 378-003PCT13. The method of Claim 9, wherein the human diseases is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB 1, GDI1 , GNAQ, S A A 1 , CRP, S A A2, TGFB 111 , GPI, ARPC 1 B , NAP 1 LI , HPSE, PGAM4, HK 1 , STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, AP0C2, IGFALS, AP0C3, APOB, AP0A2, ITIH1, ITIH2, TTR, LPA, P0N1, HLA-A, APOD, AP0A1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, AP0A4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1.

14. The method of Claim 9, wherein the human diseases is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, AP0C2, IGFALS, AP0C3, APOB, AP0A2, P0N1, AP0A1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1 , YWHAB, RAB1B, SERPINA 10, HSPD1 , HLA-C, CPN1 , IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA 1 A, or TGFB1.

15. The method of Claim 9, wherein the human diseases is AD, and wherein polypeptide for detecting AD is an antibody against FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, AP0L1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LING01, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1 , MEGF8, BMP6, HRNR, N0TCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2,Docket No. 378-003PCTYWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1 , CCT8, HNRNPH1 , VDAC1 , HNRNPF, SSRP1 , SLC25 A4, PGK1 , FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7.

16. The method of Claim 9, wherein the human disease is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPTNE1 , ANXA2, OMG, APLP2, GPLD1 , NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TP11, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A,Docket No. 378-003PCTVCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl -3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

17. The method of Claim 9, wherein the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against KRT1, IAPP, IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, Fl 3 Al, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

18. The method of Claim 11-17, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

19. The method of claims 11-17, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

20. Use of an isoxazole to detect a human disease in any method of claims 1-19.

21. A method for detecting a human disease in a human subject, comprising, detecting a presence of a biomarker from an obtained biofluid sample, and optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample, andDocket No. 378-003PCT wherein the human disease is selected from prediabetes, diabetes, lung cancer, pancreatic cancer, Alzheimer’s disease (AD), Parkinson disease dementia (PD), and dementia with Lewy body (DLB). wherein, for prediabetes, the biomarker is selected from IAPP, p-TDP-43, amyloid 0, a- synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B; wherein, for diabetes, the biomarker is selected from IAPP, p-TDP-43, amyloid 0, a- synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-30, IGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERP1NA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE; wherein, for lung cancer, the biomarker is selected from Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, 1NF2, CCT6A, BTK, SERPINB1, 1GKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPINA4, AZGP1, SHBG, SERPINA5, ITIH3, TF, HPR, APOE, APOM, IGKV3D-11, GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1; wherein, for pancreatic cancer, the biomarker is selected from p53, C7, C9, F B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, APOA1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA 1 A, or TGFB1; wherein, for AD, the biomarker is selected from FN1, LTBP4, PLXNB2, SNED1, AFM, ANK.I, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERP1NE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD,Docket No. 378-003PCTPROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1 , H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VDAC1, HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, K1AA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7; wherein, for PD, the biomarker is selected from FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SLITRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ,Docket No. 378-003PCTHNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1 , H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB 1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1 , RPL18A, TARSI , YWHAG, ILF2, DBN1 , HNRNPC, RPL11 , RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B 1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7, and wherein for DLB, the biomarker is selected from KRT1 , TAPP, IGHG4, IGHV5-10-1 , IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, F13A1, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

22. The method of Claim 21, wherein the obtained biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

23. The method of Claims 21-22, wherein the human disease is prediabetes.

24. The method of Claims 21-22, wherein the human disease is diabetes.

25. The method of Claims 21-22, wherein the human disease is lung cancer.

26. The method of Claims 21-22, wherein the human disease is pancreatic cancer.Docket No. 378-003PCT27. The method of Claims 21-22, wherein the human disease is AD.

28. The method of Claims 21-22, wherein the human disease is PD.

29. The method of Claims 21-22, wherein the human disease is DLB.

30. The method of claims 21-29, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

31. The method of claims 21-30, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

32. The method of claim 31, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

33. The method of Claim 32, wherein the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against IAPP, p-TDP-43, amyloid 0, a- synuclein, IGKV1-5, SERPINA10, IGHV3-74, APOC3, PARVB, IGHV3-23, CFL1, IGLC2, TTR, SAA4, HBA1, HBB, or CLEC3B.

34. The method of Claim 32, wherein the human diseases is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against IAPP, p-TDP-43, amyloid 0, a- synuclein, IAPP, phospho-TDP-43, amyloid beta, PLEK, KRT1, IGA2, LBP, IGHV3-30,Docket No. 378-003PCTIGHV4-28, C4B, APOB, AMBP, TUBB, GAPDH, KRT2, KRT10, SERPINA10, IGHV3-74, APOC3, IGHV3-23, IGLC2, CLEC3B, IGKV3-7, IGKV3D-20, IGKV1-6, CD5L, IGHM, IGKV1-17, IGHV5-10-1, or YWHAE.

35. The method of Claim 32, wherein the human disease is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Rb, IGHV5-10-1, ECHI, SRC, GP5, TUBA1A, ZYX, LBP, CTTN, F13A1, HSPB1, GANAB, CD36, HSP90AA1, TGFB1, GDI1, GNAQ, SAA1, CRP, SAA2, TGFB1H, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, HK1, STXBP2, INF2, CCT6A, BTK, SERPINB1, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, AP0A2, ITIH1, ITIH2, TTR, LPA, PON1, HLA-A, APOD, APOA1, SAA4, CLEC3B, AHSG, SERPTNA4, AZGP1 , SHBG, SERPTNA5, ITTH3, TF, HPR, APOE, APOM, IGKV3D-1 1 , GPX3, FCN3, SERPINC1, CPB2, IGKV1-5, RBP4, APOA4, PGLYRP2, IGHV3-3O, ALB, C4BPB, AFM, GC, IGHG4, HBA2, SERPINA6, SERPINF2, CLU, LGALS3BP, or KLKB1.

36. The method of Claim 32, wherein the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against p53, C7, C9, F13B, CANX, GANAB, GNAQ, SAA1, CRP, SAA2, TGFB1I1, GPI, ARPC1B, NAP1L1, HPSE, PGAM4, PLTP, IGKV6D-21, APOC2, IGFALS, APOC3, APOB, APOA2, PON1, AP0A1, CLEC3B, SHBG, SERPINA5, FCN3, CPB2, IGHV3-30, LGALS3BP, IGG1, IGKV1-39, PF4V1, IGKV1D-33, IGKV2-30, GNB1, YWHAB, RAB1B, SERPINA10, HSPD1, HLA-C, CPN1, IGHV4-4, CAPNS1, HLA-B, TPM1, IGHV1-3, TUBA 1 A, or TGFB1.

37. The method of Claim 32, wherein the human disease is AD, and wherein polypeptide for detecting AD is an antibody against FN1, LTBP4, PLXNB2, SNED1, AFM, ANK1, SPTB, KLK6, THBS2, ACTBL2, APOL1, SERPINE1, ANXA2, OMG, ACTN1, CD5L, GPLD1, NRCAM, LTBP2, HABP2, BGN, BTD, APOB, CHRD, IGKV3D-15, C4BPB, IGHV5-10-1, HBD, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CAI, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CD81, STOM, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, ITIH3, NEGRI, IGKV1-5, LAMC1, FBLN7, COL6A2, SPTA1, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, GASK1B, LAMB3, IGHV5-51, FSTL5, SLITRK1, ROBO1, MASP1, TNXB, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, N0TCH3,Docket No. 378-003PCTTMEM132A, H4C1, HNRNPA1, YWHAZ, HNRNPA2B1, HNRNPA3, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, CAPZB, EEF1G, ARPC3, KPNB1, FAM3C, RACK1, TUBB3, TAGLN2, YWHAQ, HNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, PABPC1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, VSTM2A, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, HSPD1, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, ELAVL4, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, HNRNPU, XPO1, CCT8, HNRNPH1, VD AC 1 , HNRNPF, SSRP1, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1, HNRNPC, RPL11, RPS3, PPIA, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, RPS9, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, CDH2, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS10, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, TCP1, RPS24, MYL6, G6PD, or RPS7.

38. The method of Claim 32, wherein the human disease is PD, and wherein polypeptide for detecting PD is an antibody against FN1, A2M, CP, SPARCL1, CHL1, RELN, LTBP4, PLXNB2, SNED1, CHGB, AFM, ANK1, KLK6, THBS2, ACTBL2, SEZ6, APOL1, SERPINE1, ANXA2, OMG, APLP2, GPLD1, NRCAM, LTBP2, HABP2, NELL2, BGN, BTD, CHRD, IGKV3D-15, IGHV5-10-1, CD109, QSOX2, PLOD1, MEGF10, FGFR1, LMAN1, CNTNAP4, MAN2A2, PLD3, MRC2, KRT14, GPC1, CKB, NCAN, MYOC, SEMA4B, NPTX2, COL3A1, FAM20C, LAMB1, SEZ6L, NEGRI, LAMC1, FBLN7, COL6A2, B3GNT9, CFHR3, CTSO, LTBP1, LRRC4B, LINGO1, NRXN1, PTPRD, PROC, KRT16, IGHV5-51, SL1TRK1, ROBO1, MASP1, L1CAM, SEZ6L2, CPXM2, PLAU, TNR, NRXN3, VAT1, MEGF8, BMP6, HRNR, NOTCH3, TMEM132A, PTPRF, LAMB2, MAN2A1, ACTN1, HPR, IGHV3-9, DHX15, PSMA6, ST13, CFL1, LDHA, H4C1, HSPA8, CSNK2A1, RPL4, TPI1, KRT6B, RPL14, HNRNPA2B1, NOP56, HNRNPA3, EEF2, HNRNPAB, RPSA, MDH1, AP1B1, SNRPD3, RPL12, CAPZA1, ATP6V1B2, NOP58, TARDBP, CCT4, DPYSL3, EEF1G, ARPC3, KPNB1, FAM3C, TUBB3, TAGLN2, YWHAQ,Docket No. 378-003PCTHNRNPM, CCT7, SNRNP70, PGAM1, HNRNPUL2, ACTG1, CCT3, GARS1, SND1, DHX9, ANXA5, EFTUD2, ILF3, DDX39B, GDI2, POSTN, RAB10, TUBB4B, SET, RPLPO, HNRNPH2, FBL, TRA2B, CAND1, H2AC4, TUBB, RAB39B, TPM3, CPB2, RAN, H3-3A, VCP, ELAVL1, TUBA1C, H2BC12, PTGES3, GNB1, EPRS, IGKV1-9, RAP1B, COROIC, NLGN1, CBX5, VAT1L, RPL7A, PTBP1, TKT, HNRNPK, RARS, SLC25A5, PCBP3, RPL17, MDH2, ACLY, EIF5A, EIF4A1, IGLC7, RUVBL1, MGAT5, EZR, SYNCRIP, GOT1, TUBA1A, EEF1A1, PCBP2, XPO1, HNRNPH1, VDAC1, HNRNPF, SLC25A4, PGK1, FUS, YBX1, RPL18A, TARSI, YWHAG, ILF2, DBN1 , HNRNPC, RPL11 , RPS3, ATP5F1B, H3C1, HNRNPD, NAP1L1, AP2B1, HNRNPDL, RPS8, RPL36, TUBA1B, YARS, MYH10, RBMX, PRPH, TBC1D15, CLTC, KIAA0319L, TUBB4A, SRSF7, SFRP4, SRSF3, RPL15, RPS1O, RPL7, DDX5, CRMP1, HIST2H3A, U2AF1L5, RPS3A, PA2G4, Hl-3, PHB2, P4HB, HNRNPL, H2AFY, RPL10, SF3B1, CCT2, CALM1, RPL5, H2AFX, RPS4X, CCT6A, MEST, RPL24, EIF3B, AARS, UBE2NL, NCL, RPS24, MYL6, G6PD, or RPS7.

39. The method of Claim 32, wherein the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against KRT1, IAPP, IGHG4, IGHV5-10-1, IGHA1, IGA2, FN1, LBP, IGHV4-28, AMBP, IGHV3-48, HLA-A, F10, IGKV1-27, SERPINA10, PARVB, IGLC2, TTR, HBA1, HBB, CLEC3B, CAI, APOA1, STOM, C1QA, CD5L, GP5, IGFALS, CPN1, IGKV1-9, Fl 3 Al, IGHM, APOA2, KRT9, SERPINA7, or YWHAE.

40. The method of claims 32-39, wherein biofluid is plasma or CSF.

41. The method of claims 32-40, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

42. Use of the biomarker to detect the human disease in any method of claims 32-41.

43. A method for detecting conformational disease in a human subject, comprising, detecting a presence of amyloid oligomers from an obtained biofluid sample, andDocket No. 378-003PCT optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

44. The method of Claim 43, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

45. The method of Claims 43-44, wherein the amyloid oligomer is selected from Al l recognized oligomers.

46. The method of claims 43-45, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

47. The method of claims 43-46, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

48. The method of claim 47, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

49. The method of Claim 48, wherein the human diseases is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against Al l.

50. The method of Claim 48, wherein the human diseases is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against Al l.Docket No. 378-003PCT51. The method of Claim 48, wherein the human disease is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against Al l.

52. The method of Claim 48, wherein the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against Al l.

53. The method of Claim 48, wherein the human disease is AD, and wherein the polypeptide for detecting AD is an antibody against Al l.

54. The method of Claim 48, wherein the human disease is PD, and wherein the polypeptide for detecting PD is an antibody against Al l.

55. The method of Claim 48, wherein the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against All.

56. The method of Claim 48, wherein the human disease is ALS, and wherein the polypeptide for detecting ALS is an antibody against Al l.

57. The method of claims 47-56, wherein biofluid is plasma or CSF.

58. The method of claims 47-57, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

59. Use of Al 1 recognized oligomers to detect conformational diseases in any method of claims 43-58.

60. A method for detecting conformational disease in a human subject at the asymptomatic and prodromal stage, comprising,Docket No. 378-003PCT detecting a presence of cross 0-, amyloid oligomers from an obtained biofluid sample, and optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

61. The method of Claim 60, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva, CSF or plasma, and especially CSF or plasma.

62. The method of Claims 60-61, wherein the cross 0-, amyloid oligomer is Al l recognized proteins.

63. The method of claims 60-62, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

64. The method of claims 60-63, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.

65. The method of claim 64, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

66. The method of Claim 65, wherein the polypeptide for detecting sporadic or SOD1 inherited ALS is an antibody against amyloid oligomers.

67. The method of claims 64-66, wherein biofluid is plasma or CSF.Docket No. 378-003PCT68. The method of claims 64-67, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

69. Use of Al 1 recognized protein to detect sporadic or SOD1 inherited ALS in any method of claims 60-68.

70. Use of any described substance or composition for diagnosing the human disease in each claim 1-69.

71. A method for detecting conformational disease in a human subject, comprising, detecting a presence of LBP from an obtained biofluid sample, and optionally obtaining a biofluid sample from the subject to obtain the obtained biofluid sample.

72. The method of Claim 71, wherein the biofluid sample is urine, whole blood, plasma, or serum, cerebrospinal fluid (CSF), saliva, or mucosa, such as, urine, saliva or plasma, and especially plasma.

73. The method of claims 71-72, further comprising thereafter treating the human subject for the human disease or thereafter changing an existing treatment of the human subject for the human disease based on the detecting the presents of the biofluid isoxazole composition, such as a treatment including pharmaceutical therapy for the human disease, and optionally further comprising diagnosing the human disease in the human subject.

74. The method of claims 71-73, further comprising adding a polypeptide to the obtained biofluid sample to facilitate detection by an immune assay, such as a blot assay, a chemiluminescence immunoassay, an enzyme-linked immunosorbent assay (ELISA), a light scattering immunoassay, a radiolabeled immunoassay, in particular, ELISA or a Western blot.Docket No. 378-003PCT75. The method of claim 74, wherein the polypeptide is (a) an antibody, or (b) an immunoglobulin chain, or a binding domain thereof which binds to the biomarker.

76. The method of Claim 74, wherein the human disease is prediabetes, and wherein the polypeptide for detecting prediabetes is an antibody against LBP.

77. The method of Claim 74, wherein the human disease is diabetes, and wherein the polypeptide for detecting diabetes is an antibody against LBP.

78. The method of Claim 74, wherein the human disease is lung cancer, and wherein the polypeptide for detecting lung cancer is an antibody against LBP.

79. The method of Claim 74, wherein the human disease is pancreatic cancer, and wherein the polypeptide for detecting pancreatic cancer is an antibody against LBP.

80. The method of Claim 74, wherein the human disease is AD, and wherein the polypeptide for detecting AD is an antibody against LBP.

81. The method of Claim 74, wherein the human disease is PD, and wherein the polypeptide for detecting PD is an antibody against LBP.

82. The method of Claim 74, wherein the human disease is DLB, and wherein the polypeptide for detecting DLB is an antibody against LBP.

83. The method of Claim 74, wherein the human disease is ALS, and wherein the polypeptide for detecting ALS is an antibody against LBP.

84. The method of claims 74-83, wherein biofluid is plasma or urine.Docket No. 378-003PCT85. The method of claims 74-84, wherein the method is ELISA, such as direct, indirect, sandwich, or competitive ELISA.

86. Use of LBP to detect conformational diseases in any method of claims 71-85.

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