Journal of Circulating Biomarkers最新文献

{"title":"Serum IL-33 as a biomarker in different diseases: useful parameter or much need for clarification?","authors":"Stefan Erfurt, Meike Hoffmeister, Stefanie Oess, Katharina Asmus, Oliver Ritter, Susann Patschan, Daniel Patschan","doi":"10.33393/jcb.2021.2327","DOIUrl":"https://doi.org/10.33393/jcb.2021.2327","url":null,"abstract":"ABSTRACT Interleukin-33 (IL-33), a member of the IL-1 family, is critically involved in the modulation of the activity of a diverse range of immunocompetent cells. Essential roles have been implicated in cardioprotection, in both innate and adaptive immune responses in mucosal organs, and in the maintenance of adipose tissue cells. Over the past 10 years, several studies evaluated the usability of IL-33 as a biomarker in diseases of inflammatory and noninflammatory origin. Our group is currently evaluating the predictive role of serum IL-33 in acute kidney injury (AKI). The aim of the article is to discuss selected studies on IL-33 in different diseases and its potential role as a biomarker molecule.","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/05/1e/jcb-10-20.PMC8634375.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39940188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating erythroblast abnormality associated with systemic pathologies may indicate bone marrow damage.","authors":"Stefan Schreier, Prapaphan Budchart, Suparerk Borwornpinyo, Wichit Arpornwirat, Wannapong Triampo","doi":"10.33393/jcb.2021.2220","DOIUrl":"https://doi.org/10.33393/jcb.2021.2220","url":null,"abstract":"ABSTRACT Background: The circulating rare cell population is diverse and rich in diagnostic information. Its characterization and clinical exploitation by cell-based liquid biopsy is an ongoing research task. Bone marrow is one of the major contributors to the peripheral blood rare cell population and, consequently, determines individual rare cell profiles thus depending on bone marrow health status. Bone marrow damage has been associated with aggressive or late-stage systemic diseases and egress of various bone marrow cells into the blood circulation. The association of quantity and heterogeneity of circulating erythroblast with bone marrow damage is of particular interest. Methods: Circulating CD71high/CD45-/Hoechsthigh blast cells from healthy, noncancer- and cancer-afflicted donors were enriched by CD45 depletion and analyzed by immunofluorescence microscopy. Results: A new finding of aberrant and mitotic circulating erythroid-like cells that appear similar across blood donors afflicted with various systemic pathologies is reported. Further presented is a classification of said erythroblast-like cells in nine subcategories according to morphological differences between phenotypically similar cells. Conclusion: Aberrant and mitotic bone marrow-derived rare circulating erythroid-like cells can be detected in the blood of afflicted individuals but not in healthy donors, suggesting the cause of bone marrow damage.","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/c6/jcb-10-14.PMC8493595.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39555343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating progastrin-releasing peptide in the diagnosis of Small Cell Lung Cancer (SCLC) and in therapeutic monitoring.","authors":"Vittoria Barchiesi,&nbsp;Vittorio Simeon,&nbsp;Claudia Sandomenico,&nbsp;Monica Cantile,&nbsp;Dionigio Cerasuolo,&nbsp;Paolo Chiodini,&nbsp;Alessandro Morabito,&nbsp;Ernesta Cavalcanti","doi":"10.33393/jcb.2021.2212","DOIUrl":"https://doi.org/10.33393/jcb.2021.2212","url":null,"abstract":"ABSTRACT Introduction: Progastrin-releasing peptide (proGRP), a precursor of GRP, has been recently reported as a putative circulating biomarker for differential diagnosis between non–small cell lung cancer (NSCLC) and SCLC. We evaluated the diagnostic effectiveness of proGRP to differentiate patients with NSCLC and SCLC and the usefulness of combined measurement of proGRP and neuron-specific enolase (NSE) for diagnosing SCLC. Methods: Serum proGRP, NSE, cytokeratin 19 fragment 21-1 (CYFRA 21.1), squamous cell carcinoma antigen (SCC Ag) and carcinoembryonic antigen (CEA) were prospectively collected and measured in patients with a new diagnosis of lung cancer. Serum proGRP was also measured in healthy subjects. The serum proGRP, NSE, CYFRA 21.1 and CEA concentrations were determined by an electrochemiluminescence immunoassay and the serum SCC Ag concentration was determined by an automated immunofluorescence assay. Differences between proGRP and NSE in patients with SCLC and NSCLC were evaluated and compared using Mann-Whitney test. Results: A total of 77 patients affected by SCLC (n = 17) and NSCLC (n = 60) were enrolled in the present study. Moreover, 50 cases of healthy subjects were analyzed for proGRP. SCLC patients showed a significantly higher proGRP (1,484 pg/mL; range 168-3,777) levels compared to NSCLC patients (45 pg/mL; range 31.7-60.6), p<0.0001. In healthy subjects the median proGRP level was 36.1 (28.8-43.5) pg/mL, significantly lower than SCLC patients. ProGRP showed a higher specificity when compared to NSE, with a difference in proportion of 47.5% (95% confidence interval 32.5% to 62.5%, p<0.001). Serial measurements of proGRP in SCLC patients showed a decrease in responsive chemotherapy patients. Conclusions: ProGRP is an accurate biomarker for diagnosis of SCLC and for discrimination of SCLC from NSCLC.","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a3/59/jcb-10-9.PMC8267854.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39176433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Value of clinical laboratory test for early prediction of mortality in patients with COVID-19: the BGM score.","authors":"Laura Macias-Muñoz,&nbsp;Robin Wijngaard,&nbsp;Bernardino González-de la Presa,&nbsp;José Luis Bedini,&nbsp;Manuel Morales-Ruiz,&nbsp;Wladimiro Jiménez","doi":"10.33393/jcb.2021.2194","DOIUrl":"https://doi.org/10.33393/jcb.2021.2194","url":null,"abstract":"<p><strong>Background: </strong>COVID-19 causes high mortality and long hospitalization periods. The aim of this study was to search for new early prognostic strategies accessible to most health care centers.</p><p><strong>Methods: </strong>Laboratory results, demographic and clinical data from 500 patients with positive SARS-CoV-2 infection were included in our study. The data set was split into training and test set prior to generating different multivariate models considering the occurrence of death as the response variable. A final computational method called the BGM score was obtained by combining the previous models and is available as an interactive web application.</p><p><strong>Results: </strong>The logistic regression model comprising age, creatinine (CREA), D-dimer (DD), C-reactive protein (CRP), platelet count (PLT), and troponin I (TNI) showed a sensitivity of 47.3%, a specificity of 98.7%, a kappa of 0.56, and a balanced accuracy of 0.73. The CART classification tree yielded TNI, age, DD, and CRP as the most potent early predictors of mortality (sensitivity = 68.4%, specificity = 92.5%, kappa = 0.61, and balanced accuracy = 0.80). The artificial neural network including age, CREA, DD, CRP, PLT, and TNI yielded a sensitivity of 66.7%, a specificity of 92.3%, a kappa of 0.54, and a balanced accuracy of 0.79. Finally, the BGM score surpassed the prediction accuracy performance of the independent multivariate models, yielding a sensitivity of 73.7%, a specificity of 96.5%, a kappa of 0.74, and a balanced accuracy of 0.85.</p><p><strong>Conclusions: </strong>The BGM score may support clinicians in managing COVID-19 patients and providing focused interventions to those with an increased risk of mortality.</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/51/0b/JCB-10-01.PMC7890680.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25476723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an immunofluorescent AR-V7 circulating tumor cell assay - A blood-based test for men with metastatic prostate cancer.","authors":"David Lu,&nbsp;Rachel Krupa,&nbsp;Melissa Harvey,&nbsp;Ryon P Graf,&nbsp;Nicole Schreiber,&nbsp;Ethan Barnett,&nbsp;Emily Carbone,&nbsp;Adam Jendrisak,&nbsp;Audrey Gill,&nbsp;Sarah Orr,&nbsp;Howard I Scher,&nbsp;Joseph D Schonhoft","doi":"10.33393/jcb.2020.2163","DOIUrl":"https://doi.org/10.33393/jcb.2020.2163","url":null,"abstract":"<p><strong>Introduction: </strong>Here we describe the development of a protein immunofluorescent assay for the detection of nuclear-localized androgen receptor variant 7 (AR-V7) protein within circulating tumor cells (CTCs) identified in patient blood samples. Used in the clinic, the test result serves as a validated biomarker of futility for patients with progressing metastatic castration-resistant prostate cancer (mCRPC) who are treated with androgen receptor targeted therapies (AATT) in whom nuclear-localized AR-V7 CTCs are identified and have received level 2A evidence in the 2019 National Cancer Center Network (NCCN) guidelines (v1.0).</p><p><strong>Methods: </strong>Assay development was completed on the Epic Sciences rare cell detection platform using control cell lines of known AR-V7 status and clinical testing of mCRPC patient samples obtained at the decision point in management.</p><p><strong>Results and conclusions: </strong>Using these samples, all assay parameters, scoring criteria, and clinical cutoffs for positivity were prospectively selected and locked. After assay lock, blinded clinical validation testing was initiated on multiple, independent, clinical cohorts as reported by Scher et al (JAMA Oncol. 2016;2:1441-1449; JAMA Oncol. 2018;4:1179-1186) and Armstrong et al (J Clin Oncol. 2019;37:1120-1129).</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/32/59/JCB-9-13.PMC7951184.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25476658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung ultrasound and biomarkers in primary care: Partners for a better management of patients with heart failure?","authors":"Mar Domingo,&nbsp;Laura Conangla,&nbsp;Josep Lupón,&nbsp;Asunción Wilke,&nbsp;Gladys Juncà,&nbsp;Elena Revuelta-López,&nbsp;Xavier Tejedor,&nbsp;Antoni Bayes-Genis","doi":"10.33393/jcb.2020.2164","DOIUrl":"https://doi.org/10.33393/jcb.2020.2164","url":null,"abstract":"<p><strong>Introduction: </strong>The association of pulmonary congestion assessed by lung ultrasound (LUS) and biomarkers-other than N-terminal pro-brain natriuretic peptide (NT-proBNP)-is uncertain.</p><p><strong>Methods: </strong>We investigated the relationship between total B-line count by LUS and several biomarkers in outpatients with suspicion of heart failure (HF). Primary care patients with suspected new-onset nonacute HF were evaluated both with a 12-scan LUS protocol (8 anterolateral areas plus 4 lower posterior thoracic areas) and 11 inflammatory and cardiovascular biomarkers. A cardiologist blinded to LUS and biomarkers except NT-proBNP confirmed HF diagnosis. After log-transformation of biomarkers' concentrations, unadjusted and adjusted correlations were performed.</p><p><strong>Results: </strong>A total of 170 patients were included (age 76 ± 10 years, 67.6% women). HF diagnosis was confirmed in 38 (22.4%) patients. After adjustment by age, sex, body mass index, and renal function, total B-line sum significantly correlated with NT-proBNP (R = 0.29, p < 0.001), growth/differentiation factor-15 (GDF-15; R = 0.23, p = 0.003), high-sensitive Troponin T (hsTnT; R = 0.36, p < 0.001), soluble interleukin-1 receptor-like 1 (sST2; R = 0.29, p < 0.001), cancer antigen 125 (CA-125; R = 0.17, p = 0.03), high-sensitivity C-reactive protein (hsCRP; R = 0.20, p = 0.009), and interleukin (IL)-6 (R = 0.23, p = 0.003). In contrast, IL-33 (R = -0.01, p = 0.93), IL-1β (R = -0.10, p = 0.20), soluble neprilysin (sNEP; R = 0.09, p = 0.24), tumor necrosis factor-alpha (TNF-α; R = 0.07, p = 0.39), and TNF-α receptor superfamily member 1A (TNFRSF1A; R = 0.14, p = 0.07) did not.</p><p><strong>Conclusions: </strong>Total B-line sum correlated significantly, although moderately, with congestion and several inflammation biomarkers. Unexpectedly, the highest correlation found was with hsTnT.</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0f/57/JCB-9-8.PMC7951183.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25476724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring adipogenic and myogenic circulatory biomarkers of recurrent pressure injury risk for persons with spinal cord injury.","authors":"Kath M Bogie, Katelyn Schwartz, Youjin Li, Shengxuan Wang, Wei Dai, Jiayang Sun","doi":"10.33393/jcb.2020.2121","DOIUrl":"10.33393/jcb.2020.2121","url":null,"abstract":"ABSTRACT Purpose: To investigate linkages between circulatory adipogenic and myogenic biomarkers, gluteal intramuscular adipose tissue (IMAT), and pressure injury (PrI) history following spinal cord injury (SCI). Methods: This is an observational repeated-measures study of 30 individuals with SCI. Whole blood was collected regularly over 2-3 years. Circulatory adipogenic and myogenic gene expression was determined. IMAT was defined as above/below 15% (IMATd) or percentage (IMAT%). PrI history was defined as recurrent PrI (RPrI) or PrI number (nPrI). Model development used R packages (version 3.5.1). Univariate analysis screened for discriminating genes for downstream multivariate and combined models of averaged and longitudinal data for binary (RPrI/IMATd) and finer scales (nPrI/IMAT%). Results: For adipogenesis, Krüppel-like factor 4 was the top RPrI predictor together with resistin and cyclin D1, and sirtuin 2 was the top IMAT predictor. For myogenesis, the top RPrI predictor was dysferlin 2B, and pyruvate dehydrogenase kinase-4 was the top IMAT predictor together with dystrophin. Conclusion: Circulatory adipogenic and myogenic biomarkers have statistically significant relationships with PrI history and IMAT for persons with SCI. Biomarkers of interest may act synergistically or additively. Variable importance rankings can reveal nonlinear correlations among the predictors. Biomarkers of interest may act synergistically or additively, thus multiple genes may need to be included for prediction with finer distinction.","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7e/e0/JCB-9-1.PMC7883629.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25379717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical validation of the CellMax platform for early detection of cancer by enumeration of rare circulating tumor cells.","authors":"Pratyush Gupta,&nbsp;Zulfiqar Gulzar,&nbsp;Ben Hsieh,&nbsp;Austin Lim,&nbsp;Drew Watson,&nbsp;Rui Mei","doi":"10.1177/1849454419899214","DOIUrl":"https://doi.org/10.1177/1849454419899214","url":null,"abstract":"<p><p>The CellMax (CMx®) platform was developed to enrich for epithelial circulating tumor cells (CTCs) in the whole blood. This report provides assay performance data, including accuracy, linearity, limit of blank, limit of detection (LOD), specificity, and precision of enumeration of cancer cell line cells (CLCs) spiked in cell culture medium or healthy donor blood samples. Additionally, assay specificity was demonstrated in 32 young healthy donors and clinical feasibility was demonstrated in a cohort of 47 subjects consisting of healthy donors and patients who were colonoscopy verified to have colorectal cancer, adenomas, or a negative result. The CMx platform demonstrated high accuracy, linearity, and sensitivity for the enumeration of all CLC concentrations tested, including the extremely low range of 1 to 10 cells in 2 mL of blood, which is most relevant for early cancer detection. Theoretically, the assay LOD is 0.71 CTCs in 2 mL of blood. The analytical specificity was 100% demonstrated using 32 young healthy donor samples. We also demonstrated precision across multiple days and multiple operators, with good reproducibility of recovery efficiency. In a clinical feasibility study, the CMx platform identified 8 of 10 diseased subjects as positive (80% clinical sensitivity) and 4 of 5 controls as negative (80% clinical specificity). We also compared processing time and transportation effects for similar blood samples from two different sites and assessed an artificial intelligence-based counting method. Finally, unlike other platforms for which captured CTCs are retained on ferromagnetic beads or tethered to the slide surface, the CMx platform's unique airfoam-enabled release of CTCs allows captured cells to be transferred from a microfluidic chip to an Eppendorf tube, enabling a seamless transition to downstream applications such as genetic analyses and live cell manipulations.</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1849454419899214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37529806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic characterization of extracellular vesicles in human serum.","authors":"Suming Chen, Amrita Datta-Chaudhuri, Pragney Deme, Alex Dickens, Raha Dastgheyb, Pavan Bhargava, Honghao Bi, Norman J Haughey","doi":"10.1177/1849454419879848","DOIUrl":"10.1177/1849454419879848","url":null,"abstract":"<p><p>There is a wide variety of extracellular vesicles (EVs) that differ in size and cargo composition. EVs isolated from human plasma or serum carry lipid, protein, and RNA cargo that provides insights to the regulation of normal physiological processes, and to pathological states. Specific populations of EVs have been proposed to contain protein and RNA cargo that are biomarkers for neurologic and systemic diseases. Although there is a considerable amount of evidence that circulating lipids are biomarkers for multiple disease states, it not clear if these lipid biomarkers are enriched in EVs, or if specific populations of EVs are enriched for particular classes of lipid. A highly reproducible workflow for the analysis of lipid content in EVs isolated from human plasma or serum would facilitate this area of research. Here we optimized an MS/MS^ALL workflow for the untargeted analysis of the lipid content in EVs isolated from human serum. A simple sequential ultracentrifugation protocol isolated three distinct types of serum EVs that were identified based on size, targeted protein, and untargeted lipidomic analyses. EVs in the upper and middle fractions were approximately 140 nm in diameter, while EVs in the pellet were approximately 110 nm in diameter. EVs in the upper most buoyant fractions contained the highest concentration of lipids, were enriched with phospholipids, and immunopositive for the cytoskeletal markers actin, α-actinin, and the mitochondrial protein mitofillin, but negative for the typical EV markers CD63, TSG101, and flotillin. A central fraction of EVs was devoid of cytoskeletal and mitochondrial markers, and positive for CD63, and TSG101, but negative for flotillin. The EV pellet contained no cytoskeletal or mitochondrial markers, but was positive for CD63, TSG101, and flotillin. The EV pellet contained the lowest concentration of most lipids, but was enriched with ceramide. These results provided new insights into the lipid composition of EVs isolated from serum using a simple ultracentrifugation isolation method suitable for lipidomic analysis by mass spectrometry.</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42113057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of cathepsin K biomarker in synovial fluid as a free-drug-driven process.","authors":"Bennett Ma,&nbsp;Gregg Wesolowski,&nbsp;Bin Luo,&nbsp;Traci Lifsted,&nbsp;Keith Wessner,&nbsp;Gary Adamson,&nbsp;Helmut Glantschnig,&nbsp;Laura S Lubbers","doi":"10.1177/1849454418821819","DOIUrl":"https://doi.org/10.1177/1849454418821819","url":null,"abstract":"<p><p>Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized to explore the potential of reduced target engagement and/or suboptimal exposure (free drug) as limiting factors to the pharmacological potential of CatK inhibitors in the knee joint. Following oral administration of MK-1256 at a dose level achieving maximal inhibition of urinary biomarker (helical peptide) in dogs, full suppression of the biomarker in synovial fluid was observed. Subsequent tissue distribution studies conducted in dogs and rabbits revealed that MK-1256 levels in synovial fluid and cartilage were consistent with the free-drug hypothesis. Reasonable projection (within twofold) of drug levels in these tissues can be made based on plasma drug concentration with adjustments for binding factors. These results indicate that the previously observed efficacies in the animal models were not limited by compound distribution or target engagement in the knee tissues.</p>","PeriodicalId":37524,"journal":{"name":"Journal of Circulating Biomarkers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1849454418821819","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36888748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}