Showing papers on "Biomarker (medicine) published in 2017"

Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

Abstract: The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease.

Abstract: BACKGROUND: Growth differentiation factor 15 (GDF-15) is expressed and secreted in response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation Cardiovascular (CV) disease is a major driver of GDF-15 production GDF-15 has favorable preanalytic characteristics and can be measured in serum and plasma by immunoassay CONTENT: In community-dwelling individuals higher concentrations of GDF-15 are associated with increased risks of developing CV disease, chronic kidney disease, and cancer, independent of traditional CV risk factors, renal function, and other biomarkers (C-reactive protein, B-type natriuretic peptide, cardiac troponin) Low concentrations of GDF-15 are closely associated with longevity GDF-15 is as an independent marker of all-cause mortality and CV events in patients with coronary artery disease, and may help select patients with non–ST-elevation acute coronary syndrome for early revascularization and more intensive medical therapies GDF-15 is independently associated with mortality and nonfatal events in atrial fibrillation and heart failure (HF) with preserved or reduced ejection fraction GDF-15 reflects chronic disease burden and acute perturbations in HF and responds to improvements in hemodynamic status GDF-15 is independently associated with major bleeding in patients receiving antithrombotic therapies and has been included in a new bleeding risk score, which may become useful for decision support SUMMARY: GDF-15 captures distinct aspects of CV disease development, progression, and prognosis, which are not represented by clinical risk predictors and other biomarkers The usefulness of GDF-15 to guide management decisions and discover new treatment targets should be further explored

Liquid biopsy: a step forward towards precision medicine in urologic malignancies

Abstract: There is a growing trend towards exploring the use of a minimally invasive “liquid biopsy” to identify biomarkers in a number of cancers, including urologic malignancies. Multiple aspects can be assessed in circulating cell-free DNA, including cell-free DNA levels, integrity, methylation and mutations. Other prospective liquid biopsy markers include circulating tumor cells, circulating RNAs (miRNA, lncRNAs and mRNAs), cell-free proteins, peptides and exosomes have also emerged as non-invasive cancer biomarkers. These circulating molecules can be detected in various biological fluids, including blood, urine, saliva and seminal plasma. Liquid biopsies hold great promise for personalized medicine due to their ability to provide multiple non-invasive global snapshots of the primary and metastatic tumors. Molecular profiling of circulating molecules has been a stepping-stone to the successful introduction of several non-invasive multi-marker tests into the clinic. In this review, we provide an overview of the current state of cell-free DNA-based kidney, prostate and bladder cancer biomarker research and discuss the potential utility other circulating molecules. We will also discuss the challenges and limitations facing non-invasive cancer biomarker discovery and the benefits of this growing area of translational research.

The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma.

Abstract: Circular RNAs (circRNA) represent a novel class of widespread and diverse endogenous RNAs that regulate gene expression in mammals. microRNA-7 (miR-7) is a well-demonstrated suppressor of hepatocellular carcinoma (HCC). Recent studies have showed that one such circRNA, ciRS-7 (also termed as Cdr1as) was the inhibitor and sponge of miR-7 in the embryonic zebrafish midbrain and islet cells. However, the relationships among ciRS-7, miR-7 and clinical features of HCC remain to be clarified. Expression levels of ciRS-7, miR-7 and three miR-7-targeted mRNAs in 108 pairs of HCC and their matched non-tumor tissues were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The protein production of these three miR-7-targeted mRNAs was further verified by Western blot. The relationship between ciRS-7 level and clinicopathological features as well as the recurrence of HCC patients was analyzed. The univariate and multivariate logistic regression analyses were used to detect the risk factors of hepatic microvascular invasion (MVI). The correlation among ciRS-7, miR-7 and miR-7-targeted mRNAs was evaluated using Spearman’s correlation test. There was no significant difference of ciRS-7 expression levels between the HCC tissues and the matched non-tumor tissues (0.67 ± 1.49 vs. 0.44 ± 0.45, p = 0.13), and the ciRS-7 levels in more than half of HCC tissues (65 out of 108, 60.2 %) were down-regulated when compared with their matched non-tumor tissues. However, the expression of ciRS-7 was significantly correlated with the following three clinicopathological characteristics of HCC patients: age <40 years (p = 0.02), serum AFP ≥400 ng/µl (p < 0.01) and hepatic MVI (p = 0.03). Meanwhile, up-regulated ciRS-7 expression was not only an independent risk factor of hepatic MVI but also had a capable predictive ability for MVI (AUC = 0.68, p = 0.001) at the cut-off value of 0.135. Furthermore, the expression of ciRS-7 in HCC tissues with concurrent MVI was inversely correlated with that of miR-7 (r = −0.39, p = 0.007) and positively related with that of two miR-7-targeted genes [PIK3CD (r = 0.55, p < 0.001) and p70S6K (r = 0.34, p = 0.021)]. In addition, the median recurrent time of patients from higher ciRS-7 level group was shorter than that of lower ciRS-7 group (18 vs. 25 months), but no significant difference was observed (p = 0.38). The expression levels of ciRS-7 were comparable between HCC and matched non-tumor tissues. However, the highly ciRS-7 expression in HCC tissues was significantly correlated with hepatic MVI, AFP level and younger age and thus partly related with the deterioration of HCC. Especially, ciRS-7 was one of the independent factors of hepatic MVI. These data suggested that ciRS-7 may be a promising biomarker of hepatic MVI and a novel therapy target for restraining MVI.

Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy.

Abstract: Immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration (FDA) for patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin lymphoma. In the latest announcement, the FDA has granted accelerated approval to pembrolizumab for pediatric and adult patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient solid tumors. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than organ-based approach. MSI-H, either due to inherited germline mutations of mismatch repair genes or epigenetic inactivation of these genes, is found in a subset of colorectal and noncolorectal carcinomas. It is known that MSI-H causes a build up of somatic mutations in tumor cells and leads to a spectrum of molecular and biological changes including high tumor mutational burden, increased expression of neoantigens and abundant tumor-infiltrating lymphocytes. These changes have been linked to increased sensitivity to checkpoint inhibitor drugs. In this mini review, we provide an update on MSI-related solid tumors with special focus on the predictive role of MSI for checkpoint immunotherapy.

Biomarkers in acute kidney injury – pathophysiological basis and clinical performance

Abstract: Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

Neuromyelitis Spectrum Disorders

Abstract: The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG-associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG-associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.

Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response.

Abstract: While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from nonresponders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and nonresponders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical application. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy. Cancer Res; 77(9); 2318-27. ©2017 AACR.

Correction: Corrigendum: Electrical Detection of Dengue Biomarker Using Egg Yolk Immunoglobulin as the Biological Recognition Element

Abstract: Scientific Reports 5: Article number: 7865; published online: 19 January 2015; updated: 30 June 2017 This Article contains an error in the legend of Figure 3. “(a) Dynamic response of the proposed immunosensor upon the addition of 1 mg.mL−1 NS1 in the measuring cell.” should read: “(a) Dynamic response of the proposed immunosensor upon the addition of 1 μg.

Circulating microRNAs as Potential Biomarkers of Infectious Disease.

Abstract: MicroRNAs (miRNAs) are a class of small non-coding endogenous RNA molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. Thousands of these molecules have been discovered to date and multiple miRNAs have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology and control of infection. The fundamental regulatory role of miRNAs in a variety of biological processes suggests that differential expression of these transcripts may be exploited as a novel source of molecular biomarkers for many different disease pathologies or abnormalities. This has been emphasized by the recent discovery of remarkably stable miRNAs in mammalian biofluids, which may originate from intracellular processes elsewhere in the body. The potential of circulating miRNAs as biomarkers of disease has mainly been demonstrated for various types of cancer. More recently, however, attention has focused on the use of circulating miRNAs as diagnostic/prognostic biomarkers of infectious disease; for example: human tuberculosis caused by infection with Mycobacterium tuberculosis, sepsis caused by multiple infectious agents, and viral hepatitis. Here we review these developments and discuss prospects and challenges for translating circulating miRNA into novel diagnostics for infectious disease.

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases.

Abstract: There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit the role of Beta 2 microglobulin (β2M) as a biomarker in patients with Chronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD). Prior to reviewing the numerous clinical studies in the area, we describe the basic biology of β2M, focusing in particular on its role in maintaining the serum albumin levels and reclaiming the albumin in tubular fluid through the actions of the neonatal Fc receptor. Disorders of abnormal β2M function arise as a result of altered binding of β2M to its protein cofactors and the clinical manifestations are exemplified by rare human genetic conditions and mice knockouts. We highlight the utility of β2M as a predictor of renal function and clinical outcomes in recent large database studies against predictions made by recently developed whole body population kinetic models. Furthermore, we discuss recent animal data suggesting that contrary to textbook dogma urinary β2M may be marker for glomerular rather than tubular pathology. We review the existing literature about β2M as a biomarker in patients receiving renal replacement therapy, with particular emphasis on large outcomes trials. We note emerging proteomic data suggest that β2M is a promising marker of Chronic Allograft Nephropathy. Finally, we present data about the role of β2M as a biomarker in a number of non-renal diseases. The goal of this comprehensive review is to direct attention to the multi-faceted role of β2M as a biomarker, and its exciting biology in order to propose the next steps thar are required to bring this recently rediscovered biomarkers into the 21st century.

Biomarkers—A General Review

Abstract: A biomarker is a biological observation that substitutes for and ideally predicts a clinically relevant endpoint or intermediate outcome that is more difficult to observe. The use of clinical biomarkers is easier and less expensive than direct measurement of the final clinical endpoint, and biomarkers are usually measured over a shorter time span. They can be used in disease screening, diagnosis, characterization, and monitoring; as prognostic indicators; for developing individualized therapeutic interventions; for predicting and treating adverse drug reactions; for identifying cell types; and for pharmacodynamic and dose-response studies. To understand the value of a biomarker, it is necessary to know the pathophysiological relationship between the biomarker and the relevant clinical endpoint. Good biomarkers should be measurable with little or no variability, should have a sizeable signal to noise ratio, and should change promptly and reliably in response to changes in the condition or its therapy. © 2017 by John Wiley & Sons, Inc.

MicroRNAs as Peripheral Biomarkers in Aging and Age-Related Diseases.

Abstract: MicroRNAs (miRNAs) are found in the circulatory biofluids considering the important molecules for biomarker study in aging and age-related diseases. Blood or blood components (serum/plasma) are primary sources of circulatory miRNAs and can release these in cell-free form either bound with some protein components or encapsulated with microvesicle particles, called exosomes. miRNAs are quite stable in the peripheral circulation and can be detected by high-throughput techniques like qRT-PCR, microarray, and sequencing. Intracellular miRNAs could modulate mRNA activity through target-specific binding and play a crucial role in intercellular communications. At a pathological level, changes in cellular homeostasis lead to the modulation of molecular function of cells; as a result, miRNA expression is deregulated. Deregulated miRNAs came out from cells and frequently circulate in extracellular body fluids as part of various human diseases. Most common aging-associated diseases are cardiovascular disease, cancer, arthritis, dementia, cataract, osteoporosis, diabetes, hypertension, and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Variation in the miRNA signature in a diseased peripheral circulatory system opens up a new avenue in the field of biomarker discovery. Here, we measure the biomarker potential of circulatory miRNAs in aging and various aging-related pathologies. However, further more confirmatory researches are needed to elaborate these findings at the translation level.

Biomarker signatures of aging.

Abstract: Summary Because people age differently, age is not a sufficient marker of susceptibility to disabilities, morbidities, and mortality. We measured nineteen blood biomarkers that include constituents of standard hematological measures, lipid biomarkers, and markers of inflammation and frailty in 4704 participants of the Long Life Family Study (LLFS), age range 30–110 years, and used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging. The signatures show that dysregulation of a single biomarker can change with patterns of other biomarkers, and age-related changes of individual biomarkers alone do not necessarily indicate disease or functional decline.

Circulating Exosomal MicroRNA-21 as a Biomarker in Each Tumor Stage of Colorectal Cancer.

Abstract: Objective: We clarified the predictive and prognostic value of circulating plasma exosomal microRNA-21 (miR-21) in each TNM stage of colorectal cancer (CRC) patie

PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data.

Abstract: Aim: The treatment of non-small-cell lung cancer has changed after the development of the immune checkpoint inhibitors. Although the most studied biomarker is PD-L1 expression, its clinical significance is still debatable. In this article, we show the updated survival analysis of all published data. Methods: We searched in network and conference data sources for relevant clinical studies of immunotherapy for non-small-cell lung cancer that assessed the PD-L1 expression even as an exploratory analysis. The updated survival hazard ratios (HR) were included in the analysis. Results: 14 studies with 2857 patients were included (2019 treated with immunotherapy). The response rate was as higher among PD-L1-positive patients (RR: 2.19, 95% CI: 1.63–2.94). PD-L1 expression was also related to better progression-free survival (HR: 0.69, 95% CI: 0.57–0.85) and better overall survival (HR: 0.77, 95% CI: 0.67–0.89). Conclusion: PD-L1 overexpression predicts activity as well as better survival for patients treated wit...

Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response.

Abstract: We have seen a notable increase in the application of PD-1/PD-L1 inhibitors for the treatment of several solid and hematogenous malignancies including metastatic melanoma, non-small-cell lung cancer and lymphoma to name a few. The need for biomarkers for identification of a suitable patient population for this type of therapy is now pressing. While specific biomarker assays have been developed for these checkpoint inhibitors based on their respective epitopes, the available studies suggested the clinical utility of these biomarker assays is for response stratification and not patient selection. Further improvement in assay development is needed to utilize this type of assay in identification of ideal patient population for this therapy.

GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk.

Abstract: GlycA is a novel spectroscopic marker of systemic inflammation with low intra-individual variability and other attributes favoring its clinical use in patients with chronic inflammatory and autoimmune diseases. GlycA is unique in its composite nature, reflecting both increased glycan complexity and circulating acute phase protein levels during local and systemic inflammation. Recent studies of GlycA from cross-sectional, observational and interventional studies have been highly informative, demonstrating that GlycA is elevated in acute and chronic inflammation, predicts death in healthy individuals and is associated with disease severity in patients with chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and lupus. Moreover, following treatment with biological therapy in psoriasis, reduction in skin disease severity was accompanied by a decrease in GlycA levels and improvement in vascular inflammation. Collectively, these findings suggest GlycA is a marker that tracks systemic inflammation and subclinical vascular inflammation. However, larger prospective studies and randomized trials are necessary in order to assess the impact of novel therapies on GlycA in patients with chronic inflammatory conditions, which may be concomitant with cardiovascular benefits.

β-Defensin 2 is a responsive biomarker of IL-17A–driven skin pathology in patients with psoriasis

Abstract: Background IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. Objective We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A–driven pathology. Methods We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti–IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. Results IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P P P r = 0.70, n = 199, P r = 0.53, n = 281, P Conclusion IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL-17A–driven skin pathology.

Circulating exosomal miR-125a-3p as a novel biomarker for early-stage colon cancer

Abstract: Circulating exosome holds great potentials as biomarker for diagnosis and prognosis of human cancers. Previously, we have applied small RNA sequencing to identify aberrantly expressed exosomal miRNAs as candidates for diagnostic markers in colon cancer patients. In this validation cohort, plasma derived exosomal miRNA was isolated from 50 early-stage colon cancer patients and 50 matched healthy volunteers. Real-time qRT-PCR revealed that miR-125a-3p, miR-320c were significantly up-regulated in plasma exosomes of the patients with early stage colon cancer. ROC curve showed that miR-125a-3p abundant level may predict colon cancer with an area of under the curve (AUC) of 68.5%, in comparison to that of CEA at 83.6%. Combination of miR-125a-3P and CEA improved the AUC to 85.5%. In addition, plasma exosome level of miR-125a-3p and miR-320c showed significant correlation with nerve infiltration (P 0.05). On the contrary, plasma CEA level is correlated with tumor size, infiltration depth, and differentiation degree (P < 0.05, r = 0.3009–0.7270), but not with nerve infiltration (P = 0.744). In conclusion, this follow-up study demonstrated circulating plasma exosomal miR-125a-3p is readily accessible as diagnosis biomarker for early-stage colon cancer. When combined with conventional diagnostic markers, miR-125a-3p can improve the diagnostic power.

Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity?

Abstract: Serum autoantibodies have a wide range of glycosylation patterns. In this Review, the authors describe the role of autoantibody glycosylation in the pathology of autoimmune disease, and how understanding the role of specific antibody glycoforms might optimize current treatment approaches. A loss of humoral tolerance is a hallmark of many autoimmune diseases and the detection of self-reactive antibodies (autoantibodies) of the immunoglobulin G (IgG) isotype is widely used as a biomarker and diagnostic tool. However, autoantibodies might also be present in individuals without autoimmune disease, thus limiting their usefulness as a sole indicator of disease development. Moreover, while clear evidence exists of the pathogenic effects of autoantibodies in mouse model systems, the contribution of autoantibodies to the pathology of many autoimmune diseases has yet to be established. In this Review, the authors discuss the changes in total serum IgG and autoantibody glycosylation that occur during autoimmune disease and how these changes might help to predict disease development in the future. Furthermore, current knowledge of the signals regulating antibody glycosylation and how individual antibody glycoforms could be used to optimize current treatment approaches will be discussed.