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1.
Nat Commun ; 11(1): 2197, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366845

RESUMO

Emerging urinary biomarkers continue to show promise in evaluating lupus nephritis (LN). Here, we screen urine from active LN patients for 1129 proteins using an aptamer-based platform, followed by ELISA validation in two independent cohorts comprised of 127 inactive lupus, 107 active LN, 67 active non-renal lupus patients and 74 healthy controls, of three different ethnicities. Urine proteins that best distinguish active LN from inactive disease are ALCAM, PF-4, properdin, and VCAM-1 among African-Americans, sE-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians. Most of these correlate significantly with disease activity indices in the respective ethnic groups, and surpass conventional metrics in identifying active LN, with better sensitivity, and negative/positive predictive values. Several elevated urinary molecules are also expressed within the kidneys in LN, based on single-cell RNAseq analysis. Longitudinal studies are warranted to assess the utility of these biomarkers in tracking lupus nephritis.


Assuntos
Aptâmeros de Peptídeos/metabolismo , Biomarcadores/urina , Nefrite Lúpica/diagnóstico , Proteínas/análise , Molécula de Adesão de Leucócito Ativado/urina , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Povo Asiático/estatística & dados numéricos , Selectina E/análise , Feminino , Humanos , Nefrite Lúpica/etnologia , Nefrite Lúpica/urina , Properdina/urina , Sensibilidade e Especificidade , Molécula 1 de Adesão de Célula Vascular/urina , População Branca/estatística & dados numéricos , Adulto Jovem
2.
Oncotarget ; 8(1): 722-741, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27894096

RESUMO

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.


Assuntos
Molécula de Adesão de Leucócito Ativado/urina , Biomarcadores Tumorais , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/urina , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Idoso , Estudos de Coortes , Biologia Computacional/métodos , Cistectomia/métodos , Bases de Dados Genéticas , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgia
3.
J Proteome Res ; 14(8): 3123-35, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26143644

RESUMO

Individuals with type 1 diabetes (T1D) often have higher than normal blood glucose levels, causing advanced glycation end product formation and inflammation and increasing the risk of vascular complications years or decades later. To examine the urinary proteome in juveniles with T1D for signatures indicative of inflammatory consequences of hyperglycemia, we profiled the proteome of 40 T1D patients with an average of 6.3 years after disease onset and normal or elevated HbA1C levels, in comparison with a cohort of 41 healthy siblings. Using shotgun proteomics, 1036 proteins were identified, on average, per experiment, and 50 proteins showed significant abundance differences using a Wilcoxon signed-rank test (FDR q-value ≤ 0.05). Thirteen lysosomal proteins were increased in abundance in the T1D versus control cohort. Fifteen proteins with functional roles in vascular permeability and adhesion were quantitatively changed, including CD166 antigen and angiotensin-converting enzyme 2. α-N-Acetyl-galactosaminidase and α-fucosidase 2, two differentially abundant lysosomal enzymes, were detected in western blots with often elevated quantities in the T1D versus control cohort. Increased release of proteins derived from lysosomes and vascular epithelium into urine may result from hyperglycemia-associated inflammation in the kidney vasculature.


Assuntos
Diabetes Mellitus Tipo 1/urina , Enzimas/urina , Proteoma/metabolismo , Proteômica/métodos , Irmãos , Molécula de Adesão de Leucócito Ativado/metabolismo , Molécula de Adesão de Leucócito Ativado/urina , Adolescente , Enzima de Conversão de Angiotensina 2 , Western Blotting , Criança , Cromatografia Líquida , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Enzimas/metabolismo , Feminino , Humanos , Lisossomos/enzimologia , Lisossomos/metabolismo , Masculino , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/urina , Espectrometria de Massas em Tandem , alfa-L-Fucosidase/metabolismo , alfa-L-Fucosidase/urina , alfa-N-Acetilgalactosaminidase/metabolismo , alfa-N-Acetilgalactosaminidase/urina
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