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• Bone Health & Osteoporosis - what women should know

Osteoporosis is a disease that weakens bone. When women get older, at the time around menopause, bone loss increases. Poor nutrition, lack of exercise, hormonal changes and other factors influence bone health. Early intervention can delay the development of osteoporosis and novel biomarkers may help to identify people at risk.

Bone Health & Osteoporosis – what women should know

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Bone Health & Osteoporosis – what women should know

Related publications

The effect of exercise intensity on bone in postmenopausal women (part 2): A meta-analysis.

Kistler-Fischbacher M, Weeks BK, Beck BR. Bone. 2021 Feb;143:115697. doi: 10.1016/j.bone.2020.115697. Epub 2020 Dec 24. PMID: 33357834.

Abstract

Background: Previous reviews have concluded that exercise has only modest effects on bone mineral density (BMD) in postmenopausal women. Despite the well-recognized strong positive relationship between load magnitude and bone response observed from animal research, the majority of human trials have examined the effects of only low to moderate intensity exercise on bone. We speculated that meta-analysing according to intensity may reveal a more potent exercise effect at higher intensity.

Objectives: To determine the effects of low, moderate and high intensity exercise on BMD at the spine and hip in postmenopausal women.

Methods: Electronic databases and reference lists were searched for RCTs that examined the effect of exercise compared to control on DXA-derived lumbar spine, femoral neck or total hip BMD in healthy postmenopausal women. Interventions were classified as low, moderate or high intensity and pooled based on classification. Mean differences (MD) were calculated using random effects models and a risk of bias analysis was undertaken. To determine the effect of different exercise types (resistance and impact training) on BMD outcomes, subgroup analyses for all intensity categories and outcomes were conducted. Separate meta-analyses were undertaken to examine the influence of adding exercise to a bone medication intervention and to examine exercise effects on fracture risk.

Results: Fifty-three trials, testing 63 interventions (19 low, 40 moderate, 4 high intensity) were included. At the lumbar spine, high intensity exercise yielded greater BMD effects (MD = 0.031 g/cm² 95% CI [0.012, 0.049], p = 0.002) than moderate (MD = 0.012 g/cm² 95% CI [0.008, 0.017], p < 0.001) and low intensity (MD = 0.010 g/cm² 95% CI [0.005, 0.015], p < 0.001). Low and moderate intensity exercise was equally effective at the femoral neck (low: 0.011 g/cm² 95% CI [0.006, 0.016], p < 0.001; moderate: 0.011 g/cm² 95% CI [0.007, 0.015], p < 0.001), but no effect of high-intensity exercise was observed. Moderate intensity exercise increased total hip BMD (0.008 g/cm² 95% CI [0.004, 0.012], p < 0.001), but low intensity did not. There were insufficient data to meta-analyse the effect of high intensity exercise at the total hip. Resistance training, potentially in combination with impact training, appears to be the most effective osteogenic stimulus at the spine and hip. Findings from meta-regression analyses were not informative and no influence of exercise on medication efficacy was observed. Risk of bias was mainly low or unclear due to insufficient information reported.

Conclusion: High intensity exercise is a more effective stimulus for lumbar spine BMD than low or moderate intensity, but not femoral neck BMD, however, the latter finding may be due to lack of power. While data from high-intensity exercise interventions are limited, the current comprehensive meta-analysis demonstrates the same positive relationship between load magnitude and bone response in humans that is observed in animal research. Findings have implications for optimal exercise prescription for osteoporosis in postmenopausal women.

Nutrition in the prevention and control of osteoporosis.

Ortega RM, Jiménez Ortega AI, Martínez García RM, Cuadrado Soto E, Aparicio A, López-Sobaler AM. Nutrición en la prevención y el control de la osteoporosis Nutr Hosp. 2021 Jan 13;37(Spec No2):63-66. Spanish. doi: 10.20960/nh.03360. PMID: 32993301.

Abstract

Objective: although osteoporosis develops in advanced stages of life, it must be prevented and stopped from the pediatric age, acting on modifiable factors, especially diet and lifestyle. The objective of this work is to review the latest evidence on nutritional improvements that can help in the prevention and control of the disease. Methods: bibliographic search related to the topic. Results: it is advisable to avoid energy restrictions, especially in postmenopausal women and particularly if they have osteopenia/osteoporosis since, in relation to these pathologies, excess weight may be preferable, rather than underweight. Protein intake higher than the recommended one is beneficial for the bone, provided that the calcium intake is adequate. Excessive intake of sugar and saturated fat should be avoided, but attempts should be made to achieve the nutritional goals set for ω-3 polyunsaturated fatty acids and fiber. It is important to monitor vitamin D status and calcium intake, which is inadequate in high percentages of individuals, as well as improving the contribution of vitamins K, C and group B, and also magnesium, potassium, iron, zinc, copper, fluorine, manganese, silicon and boron, and avoiding the excessive contribution of phosphorus and sodium. Conclusions: osteoporosis is an underdiagnosed pathology and of increasing prevalence. Due to its high morbidity and mortality, prevention is important and, from a nutritional point of view, it is convenient to bring the diet closer to the theoretical ideal. In general, increasing the consumption of dairy products, fish, vegetables and fruits, as well as reducing the consumption of salt, during childhood and throughout life, seems convenient for the bone improvement of most of the population.

Osteoporosis

Compston JE, McClung MR, Leslie WD. Lancet. 2019 Jan 26;393(10169):364-376. doi: 10.1016/S0140-6736(18)32112-3. PMID: 30696576.

 Abstract

Fractures resulting from osteoporosis become increasingly common in women after age 55 years and men after age 65 years, resulting in substantial bone-associated morbidities, and increased mortality and health-care costs. Research advances have led to a more accurate assessment of fracture risk and have increased the range of therapeutic options available to prevent fractures. Fracture risk algorithms that combine clinical risk factors and bone mineral density are now widely used in clinical practice to target high-risk individuals for treatment. The discovery of key pathways regulating bone resorption and formation has identified new approaches to treatment with distinctive mechanisms of action. Osteoporosis is a chronic condition and long-term, sometimes lifelong, management is required. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. In people at a very high or imminent risk of fracture, therapy with teriparatide or abaloparatide should be considered; however, since treatment duration with these drugs is restricted to 18-24 months, treatment should be continued with an antiresorptive drug. Individuals at high risk of fractures do not receive adequate treatment and strategies to address this treatment gap-eg, widespread implementation of Fracture Liaison Services and improvement of adherence to therapy-are important challenges for the future.

The Utility of Biomarkers in Osteoporosis Management.

Garnero P. Mol Diagn Ther. 2017 Aug;21(4):401-418. doi: 10.1007/s40291-017-0272-1. PMID: 28271451.

Abstract

The measurement of bone turnover markers is useful for the clinical investigation of patients with osteoporosis. Among the available biochemical markers, the measurements of serum procollagen type I N-terminal propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) have been recommended as reference markers of bone formation and bone resorption, respectively. The important sources of preanalytical and analytical variability have been identified for both markers, and precise measurement can now be obtained. Reference interval data for PINP and CTX have been generated across different geographical locations, which allows optimum clinical interpretation. However, conventional protein-based markers have some limitations, including a lack of specificity for bone tissue, and their inability to reflect osteocyte activity or periosteal metabolism. Thus, novel markers such as periostin, sclerostin and, sphingosine 1-phosphate have been developed to address some of these shortcomings. Recent studies suggest that the measurements of circulating microRNAs, a new class of marker, may represent early biological markers in osteoporosis. Bone markers have been shown to be a useful adjunct to bone mineral density for identifying postmenopausal women at high risk for fracture. Because levels of bone markers respond rapidly to both anabolic and anticatabolic drugs, they are very useful for investigating the mechanism of action of new therapies and, potentially, for predicting their efficacy to reduce fracture risk.

Liver transplantation has become a routine treatment for children with end stage liver failure. Antibody-mediated rejection of the transplant can be monitored by C4d.  This recent study utilized the Biomedica “anti-C4d antibody”:

Liver Histopathology in Late Protocol Biopsies after Pediatric Liver Transplantation.

Markiewicz-Kijewska M, Szymańska S, Pyzlak M, Kaliciński P, Teisseyre J, Kowalski A, Jankowska I, Czubkowski P, Ismail H. Children (Basel). 2021 Aug 1;8(8):671. doi: 10.3390/children8080671. PMID: 34438562; PMCID: PMC8392008.

Liver Transplant: antibody-mediated rejection monitored by C4d

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Abstract

Liver transplantation has become a routine treatment for children with end stage liver failure. Recently, the long term survival of pediatric patients after liver transplantation has improved, with a life expectancy much longer than that of adult recipients, but also with longer exposition of the graft to various injuries, including immunological, inflammatory and others. Biochemical tests, although important, do not always reflect graft injury. The aim of our study was to analyze the histopathology of the graft in late protocol biopsies and correlate it with the clinical and biochemical status of these patients. We analyzed 61 protocol liver biopsies taken from 61 patients. Biopsies were taken 9.03-17.09 years (mean 12.68, median 11.74 years) after transplantation. Liver specimens were examined particularly for the presence and stage of liver fibrosis, inflammation, steatosis, and acute or chronic cellular and humoral rejection. We did not find any abnormalities in 26 (42.6%) liver specimens. None of the patients had signs of cellular or antibody mediated rejection or chronic rejection. In 23 liver biopsies (37.7%), we found non-specific lymphoid infiltrates. Another problem was fibrosis (equal to or more than three on the Ishak scale)-we found it in 17 patients, including seven liver specimens (11.5%) with severe fibrosis (Ishak 5-6). Conclusions: Various pathomorphological abnormalities were found in more than half of patients with a median 11.74 years post-transplant follow-up. Most of them presented normal laboratory liver tests at the same time, suggesting a slow subclinical process leading to pathomorphological abnormalities. No single factor for the development of these abnormalities was found, but our study supports the need for protocol liver biopsies even in patients with normal/almost normal biochemical liver tests.

Liver Transplant: antibody-mediated rejection monitored by C4d

 Related publications

Immunostaining Patterns of Posttransplant Liver Biopsies Using 2 Anti-C4d Antibodies  

Chen L, Himmelfarb EA, Sun M, Choi EK, Fan L, Lai J, Kim CJ, Xu H, Wang HL. Appl Immunohistochem Mol Morphol. 2020 Feb;28(2):146-153. doi: 10.1097/PAI.0000000000000723. PMID: 32044883.  

Citation Biomedica C4d antibody (purchased through Alpco, US, cat. no. BI-RC4D)

 Abstract

Histopathologic diagnosis of antibody-mediated rejection in posttransplant liver biopsies is challenging. The recently proposed diagnostic criteria by the Banff Working Group on Liver Allograft Pathology require positive C4d immunohistochemical staining to establish the diagnosis. However, the reported C4d staining patterns vary widely in different studies. One potential explanation may be due to different antibody preparations used by different investigators. In this study, posttransplant liver biopsies from 69 patients histopathologically diagnosed with acute cellular rejection, chronic rejection, or recurrent hepatitis C were immunohistochemically stained using 2 polyclonal anti-C4d antibodies. On the basis of the distribution of C4d immunoreactivity, 5 different staining patterns were observed: portal vein and capillary, hepatic artery, portal stroma, central vein, and sinusoids. The frequency, extent, and intensity of positive C4d staining with the 2 antibody preparations differed significantly for portal veins/capillaries and central veins, but not for hepatic arteries and portal stroma. Positive sinusoidal staining was seen in only 1 case. There were no significant differences in the frequency, extent, and intensity of positive C4d staining among the acute cellular rejection, chronic rejection, and recurrent hepatitis C groups with the 2 anti-C4d antibodies. These data show that different anti-C4d antibodies can show different staining patterns, which may lead to different interpretation. Caution is thus needed when selecting C4d antibodies for clinical use to aid in the diagnosis of antibody-mediated rejection.

Antibody-Mediated Rejection After Liver Transplant  

Lee M. Gastroenterol Clin North Am. 2017 Jun;46(2):297-309. doi: 10.1016/j.gtc.2017.01.005. PMID: 28506366.

Abstract

Antibody-mediated rejection (AMR) in liver transplants is a field in its infancy compared with its allograft cohorts of the kidney and lung. Acute AMR is diagnosed based on specific clinical and histopathologic criteria: serum donor specific antibodies, C4d staining, histopathologic findings on liver biopsy, and exclusion of other entities. In contrast, the histologic features of chronic AMR are not as specific and it is a more challenging diagnosis to make. Treatments of acute and chronic AMR include some combination of steroids, immune-modulating agents, intravenous immunoglobulin, plasmapheresis, and proteasome inhibitors.

Routine C4d immunohistochemistry in cardiac allografts: Long-term outcomes

Husain AN, Mirza KM, Fedson SE. J Heart Lung Transplant. 2017 Dec;36(12):1329-1335. doi: 10.1016/j.healun.2017.09.004. Epub 2017 Sep 14. PMID: 28988608.

 C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients

Luk A, Alba AC, Butany J, Tinckam K, Delgado D, Ross HJ. Transpl Int. 2015 Jul;28(7):857-63. doi: 10.1111/tri.12560. Epub 2015 Mar 27. PMID: 25778989.

 

Major depressive disorder (MDD) is a leading psychiatric illness across the world. Around 30-60% of patients with depression do not respond to available anti-depressive treatments. The proinflammatory cytokine IL-6 has a crucial role in the development of MDD. IL-6 is consistently increased in blood samples of MDD patients. Blood IL-6 level correlates with depression scores. Inhibiting IL-6 could offer a new approach in treating depression.

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Blood IL-6 level correlates with Depression Scores 

Role of Interleukin-6 in Depressive Disorder. Int J Mol Sci. 2020 Mar 22;21(6):2194. doi: 10.3390/ijms21062194. PMID: 32235786; PMCID: PMC7139933.

Ting EY et al., J. Int J Mol Sci. 2020 Mar 22;21(6):2194. doi: 10.3390/ijms21062194. PMID: 32235786. Full text link

Abstract link

Major depressive disorder (MDD), which is a leading psychiatric illness across the world, severely affects quality of life and causes an increased incidence of suicide. Evidence from animal as well as clinical studies have indicated that increased peripheral or central cytokine interleukin-6 (IL-6) levels play an important role in stress reaction and depressive disorder, especially physical disorders comorbid with depression. Increased release of IL-6 in MDD has been found to be a factor associated with MDD prognosis and therapeutic response, and may affect a wide range of depressive symptomatology. However, study results of the IL6 genetic effects in MDD are controversial. Increased IL-6 activity may cause depression through activation of hypothalamic-pituitary-adrenal axis or influence of the neurotransmitter metabolism. The important role of neuroinflammation in MDD pathogenesis has created a new perspective that the combining of blood IL-6 and other depression-related cytokine levels may help to classify MDD biological subtypes, which may allow physicians to identify the optimal treatment for MDD patients. To modulate the IL-6 activity by IL-6-related agents, current antidepressive agents, herb medication, pre-/probiotics or non-pharmacological interventions may hold great promise for the MDD patients with inflammatory features.

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 Related publications

 On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?

Roohi E et al., J Neuroinflammation. 2021 Feb 16;18(1):45. doi: 10.1186/s12974-021-02100-7. PMID: 33593388; PMCID: PMC7884972. Abstract link

Abstract

Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill.

Knight JM et al., Transl Psychiatry. 2021 Jan 18;11(1):58. doi: 10.1038/s41398-020-01164-y. PMID: 33462203; PMCID: PMC7812704. Abstract link

 Abstract

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II-IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more-not less-depressive symptoms.

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Clinical biomarker validation. Allinson JL. Bioanalysis. 2018 Jun 1;10(12):957-968. doi: 10.4155/bio-2018-0061. Epub 2018 Jun 20. PMID: 29923754.

Abstract

Pre-analytical processes in medical diagnostics: New regulatory requirements and standards. Dagher G, Becker KF, Bonin S, Foy C, Gelmini S, Kubista M, Kungl P, Oelmueller U, Parkes H, Pinzani P, Riegman P, Schröder U, Stumptner C, Turano P, Sjöback R, Wutte A, Zatloukal K.N Biotechnol. 2019 Sep 25;52:121-125. doi: 10.1016/j.nbt.2019.05.002. Epub 2019 May 15. PMID: 31102798.

Abstract

Biomarkers serve as markers for cancer progression and prognosis and represent promising therapeutic targets. Improving our understanding of how cancers originate, grow and spread may help to reduce the risk and burden of the disease. Cancer biomarker research has identified Neuropilin-1 and Semaphorin 4D  as novel protein markers  and promising  therapeutic targets. These proteins can easily be detected in human serum and plasma by ELISA assay.

Innovative Biomarkers in Oncology

Check out our biomarker kits for cancer research link

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Neuropilin-1 ELISA – BI-20409 – Product link

Semaphorin 4D ELISA – BI-20405 – Product link

Innovative Biomarkers in Oncology 

Related publications

Neuropilins Controlling Cancer Therapy Responsiveness. Full text link

Napolitano V, Tamagnone L. Int J Mol Sci. 2019 Apr 25;20(8):2049. doi: 10.3390/ijms20082049. PMID: 31027288. 

Abstract

Neuropilins (NRPs) are cell surface glycoproteins, acting as co-receptors for secreted Semaphorins (SEMAs) and for members of the vascular endothelial growth factor (VEGF) family; they have been initially implicated in axon guidance and angiogenesis regulation, and more recently in cancer progression. In addition, NRPs have been shown to control many other fundamental signaling pathways, especially mediated by tyrosine kinase receptors (RTKs) of growth factors, such as HGF (hepatocyte growth factor), PDGF (platelet derived growth factor) and EGF (epidermal growth factor). This enables NRPs to control a range of pivotal mechanisms in the cancer context, from tumor cell proliferation and metastatic dissemination, to tumor angiogenesis and immune escape. Moreover, cancer treatment failures due to resistance to innovative oncogene-targeted drugs is typically associated with the activity of alternative RTK-dependent pathways; and neuropilins’ capacity to control oncogenic signaling cascades supports the hypothesis that they could elicit such mechanisms in cancer cells, in order to escape cytotoxic stress and therapeutic attacks. Intriguingly, several studies have recently assayed the impact of NRPs inhibition in combination with diverse anti-cancer drugs. In this minireview, we will discuss the state-of-art about the relevance of NRPs as potential predictive biomarkers of drug response, and the rationale to target these proteins in combination with other anticancer therapies.

Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer. Full text link

Mastrantonio R, You H, Tamagnone L. Theranostics. 2021 Jan 15;11(7):3262-3277. doi: 10.7150/thno.54023. PMID: 33537086; PMCID: PMC7847692.

 Abstract

Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.

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DKK-1 (Dickkopf-1) ELISA kit – BI-20413 –  Product link

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√  Widely cited +160 references!

 DKK1 promotes migration and invasion of non-small cell lung cancer via β-catenin signaling pathway. Full text link

Zhang J, Zhang X, Zhao X, Jiang M, Gu M, Wang Z, Yue W Tumour Biol. 2017. 39(7):1010428317703820. doi: 10.1177/1010428317703820. PMID: 28677426.

 Dickkopf-1: A Promising Target for Cancer Immunotherapy. Full text link

Chu HY, Chen Z, Wang L, Zhang ZK, Tan X, Liu S, Zhang BT, Lu A, Yu Y, Zhang G. Front Immunol. 2021 May 20;12:658097. doi: 10.3389/fimmu.2021.658097. PMID: 34093545; PMCID: PMC8174842.

 Leucine-rich alpha-2-glycoprotein (LRG) ELISA kit – BI-LRG1 –  Product link

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Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines. Full text link

Oncotarget. Takemoto N, Serada S, Fujimoto M, Honda H, Ohkawara T, Takahashi T, Nomura S, Inohara H, Naka T. 2015. 10;6(13):11009-22. doi: 10.18632/oncotarget.3557. PMID: 25826092; PMCID: PMC4484435.

Detection of leucine-rich alpha-2-glycoprotein 1-containing immunocomplexes in the plasma of lung cancer patients with epitope-specific mAbs. Abstract link.

Lázár J, Kovács A, Tornyi I, Takács L, Kurucz I. Cancer Biomark. 2021 Nov 1. doi: 10.3233/CBM-210164. Epub ahead of print. PMID: 34744074.

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LRG monitors disease activity in inflammatory bowel disease (IBD)  receiving adalimumab

 Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis affects millions of individuals worldwide. IBD is caused by chronic inflammation  in the gut. Though biologics such as TNF-α inhibitors (e.g. adalimumab) are highly effective in the treatment of IMD they can lose their efficacy over time. A recent report identifies LRG (leucine-rich alpha-2 glycoprotein), a novel serum biomarker, to be useful in monitoring disease activity in IBD patients. LRG is strongly associated with mucosal healing and it better reflects endoscopic activity during adalimumab treatment than C-reactive protein (CRP) and fecal calprotectin (fCal).  Click here to learn more.

Check out the Biomedica LRG ELISA  

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Monitoring IBD disease activity with serum marker LRG

Leucine-Rich Alpha-2 Glycoprotein May Be Predictive of the Adalimumab Trough Level and Antidrug Antibody Development for Patients with Inflammatory Bowel Disease: A Sub-Analysis of the PLANET Study. Yanai S Digestion. 2021;102(6):929-937. doi: 10.1159/000517339. Epub 2021 Jul 16. PMID: 34350873; PMCID: PMC8619792. Full text link .

Abstract link

Introduction: The aim of this study was to examine whether biomarkers are predictive of the adalimumab (ADA) trough level and antidrug antibody development in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Methods: Using data obtained in a prospective, multicenter, observational study (PLANET), we assessed serial changes in a novel biomarker – leucine-rich alpha-2 glycoprotein (LRG) – during ADA treatment for patients with active CD and UC. We measured serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCAL) at weeks 0, 12, 24, and 52. The ADA trough level and anti-ADA antibody (AAA) were also measured at weeks 12 and 52. Correlations between the ADA trough level, AAA, and biomarkers were examined. Results: In all, 34 patients with CD and 47 patients with UC were enrolled. The ADA trough level at week 12 or at the time of ADA withdrawal was 8.5 ± 3.9 in the AAA-negative group (n = 70) and 2.9 ± 2.7 μg/mL in the AAA-positive group (n = 8) (p < 0.0001). The ADA trough level at week 12 or at the time of ADA withdrawal was associated with pretreatment LRG (p = 0.0437 and r = -0.23). Conclusion: LRG, rather than CRP or fCAL, may be a marker for predicting the trough level of ADA for patients with CD and UC treated with ADA.

Monitoring IBD disease activity with serum marker LRG

Related publications:

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study. Shinzaki S et al., J Gastroenterol. 2021. 56(6):560-569. doi: 10.1007/s00535-021-01793-0. Epub 2021 May 3. PMID: 33942166; PMCID: PMC8137624.

 

Abstract  link

Background: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). Methods: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn’s disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. Results: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). Conclusions: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

Leucine-rich alpha-2 glycoprotein as a marker of mucosal healing in inflammatory bowel disease. Yasutomi E et al., Sci Rep. 2021 May 27;11(1):11086. doi: 10.1038/s41598-021-90441-x. PMID: 34045529; PMCID: PMC8160157. Full text link.

 

Abstract link

Leucine-rich alpha-2 glycoprotein (LRG) may be a novel serum biomarker for patients with inflammatory bowel disease. The association of LRG with the endoscopic activity and predictability of mucosal healing (MH) was determined and compared with those of C-reactive protein (CRP) and fecal markers (fecal immunochemical test [FIT] and fecal calprotectin [Fcal]) in 166 ulcerative colitis (UC) and 56 Crohn’s disease (CD) patients. In UC, LRG was correlated with the endoscopic activity and could predict MH, but the performance was not superior to that of fecal markers (areas under the curve [AUCs] for predicting MH: LRG: 0.61, CRP: 0.59, FIT: 0.75, and Fcal: 0.72). In CD, the performance of LRG was equivalent to that of CRP and Fcal (AUCs for predicting MH: LRG: 0.82, CRP: 0.82, FIT: 0.70, and Fcal: 0.88). LRG was able to discriminate patients with MH from those with endoscopic activity among UC and CD patients with normal CRP levels. LRG was associated with endoscopic activity and could predict MH in both UC and CD patients. It may be particularly useful in CD.

 

Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease. Kato M et al.,  PLoS One. 2021 Jul 9;16(7):e0254548. doi: 10.1371/journal.pone.0254548. PMID: 34242369; PMCID: PMC8270420. Abstract link.

Paget’s disease of bone is a chronic disease of the skeleton. Healthy bone is remodeled in a lifelong process where mature bone tissue is removed and new bone tissue is formed. In Paget´s disease this process is out of balance which causes bones to grow larger and weaker than normal. Paget´s usually affects just one or a few bones. In some parts of the world it is the second most common bone disorder after osteoporosis. Learn more

 

PAGET´S AWARENESS DAY – 11. January

 

BIOMEDICA – Bone Disease Biomarker ELISA kits for clinical research www.bmgrp.com

Check out our brochure on bone biomarkers link

Features & Benefits of Biomedica´s ELISA Assay Kits

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Related ELISA kits

Osteoprotegerin (OPG) link ; DKK-1 link ; Sclerostin link

Related publications:

Management of Paget’s disease of bone.

Reid IR. Osteoporos Int. 2020 May;31(5):827-837. doi: 10.1007/s00198-019-05259-1. PMID: 31848640. Full text link

 

Abstract link

Paget’s disease is a progressive focal bone condition which can result in pain, low quality of life, deformity and other complications. Disease progression can be halted with potent bisphosphonates, resulting in improvement in both quality of life and pain, and normalisation of scintigraphy, plain radiographs and bone histology. Zoledronate has transformed the treatment of Paget’s disease, producing sustained remissions in almost all patients. Thus, it is now possible to normalise bone cell activity and prevent disease progression at low cost, with one or two intravenous injections of zoledronate, greatly reducing follow-up costs. Patients with Paget’s disease who are symptomatic or at risk of complications should have the opportunity to reap these therapeutic benefits. Potent bisphosphonates are highly effective in halting disease progression in Paget’s disease, but guidelines disagree about treatment indications. The efficacy, safety and low cost of zoledronate recommend its use in any patient who is symptomatic or judged to be at risk of complications from Paget’s disease.

 

Paget’s Disease of Bone.

Gennari L, Rendina D, Falchetti A, Merlotti D. Calcif Tissue Int. 2019 May;104(5):483-500. doi: 10.1007/s00223-019-00522-3. PMID: 30671590. Full text link

 

Abstract link

Paget’s disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

 

Diagnosis and Management of Paget’s Disease of Bone in Adults: A Clinical Guideline.

Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD, Gennari L, Guañabens N, Javaid MK, Layfield R, O’Neill TW, Russell RGG, Stone MD, Simpson K, Wilkinson D, Wills R, Zillikens MC, Tuck SP. J Bone Miner Res. 2019 Apr;34(4):579-604. doi: 10.1002/jbmr.3657. PMID: 30803025. Full text link

 

Abstract link  

An evidence-based clinical guideline for the diagnosis and management of Paget’s disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget’s Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed. 

NT-proBNP associated with mortality in COVID-19 patients with no history of heart failure:  The cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) plays a central role in the diagnosis and management of heart failure (HF). A recent report in patients with COVID-19 and no HF history demonstrates that high admission NT-proBNP is associated with higher mortality and healthcare resources utilization. The authors conclude that preventive strategies may be required for these patients.

Learn more: Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19. Link to full text.

Check out the Biomedica NT-proBNP ELISA (cat.no. SK-1204)

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Abstract:  Admission NT-proBNP and outcomes in patients without history of heart failure hospitalized with COVID-19.

Yoo J, Grewal P, Hotelling J, Papamanoli A, Cao K, Dhaliwal S, Jacob R, Mojahedi A, Bloom ME, Marcos LA, Skopicki HA, Kalogeropoulos AP. ESC Heart Fail. 2021. 5:4278-4287. doi: 10.1002/ehf2.13548. Epub 2021 Aug 4. PMID: 34346182; PMCID: PMC8426942.

Aims: We examined the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients admitted for coronavirus disease 2019 (COVID-19) without prior history of heart failure (HF) or cardiomyopathy. Methods and results: Retrospective cohort of consecutive adults (N = 679; median age 59 years; 38.7% women; 87.5% White; 7.1% Black; 5.4% Asian; 34.3% Hispanic) admitted with documented COVID-19 in an academic centre in Long Island, NY. Admission NT-proBNP was categorized using the European Society of Cardiology Heart Failure Association age-specific criteria for acute presentations. We examined (i) mortality and the composite of death or mechanical ventilation and (ii) out-of-hospital, intensive care unit (ICU)-free, and ventilator-free days at 28 days. Estimates were adjusted for confounders using a lasso selection process. Using age-specific criteria, 417 patients (61.4%) had low, 141 (20.8%) borderline, and 121 (17.8%) high NT-proBNP. Mortality was 5.8%, 20.6%, and 36.4% for patients with low, borderline, and high NT-proBNP, respectively. In lasso-adjusted models, high NT-proBNP was associated with higher mortality [hazard ratio (HR) 2.15; 95% confidence interval (CI) 1.06-4.39; P = 0.034] and composite endpoint rates (HR 1.66; 95%CI 1.04-2.66; P = 0.035). Patients with high NT-proBNP had 32%, 33%, and 33% fewer out-of-hospital, ICU-free, and ventilator-free days compared with low NT-proBNP counterparts. Results were consistent across age, sex, and race, and regardless of coronary artery disease or hypertension, except for stronger mortality signal with high NT-proBNP in women. Conclusions: In patients with COVID-19 and no HF history, high admission NT-proBNP is associated with higher mortality and healthcare resources utilization. Preventive strategies may be required for these patients.

Related publications:

Characterization of NT-proBNP in a large cohort of COVID-19 patients. Link to full text.

Caro-Codón J, Rey JR, Buño A, Iniesta AM, Rosillo SO, Castrejon-Castrejon S, Rodriguez-Sotelo L, Martinez LA, Marco I, Merino C, Martin-Polo L, Garcia-Veas JM, Martinez-Cossiani M, Gonzalez-Valle L, Herrero A, López-de-Sa E, Merino JL; CARD-COVID Investigators. Eur J Heart Fail. 2021. Mar;23(3):456-464. doi: 10.1002/ejhf.2095. Epub 2021 Feb 1. PMID: 33421281; PMCID: PMC8013330.

 Abstract:

Aims: Extensive research regarding the association of troponin and prognosis in coronavirus disease 2019 (COVID-19) has been performed. However, data regarding natriuretic peptides are scarce. N-terminal pro B-type natriuretic peptide (NT-proBNP) reflects haemodynamic stress and has proven useful for risk stratification in heart failure (HF) and other conditions such as pulmonary embolism and pneumonia. We aimed to adequately characterize NT-proBNP concentrations using a large cohort of patients with COVID-19, and to investigate its association with prognosis. Methods and results: Consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and available NT-proBNP determinations, from March 1st to April 20th, 2020 who completed at least 1-month follow-up or died, were studied. Of 3080 screened patients, a total of 396 (mean age 71.8 ± 14.6 years, 61.1% male) fulfilled all the selection criteria and were finally included, with a median follow-up of 53 (18-62) days. Of those, 192 (48.5%) presented NT-proBNP levels above the recommended cut-off for the identification of HF. However, only 47 fulfilled the clinical criteria for the diagnosis of HF. Patients with higher NT-proBNP during admission experienced more frequent bleeding, arrhythmias and HF decompensations. NT-proBNP was associated with mortality both in the whole study population and after excluding patients with HF. A multivariable Cox model confirmed that NT-proBNP was independently associated with mortality after adjusting for all relevant confounders (hazard ratio 1.28, 95% confidence interval 1.13-1.44, per logarithmic unit). Conclusion: NT-proBNP is frequently elevated in COVID-19. It is strongly and independently associated with mortality after adjusting for relevant confounders, including chronic HF and acute HF. Therefore, its use may improve early prognostic stratification in this condition.

Related products:

• NT-proANP ELISA (cat.no. BI-20892) Link
• Neuropilin-1 (cat.no. BI-20409) Link ;  NRP1 IN COVID-19 disease read more

Biomedica´s Periostin ELISA kit has recently been featured in a clinical study for lung cancer: Serum Periostin Predicts Survival in Lung Cancer Patients.

Lung adenocarcinoma is the most common type of lung cancer. When first diagnosed, between 30-50% of patients have bone metastasis with poor survival outcome. The extracellular matrix protein Periostin mediates the spreading of lung cancer. In vivo data suggest that bone metastatic lung cancer cells induce Periostin expression that may enhance cancer aggressivity. A recent report in patients with lung adenocarcinoma demonstrates that serum Periostin levels may be used as a prognostic biomarker to predict survival in lung cancer.

Serum Periostin Predicts Survival in Lung Cancer Patients

Learn more: Serum total periostin is an independent marker of overall survival in bone metastases of lung adenocarcinoma. Link to full text.
Massy E, Rousseau JC, Gueye M, Bonnelye E, Brevet M, Chambard L, Duruisseaux M, Borel O, Roger C, Guelminger R, Pialat JB, Gineyts E, Bouazza L, Millet M, Maury JM, Clézardin P, Girard N, Confavreux CB. J Bone Oncol. 2021. 29:100364. doi: 10.1016/j.jbo.2021.100364. PMID: 34150488; PMCID: PMC8190464.

Check out the Biomedica PERIOSTIN ELISA (cat.no. BI-20433)

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Serum total periostin is an independent marker of overall survival in bone metastases of lung adenocarcinoma

Abstract

More than 35% of lung adenocarcinoma patients have bone metastases at diagnosis and have a poor survival. Periostin, a carboxylated matrix protein, mediates lung cancer cell dissemination by promoting epithelial-mesenchymal transition, and is involved in bone response to mechanical stress and bone formation regulation. This suggests that periostin may be used as a biomarker to predict survival in lung cancer patients. Serum periostin was assessed at diagnosis in a prospective cohort of 133 patients with lung adenocarcinoma of all stages. Patients were divided into localized and bone metastatic groups. Both groups were matched to healthy controls. Survival analysis and Cox proportional hazards models were conducted in the total population and in bone metastatic group. The median serum periostin level was higher in bone metastatic (n = 67; median: 1752 pmol/L) than in the localized group (n = 66; 861 pmol/L; p < 0.0001). Patients with high periostin (>median) had a poorer overall survival in the whole population (33.3 weeks vs. NR; p < 0.0001) and the bone metastatic group (24.4 vs. 66.1 weeks; p < 0.001). In multivariate analysis, patients with high periostin had increased risk of death (HR = 2.09, 95%CI [1.06-4.13]; p = 0.03). This was also found in the bone metastatic group (HR = 3.62, 95%CI [1.74-7.52]; p = 0.0005). Immunohistochemistry on bone metastasis biopsies showed periostin expression in the bone matrix and nuclear and cytoplasmic staining in cancer cells. Serum periostin was an independent survival biomarker in all-stage and in bone metastatic lung adenocarcinoma patients. IHC data suggest that periostin might be induced in cancer cells in bone metastatic niche in addition to bone microenvironment expression.

Related publications

High serum levels of periostin are associated with a poor survival in breast cancer. Link to full text.
Rachner TD, Göbel A, Hoffmann O, Erdmann K, Kasimir-Bauer S, Breining D, Kimmig R, Hofbauer LC, Bittner AK.Breast Cancer Res Treat. 2020 Apr;180(2):515-524. doi: 10.1007/s10549-020-05570-0. Epub 2020 Feb 10.PMID: 32040688.

Abstract
Purpose: Periostin is a secreted extracellular matrix protein, which was originally described in osteoblasts. It supports osteoblastic differentiation and bone formation and has been implicated in the pathogenesis of several human malignancies, including breast cancer. However, little is known about the prognostic value of serum periostin levels in breast cancer. Methods: In this study, we analyzed serum levels of periostin in a cohort of 509 primary, non-metastatic breast cancer patients. Disseminated tumor cell (DTC) status was determined using bone marrow aspirates obtained from the anterior iliac crests. Periostin levels were stratified according to several clinical parameters and Pearson correlation analyses were performed. Kaplan-Meier survival curves were assessed by using the log-rank (Mantel-Cox) test. To identify prognostic factors, multivariate Cox regression analyses were used. Results: Mean serum levels of periostin were 505 ± 179 pmol/l. In older patients (> 60 years), periostin serum levels were significantly increased compared to younger patients (540 ± 184 pmol/l vs. 469 ± 167 pmol/l; p < 0.0001) and age was positively correlated with periostin expression (p < 0.0001). When stratifying the cohort according to periostin serum concentrations, the overall and breast cancer-specific mortality were significantly higher in those patients with high serum periostin (above median) compared to those with low periostin during a mean follow-up of 8.5 years (17.7% vs. 11.4% breast cancer-specific death; p = 0.03; hazard ratio 1.65). Periostin was confirmed to be an independent prognostic marker for breast cancer-specific survival (p = 0.017; hazard ratio 1.79). No significant differences in serum periostin were observed when stratifying the patients according to their DTC status. Conclusions: Our findings emphasize the relevance of periostin in breast cancer and reveal serum periostin as a potential marker for disease prediction, independent on the presence of micrometastases.

Overexpression of periostin predicts poor prognosis in non-small cell lung cancer. Link to full text.
Hong LZ, Wei XW, Chen JF, Shi Y.Oncol. Lett. 2013. 6:1595-1603. doi: 10.3892/ol.2013.1590. Epub 2013 Sep 18.PMID: 24273600.

Abstract
The periostin protein, encoded by the POSTN gene, is a component of the extracellular matrix, which is expressed by fibroblasts and has been observed in a variety of human malignancies. The present study aimed to detect the expression of periostin in the tissues of non-small cell lung cancer (NSCLC) patients and benign lung tumors, and to correlate the results with the clinicopathological data of the subjects, in order to evaluate periostin as a potential prognostic marker. In total, 49 NSCLC patients and 6 benign lung tumors were included in this study. The protein level of periostin was detected in paired normal/paratumor/cancer tissues by a western blot analysis and the mRNA level in paired normal/cancer tissues was detected by quantitative polymerase chain reaction (qPCR). The results were then correlated with established biological and prognostic factors. Immunohistochemistry was used to confirm the location of periostin in the NSCLC tissues. Uni- and multivariate analyses were performed using Cox’s proportional hazards regression model. The protein level of periostin was elevated in the cancer tissue of the NSCLC patients compared with the normal (P=0.017) and paratumor (P=0.000) tissues. The expression level in the male patients was much higher than in the female patients at the protein (P=0.001) and mRNA (P=0.010) levels. The mRNA level in the non-adenocarcinoma (non-ADC) patients was much higher than in the adenocarcinoma (ADC) patients (P=0.029). Periostin was demonstrated higher expression at the protein level in the pseudotumors and tuberculosis patients than in the adjacent (P=0.016) and surrounding tissues (P=0.001). Immunostaining indicated that high levels of periostin were present in the mesenchymal areas, but not in the cancer cells themselves. The patients with tumors exhibiting high-level periostin expression showed a significantly shorter survival time (P=0.036, log-rank test). The 3-year survival rate was 81.5% for patients with low-level periostin expression (periostin-L; n=27) and 45.4% for patients with high-level periostin expression (periostin-H; n=22). Similarly, pathological node (pN) status was a significant prognostic marker in the univariate Cox survival analysis. Notably, periostin-H expression was also identified as an independent prognostic factor by the multivariate analysis (P=0.011). These results showed that the overexpression of periostin predicts a poor prognosis, therefore it may be regarded as a novel molecule in the progression and development of NSCLC. The results provide an additional target for the adjuvant treatment of NSCLC.

Predictive and prognostic value of serum periostin in advanced non-small cell lung cancer patients receiving chemotherapy. Zhang Y, Yuan D, Yao Y, Sun W, Shi Y, Su X. Tumour Biol. 2017. 39(5):1010428317698367. doi: 10.1177/1010428317698367. PMID: 28459197. Full text link.

Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC). Confavreux CB, Girard N, Pialat JB, Bringuier PP, Devouassoux-Shisheboran M, Rousseau JC, Isaac S, Thivolet-Bejui F, Clezardin P, Brevet M. Bonekey Rep. 2014. 3:580. doi: 10.1038/bonekey.2014.75. PMID: 25328676; PMCID: PMC4181073. Full text link.

Diagnostic and prognostic value of serum periostin in patients with non-small cell lung cancer. Xu CH, Wang W, Lin Y, Qian LH, Zhang XW, Wang QB, Yu LK. Oncotarget. 2017. 8(12):18746-18753. doi: 10.18632/oncotarget.13004. PMID: 27816968; PMCID: PMC5386644. Full text link.

Related products:

DKK-1 (Dickkopf-1) ELISA kit – BI-20413 –  Product link

• Direct measurement – no sample pre-dilution
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• Widely cited +160 references!

DKK1 promotes migration and invasion of non-small cell lung cancer via β-catenin signaling pathway. Zhang J, Zhang X, Zhao X, Jiang M, Gu M, Wang Z, Yue W Tumour Biol. 2017. 39(7):1010428317703820. doi: 10.1177/1010428317703820. PMID: 28677426. Full text link

Dickkopf-1: A Promising Target for Cancer Immunotherapy. Chu HY, Chen Z, Wang L, Zhang ZK, Tan X, Liu S, Zhang BT, Lu A, Yu Y, Zhang G. Front Immunol. 2021 May 20;12:658097. doi: 10.3389/fimmu.2021.658097. PMID: 34093545; PMCID: PMC8174842. Full text link

Leucine-rich alpha-2-glycoprotein (LRG) ELISA kit – BI-LRG1 –  Product link

• DAY Test – results in 3.5 h
• RELIABLE – rigorously validated according to FDA/ICH/EMA guidelines 
• ALL reagents included – controls and sufficient amounts of buffers
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Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines. Oncotarget. Takemoto N, Serada S, Fujimoto M, Honda H, Ohkawara T, Takahashi T, Nomura S, Inohara H, Naka T. 2015. 10;6(13):11009-22. doi: 10.18632/oncotarget.3557. PMID: 25826092; PMCID: PMC4484435. Full text link.

Exosomal Leucine-Rich-Alpha2-Glycoprotein 1 Derived from Non-Small-Cell Lung Cancer Cells Promotes Angiogenesis via TGF-β Signal Pathway. Li Z, Zeng C, Nong Q, Long F, Liu J, Mu Z, Chen B, Wu D, Wu H. Mol Ther Oncolytics. 2019. 7;14:313-322. doi: 10.1016/j.omto.2019.08.001. PMID: 31528707; PMCID: PMC6739429. Full text link.

Detection of leucine-rich alpha-2-glycoprotein 1-containing immunocomplexes in the plasma of lung cancer patients with epitope-specific mAbs. Lázár J, Kovács A, Tornyi I, Takács L, Kurucz I. Cancer Biomark. 2021 Nov 1. doi: 10.3233/CBM-210164. Epub ahead of print. PMID: 34744074. Abstract link.

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Blood and urine biomarkers are tools to detect diseases, discover drugs and monitor patients. Biomarker research has identified Endostatin and Vanin-1 as promising novel markers to detect microvascular tissue injuries and renal tubular damage in drug-induced acute kidney injury, respectively. These and other proteins e.g. FGF23 and Periostin can easily be detected by ELISA. Check out our assay portfolio for clinical and preclinical research – novel biomarkers in clinical nephrology: www.bmgrp.com.

Assay Highlights:
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 Biomarkers in Clinical Nephrology – FGF23 ∙ Endostatin ∙ Periostin ∙ Vanin-1

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Related Publications:

ENDOSTATIN  FOR THE DETECTION OF ADVANCED MICROVASCULAR KIDNEY DAMAGE AND THE PROGRESSION OF KIDNEY DISEASE

Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes. Chauhan K et al.,  Kidney Int,  2019; 95(2):439-446. Link. “Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors.”

The association between endostatin and kidney disease and mortality in patients with type 2 diabetes. Carlsson et al., Diabetes Metab, 2016; 42(5):351-357. Link. “In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers.”

Endostatin in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events and survival.  Kanbay et al., Eur J Intern Med, 2016; 33:81-87. Link. “Endostatin levels are independently associated with incident CVE in CKD patients.”

Elevated plasma levels of endostatin are associated with chronic kidney disease. Chen et al., Am J Nephrol, 2012; 35(4):335-340. Link. “These data indicate that elevated plasma endostatin is strongly and independently associated with CKD.”

VANIN-1   A MARKER FOR DRUG-INDUCED & SPONTANEOUS ACUTE KIDNEY INJURY AND OBSTRUCTIVE & DIABETIC NEPHROPATHY

Urinary vanin-1 associated with chronic kidney disease in hypertensive patients: A pilot study. Hosohata K et al.,  J Clin Hypertens (Greenwich). 2020 Aug;22(8):1458-1465. Link. “ .. urinary vanin-1 is associated with lower eGFR and higher UPCR and UACR, and might be a potential marker of decreased kidney function in hypertensive patients.”  

A Novel Biomarker for Acute Kidney Injury, Vanin-1, for Obstructive Nephropathy: A Prospective Cohort Pilot Study. Washino et al., Int J Mol Sci, 2019; 20(4).  Link. “Urinary Vanin-1 is a useful biomarker to detect and monitor the clinical course of obstructive nephropathy.”

Urinary Vanin-1 as a Novel Biomarker for Early Detection of Drug-Induced Acute Kidney Injury. Hosohata et al., J Pharm Exp Ther, 2002; 341(3):656–662. Link. “… compared with urinary Kim-1 and NGAL, urinary vanin-1 is an earlier and equally sensitive biomarker for drug-induced AKI.”

Vanin-1: A Potential Biomarker for Nephrotoxicant-Induced Renal Injury. Hosohata et al., Toxicology, 2011; 290(1):82–88.  Link. “These results suggest that vanin-1 is a useful and rapid biomarker for renal tubular injury induced by organic solvents.”

Early Detection of Renal Injury Using Urinary Vanin-1 in Rats with Experimental Colitis. Hosohata et al., J App Tox, 2014; 34(2):184–190. Link. “Compared with Kim-1 and MCP-1, vanin-1 might be an earlier biomarker for the detection of renal injury in rats with experimental colitis.”

Proteomic identification of vanin-1 as a marker of kidney damage in a rat model of type 1 diabetic nephropathy. Fugmann T et al.,  Kidney Int. 2011: ;80(3):272-81. Link

FGF23  FOR RISK PREDICTION IN CHRONIC RENAL INSUFFICIENCY AND TO DETERMINE CARDIOVASCULAR RISK IN CKD

Association of Fibroblast Growth Factor 23 with Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study. Mehta et al., JAMA Cardiology, 2016; 1(5):548-556. Link . “Elevated FGF23 is independently associated with prevalent and incident atrial fibrillation in patients with mild to severe CKD.”

Fibroblast growth factor 23 in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study.  Lyngbakkena et al., Clin Biochem, 2018; 52:41-47 . Link. “Circulating FGF23 concentrations provide incremental prognostic information to established risk indices in patients with acute dyspnea.”

FGF23 and vitamin D metabolism in chronic kidney disease – mineral bone disorder.  Piec et al., Bone Abstracts, 2016; 5:P469. Link. “cFGF23 is raised in patients with CKD as a compensatory response to hyperphosphatemia or phosphate overload.”

Renal and Extrarenal Effects of Fibroblast Growth Factor 23. Vervloet, Nature Reviews, 2019; Nephrology 1(2):109–120. Link. “.. FGF23 is also a valuable biomarker as it predicts risk of a wide variety of clinical events, in particular heart failure.”

PERIOSTIN   A BIOMARKER FOR SEVERITY, PROGRESSION AND RESPONSE TO THERAPY IN HUMAN KIDNEY DISEASE ASSOCIATED TO HYPERTENSION

Identification of periostin as a critical marker of progression/reversal of hypertensive nephropathy. Guerrot et al., PLoS One, 2012; 7(3):e31974. Link.  “… the results identify Periostin as a previously unrecognized marker associated with hypertensive nephropathy.”

Periostin Induces Kidney Fibrosis after Acute Kidney Injury via the p38 MAPK Pathway. An et al., Am J Physiol Renal Physiol, 2019; 316(3):F426-F437. Link. “Periostin promotes kidney fibrosis via the p38 MAPK pathway following acute kidney injury triggered by a hypoxic or ischemic insult. Periostin ablation may protect against chronic kidney disease progression”.

Periostin as a tissue and urinary biomarker of renal injury in type 2 diabetes mellitus. Satirapoj et al., PLoS One, 2015; 17; 10(4):e0124055. Link.  “Urinary periostin is an associated renal derangement in patients with established diabetic nephropathy and it may be used as an early marker of diabetic renal injury.” 

Urinary Periostin Excretion Predicts Renal Outcome in IgA Nephropathy. Hwang et al., Am J Nephrol, 2016; 44(6):481-492. Link.  “POSTN/Cr value at initial diagnosis correlated with renal fibrosis and predicted the renal outcomes in patients with IgAN. It could be a promising urinary biomarker for renal fibrosis.”

Effects of periostin deficiency on kidney aging and lipid metabolism. An JN Aging (Albany NY). 2021. 13(19):22649-22665. Link.

Periostin in the Kidney. Wallace DP. Adv Exp Med Biol. 2019;1132:99-112. Link.

The research status and prospect of Periostin in chronic kidney disease. Jia YY, Yu Y, Li HJ. Ren Fail. 2020 Nov;42(1):1166-1172. Link.

Polycystic Kidney Disease and Renal Fibrosis. Xue C, Mei CL. Adv Exp Med Biol. 2019;1165:81-100. Link.

Periostin Promotes Cell Proliferation and Macrophage Polarization to Drive Repair after AKI. Kormann R J Am Soc Nephrol. 2020; 31(1):85-100. Link.

Kidney Injury Molecule-1 and Periostin Urinary Excretion and Tissue Expression Levels and Association with Glomerular Disease Outcomes. Wu Q Glomerular Dis. 2021 Jun;1(2):45-59. doi: 10.1159/000513166. Epub 2021. Link.

SCLEROSTIN  FOR THE DIAGNOSIS OF HIGH BONE TURNOVER IN CKD AND THE PREDICTION OF CORONARY ARTERY CALCIFICATION

Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD.  Behets et al., PLOS ONE, 2017; 12(5). Link.  “Sclerostin, as opposed to DKK1, may qualify as a biomarker of CKD-MBD, particularly in dialysis patients.”

Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients. Cejka et al., Nephrol Dial Transplant, 2012; 27:226-230.  Link. “Dialysis patients had significantly higher Sclerostin levels than controls.”

Serum Sclerostin and adverse outcomes in nondialyzed chronic kidney disease patients.  Kanbay et al., J Clin Endocrinol, 2014; 99(10):E1854–E1861. Link. “Serum sclerostin values are associated, even after multiple adjustments, with fatal and nonfatal cardiovascular events in a nondialyzed CKD population.”

Relationship between plasma levels of sclerostin, calcium–phosphate disturbances, established markers of bone turnover, and inflammation in haemodialysis patients. Pietrzyk et al., Int Urol Nephrol, 2019; 51(3):519-526. Link. “Increased circulating sclerostin levels seem to reflect slower bone turnover in HD patients. Low levels of sclerostin are associated with vitamin D deficiency and good phosphates alignment.”

Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it! Brandenburg VM et al.,  Nephrol Dial Transplant,  2019; ;34(3):408-414. Link

NT-proBNP saliva analysis for heart failure assessment. Monitoring Heart Failure – SALIVA ANALYSIS of Cardiac Marker NT-proBNP

The cardiac marker NT-pro-brain natriuretic peptide (NT-proBNP) is considered as the gold standard biomarker for the diagnosis and monitoring of heart failure (HF). It is tested in blood samples by immunochemical methods. Saliva analysis has gained importance as an alternative non-invasive and efficient tool for the diagnosis of several diseases.  A recent report investigated the use of the Biomedica ELISA assay for the determination of NT-proBNP in saliva samples collected from HF patients.  First results highlight the potential role of saliva analysis for HF assessment through NT-proBNP monitoring.

 

Learn more:  Determination and stability of N-terminal pro-brain natriuretic peptide in saliva samples for monitoring heart failure.   Link to full text.  

Bellagambi FG, Petersen C, Salvo P, Ghimenti S, Franzini M, Biagini D, Hangouët M, Trivella MG, Di Francesco F, Paolicchi A, Errachid A, Fuoco R, Lomonaco T. Sci Rep. 2021. 22;11(1):13088. doi: 10.1038/s41598-021-92488-2. PMID: 34158583.

Check out the Biomedica NT-proBNP ELISA  

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 Abstract

Heart failure (HF) is the main cause of mortality worldwide, particularly in the elderly. N-terminal pro-brain natriuretic peptide (NT-proBNP) is the gold standard biomarker for HF diagnosis and therapy monitoring. It is determined in blood samples by the immunochemical methods generally adopted by most laboratories. Saliva analysis is a powerful tool for clinical applications, mainly due to its non-invasive and less risky sampling. This study describes a validated analytical procedure for NT-proBNP determination in saliva samples using a commercial Enzyme-Linked Immuno-Sorbent Assay. Linearity, matrix effect, sensitivity, recovery and assay-precision were evaluated. The analytical approach showed a linear behaviour of the signal throughout the concentrations tested, with a minimum detectable dose of 1 pg/mL, a satisfactory NT-proBNP recovery (95–110%), and acceptable precision (coefficient of variation ≤ 10%). Short-term (3 weeks) and long-term (5 months) stability of NT-proBNP in saliva samples under the storage conditions most frequently used in clinical laboratories (4, − 20, and − 80 °C) was also investigated and showed that the optimal storage conditions were at − 20 °C for up to 2.5 months. Finally, the method was tested for the determination of NT-proBNP in saliva samples collected from ten hospitalized acute HF patients. Preliminary results indicate a decrease in NT-proBNP in saliva from admission to discharge, thus suggesting that this procedure is an effective saliva-based point-of-care device for HF monitoring.

 

Related publications

NT-ProBNP levels in saliva and its clinical relevance to heart failure. Foo JY, Wan Y, Kostner K, Arivalagan A, Atherton J, Cooper-White J, Dimeski G, Punyadeera C. PLoS One. 2012;7(10):e48452. doi: 10.1371/journal.pone.0048452. PMID: 23119023. Full text link

 Abstract: Current blood based diagnostic assays to detect heart failure (HF) have large intra-individual and inter-individual variations which have made it difficult to determine whether the changes in the analyte levels reflect an actual change in disease activity. Human saliva mirrors the body’s health and well being and ∼20% of proteins that are present in blood are also found in saliva. Saliva has numerous advantages over blood as a diagnostic fluid which allows for a non-invasive, simple, and safe sample collection. The aim of our study was to develop an immunoassay to detect NT-proBNP in saliva and to determine if there is a correlation with blood levels. Methods: Saliva samples were collected from healthy volunteers (n = 40) who had no underlying heart conditions and HF patients (n = 45) at rest. Samples were stored at -80°C until analysis. A customised homogeneous sandwich AlphaLISA((R)) immunoassay was used to quantify NT-proBNP levels in saliva. Results: Our NT-proBNP immunoassay was validated against a commercial Roche assay on plasma samples collected from HF patients (n = 37) and the correlation was r(2) = 0.78 (p<0.01, y = 1.705× +1910.8). The median salivary NT-proBNP levels in the healthy and HF participants were <16 pg/mL and 76.8 pg/mL, respectively. The salivary NT-proBNP immunoassay showed a clinical sensitivity of 82.2% and specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3%, with an overall diagnostic accuracy of 90.6%. Conclusion: We have firstly demonstrated that NT-proBNP can be detected in saliva and that the levels were higher in heart failure patients compared with healthy control subjects. Further studies will be needed to demonstrate the clinical relevance of salivary NT-proBNP in unselected, previously undiagnosed populations.

 

Saliva diagnostics – Current views and directions. Exp Biol Med (Maywood). 2017 Mar;242(5):459-472. doi: 10.1177/1535370216681550. PMID: 27903834; PMCID: PMC5367650. Full text link

 Abstract: In this review, we provide an update on the current and future applications of saliva for diagnostic purposes. There are many advantages of using saliva as a biofluid. Its collection is fast, easy, inexpensive, and non-invasive. In addition, saliva, as a “mirror of the body,” can reflect the physiological and pathological state of the body. Therefore, it serves as a diagnostic and monitoring tool in many fields of science such as medicine, dentistry, and pharmacotherapy. Introduced in 2008, the term “Salivaomics” aimed to highlight the rapid development of knowledge about various “omics” constituents of saliva, including: proteome, transcriptome, micro-RNA, metabolome, and microbiome. In the last few years, researchers have developed new technologies and validated a wide range of salivary biomarkers that will soon make the use of saliva a clinical reality. However, a great need still exists for convenient and accurate point-of-care devices that can serve as a non-invasive diagnostic tool. In addition, there is an urgent need to decipher the scientific rationale and mechanisms that convey systemic diseases to saliva. Another promising technology called liquid biopsy enables detection of circulating tumor cells (CTCs) and fragments of tumor DNA in saliva, thus enabling non-invasive early detection of various cancers. The newly developed technology-electric field-induced release and measurement (EFIRM) provides near perfect detection of actionable mutations in lung cancer patients. These recent advances widened the salivary diagnostic approach from the oral cavity to the whole physiological system, and thus point towards a promising future of salivary diagnostics for personalized individual medicine applications including clinical decisions and post-treatment outcome predictions. Impact statement The purpose of this mini-review is to make an update about the present and future applications of saliva as a diagnostic biofluid in many fields of science such as dentistry, medicine and pharmacotherapy. Using saliva as a fluid for diagnostic purposes would be a huge breakthrough for both patients and healthcare providers since saliva collection is easy, non-invasive and inexpensive. We will go through the current main diagnostic applications of saliva, and provide a highlight on the emerging, newly developing technologies and tools for cancer screening, detection and monitoring.

Related products

• NT-proANP ELISA
• NT-proCNP ELISA
• Big Endothelin-1 ELISA

FGF23, a novel muscle biomarker detected in the early stages of ALS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Currently, there are no biomarkers that can predict prognosis or disease progression.  FGF23 is a protein secreted in the plasma by bone cells.  A recent report identifies skeletal muscle as a potential target of FGF23. In a  large collection of human ALS muscle samples the researchers observed that FGF23 protein is increased up to 50-fold in ALS muscle tissues .This report raises important questions of the role of FGF23 in ALS disease pathology.

 

Learn more: FGF23, a novel muscle biomarker detected in the early stages of ALS. Si Y, Kazamel M, Benatar M, Wuu J, Kwon Y, Kwan T, Jiang N, Kentrup D, Faul C, Alesce L, King PH. Sci Rep. 2021 Jun 8;11(1):12062. doi: 10.1038/s41598-021-91496-6. PMID: 34103575; PMCID: PMC8187665.

 

Check out the Biomedica FGF23 ELISA assays : 

 

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FGF23, a novel muscle biomarker detected in the early stages of ALS.

Abstract:

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1^G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1^G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

 

Related publications: 

Improving clinical trial outcomes in amyotrophic lateral sclerosis. Kiernan MC, Vucic S, Talbot K, McDermott CJ, Hardiman O, Shefner JM, Al-Chalabi A, Huynh W, Cudkowicz M, Talman P, Van den Berg LH, Dharmadasa T, Wicks P, Reilly C, Turner MR. Nat Rev Neurol. 2021 Feb;17(2):104-118. doi: 10.1038/s41582-020-00434-z. Epub 2020 Dec 18. PMID: 33340024; PMCID: PMC7747476. Full text link

 

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS). Boddy SL, Giovannelli I, Sassani M, Cooper-Knock J, Snyder MP, Segal E, Elinav E, Barker LA, Shaw PJ, McDermott CJ. BMC Med. 2021 Jan 20;19(1):13. doi: 10.1186/s12916-020-01885-3. PMID: 33468103; PMCID: PMC7816375. Full text link

 

Gene therapy for ALS: A review. Amado DA, Davidson BL. Mol Ther. 2021 Apr 9:S1525-0016(21)00195-7. doi: 10.1016/j.ymthe.2021.04.008. Epub ahead of print. PMID: 33839324. Full text link

 

Related products:

Total Neuropilin-1 ELISA (cat.no. BI-20409)

Expression of the axon-guidance protein receptor Neuropilin 1 is increased in the spinal cord and decreased in muscle of a mouse model of amyotrophic lateral sclerosis. Körner S et al., Eur J Neurosci. 2019.  

 

Cell proliferation assays are widely used in cell biology. The EZ4U kit is a simple and reliable non-radioactive two to five-hour test. The assay employs non-toxic tetrazolium salts, which are reduced to colored formazan. As this reduction process requires functional mitochondria, which are inactivated within a few minutes after cell death, this method provides an excellent tool for the discrimination between living and dead cells. The assay offers advantages over conventional dye or 3H incorporation assays. Due to its soluble end products it is easier and faster to perform than other non-radioactive cell viability assays. As the assay procedure is identical to the thymidine incorporation procedure, no changes in test protocols are necessary. An important benefit is the possibility of an ongoing cultivation after cell number determination and easy to adapt incubation times due to the non-toxic substrate. The EZ4U cell proliferation & cytotoxicity assay is well suited for a variety of biological tests, where cell viability is of importance.   Click here to learn more.

Cell Proliferation & Cytotoxicity Assay

EZ4U – Test Highlights

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√  Widely cited in more than 220 publications

 

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Latest Citations:

Cytotoxicity of combinations of the pan-KRAS inhibitor BAY-293 against primary non-small lung cancer cells.

Plangger A, Rath B, Hochmair M, Funovics M, Hamilton G. Transl Oncol. 2021 Dec;14(12):101230. doi: 10.1016/j.tranon.2021.101230. Epub 2021 Sep 28. PMID: 34598083; PMCID: PMC8488304.

 

Tolerability to non-endosomal, micron-scale cell penetration probed with magnetic particles.

Ruiz-Cánovas E, Mendoza R, Villaverde A, Corchero JL.Colloids Surf B Biointerfaces. 2021 Sep 20;208:112123. doi: 10.1016/j.colsurfb.2021.112123. Epub ahead of print. PMID: 34571468.

 

Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.

Fronik P, Poetsch I, Kastner A, Mendrina T, Hager S, Hohenwallner K, Schueffl H, Herndler-Brandstetter D, Koellensperger G, Rampler E, Kopecka J, Riganti C, Berger W, Keppler BK, Heffeter P, Kowol CR.J Med Chem. 2021 Aug 26;64(16):12132-12151. doi: 10.1021/acs.jmedchem.1c00770. Epub 2021 Aug 17. PMID: 34403254; PMCID: PMC8404199.

 

New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition.

Dyrkheeva NS, Filimonov AS, Luzina OA, Zakharenko AL, Ilina ES, Malakhova AA, Medvedev SP, Reynisson J, Volcho KP, Zakian SM, Salakhutdinov NF, Lavrik OI. Biomolecules. 2021 Jul 1;11(7):973. doi: 10.3390/biom11070973. PMID: 34356597; PMCID: PMC8301776.

 

Anti-inflammatory effects of two lupane-type triterpenes from leaves of Acanthopanax gracilistylus on LPS-induced RAW264.7 macrophages.

Jiao LUO, Xiao-jun LI and Geon-ho LEE et al. Food Science and Technology. DOI: 10.1590/fst.89721

 

Interactions of BRCA1-mutated Breast Cancer Cell Lines with Adipose-derived Stromal Cells (ADSCs).

Plangger A, Haslik W, Rath B, Neumayer C, Hamilton G.J Mammary Gland Biol Neoplasia. 2021 Sep;26(3):235-245. doi: 10.1007/s10911-021-09493-4. Epub 2021 Jul 6. PMID: 34228231.

Ovarian cancer is one of the most common types of cancer in women. Dickkopf-related protein 1 is a secreted protein postulated as a promising target for cancer immunotherapy. In this first study, researchers investigated the prognostic relevance of blood-based circulating soluble DKK-1 (sDKK-1) in ovarian cancer patients including those with wtBRCA 1/2 status.  The data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

OVARIAN CANCER & DKK-1 a blood-based biomarker

Learn more: Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients. Klotz DM, Link T, Goeckenjan M, Wimberger P, Poetsch AR, Jaschke N, Hofbauer LC, Göbel A, Rachner TD, Kuhlmann JD. Clin Chem Lab Med. 2021 Oct 25. doi: 10.1515/cclm-2021-0504. Epub ahead of print. PMID: 34687595.

 

Check out the Biomedica human DKK-1 ELISA Assay  – measures soluble DKK-1  in human serum

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√  WIDELY Cited in + 170 publications

 

OVARIAN CANCER & DKK-1 a blood-based biomarker

Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients.

Abstract

Objectives: Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown.

Methods: sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria).

Results: Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01-12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46-13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73-11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320-0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004).

Conclusions: This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA 1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

 

Related publications: 

• Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer. Betella I et al., Gynecol Oncol. 2020. (3):765-774.
• Dickkopf-1 is frequently overexpressed in ovarian serous carcinoma and involved in tumor invasion. Wang S , Zhang S. Clin Exp Metastasis. 2011. (6):581-91.
• Cordycepin inhibits human ovarian cancer by inducing autophagy and apoptosis through Dickkopf-related protein 1/β-catenin signaling. Jang HJ et al., Am J Transl Res. 2019. 11(11):6890-6906.
• Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein.  Barbolina MV et al., J Biol Chem. 2013. 288(1):141-51.
• The expression and significance of Dickkopf-1 in epithelial ovarian carcinoma. Shizhuo  et al., Int J Biol Markers. 2009. 24(3):165-70.

Breast cancer is the most common cancer in women worldwide. Improving our understanding of how breast cancer originates, grows and spreads may help to reduce the risk and burden of the disease.

Periostin and NRP1 –  markers for breast cancer survival

Biomarker research, has identified the novel protein markers Periostin and Neuropilin-1 as promising  prognostic markers for breast cancer-specific survival. These proteins can easily be detected in human serum and plasma by ELISA assay.

Periostin and NRP1 – prognostic markers for breast cancer survival

Periostin (POSTN) and Neuropilin-1 (NRP1) ELISA kits

Assay Highlights:
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Check out Biomedica´s Product Brochure Biomarkers in Oncology

PROGNOSTIC MARKERS FOR BREAST CANCER SURVIVAL

Publications on Periostin and Neuropilin-1 applied in breast cancer research:

High serum levels of periostin are associated with a poor survival in breast cancer.  Rachner TD et al., 2020,  link.

 Abstract:

Purpose: Periostin is a secreted extracellular matrix protein, which was originally described in osteoblasts. It supports osteoblastic differentiation and bone formation and has been implicated in the pathogenesis of several human malignancies, including breast cancer. However, little is known about the prognostic value of serum periostin levels in breast cancer.

Methods: In this study, we analyzed serum levels of periostin in a cohort of 509 primary, non-metastatic breast cancer patients. Disseminated tumor cell (DTC) status was determined using bone marrow aspirates obtained from the anterior iliac crests. Periostin levels were stratified according to several clinical parameters and Pearson correlation analyses were performed. Kaplan-Meier survival curves were assessed by using the log-rank (Mantel-Cox) test. To identify prognostic factors, multivariate Cox regression analyses were used.

Results: Mean serum levels of periostin were 505 ± 179 pmol/l. In older patients (> 60 years), periostin serum levels were significantly increased compared to younger patients (540 ± 184 pmol/l vs. 469 ± 167 pmol/l; p < 0.0001) and age was positively correlated with periostin expression (p < 0.0001). When stratifying the cohort according to periostin serum concentrations, the overall and breast cancer-specific mortality were significantly higher in those patients with high serum periostin (above median) compared to those with low periostin during a mean follow-up of 8.5 years (17.7% vs. 11.4% breast cancer-specific death; p = 0.03; hazard ratio 1.65). Periostin was confirmed to be an independent prognostic marker for breast cancer-specific survival (p = 0.017; hazard ratio 1.79). No significant differences in serum periostin were observed when stratifying the patients according to their DTC status.

Conclusions: Our findings emphasize the relevance of periostin in breast cancer and reveal serum periostin as a potential marker for disease prediction, independent on the presence of micrometastases.

 

Development of an engineered peptide antagonist against periostin to overcome doxorubicin resistance in breast cancer. Oo KK et al., 2021, link.

 

Abstract:

Background: Chemoresistance is one of the main problems in treatment of cancer. Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The main objective of this study was to develop an anti-PN peptide from the bacteriophage library to overcome PN effects in breast cancer (BCA) cells.

Methods: A twelve amino acids bacteriophage display library was used for biopanning against the PN active site. A selected clone was sequenced and analyzed for peptide primary structure. A peptide was synthesized and tested for the binding affinity to PN. PN effects including a proliferation, migration and a drug sensitivity test were performed using PN overexpression BCA cells or PN treatment and inhibited by an anti-PN peptide. An intracellular signaling mechanism of inhibition was studied by western blot analysis. Lastly, PN expressions in BCA patients were analyzed along with clinical data.

Results: The results showed that a candidate anti-PN peptide was synthesized and showed affinity binding to PN. PN could increase proliferation and migration of BCA cells and these effects could be inhibited by an anti-PN peptide. There was significant resistance to doxorubicin in PN-overexpressed BCA cells and this effect could be reversed by an anti-PN peptide in associations with phosphorylation of AKT and expression of survivin. In BCA patients, serum PN showed a correlation with tissue PN expression but there was no significant correlation with clinical data.

Conclusions: This finding supports that anti-PN peptide is expected to be used in the development of peptide therapy to reduce PN-induced chemoresistance in BCA.

 

 Neuropilin-1 is a marker of poor prognosis in early breast cancer. Rachner TD et al., 2021, link.

 

Abstract:

Background: Neuropilin-1 (NRP-1) is a transmembrane protein that acts as a multifunctional non-tyrosine kinase receptor with an established role in development and immunity. NRP-1 also regulates tumor biology, and high expression levels of tissue NRP-1 have been associated with a poor prognosis. Recently, ELISA-based quantification of soluble NRP-1 (sNRP-1) has become available, but little is known about the prognostic value of sNRP-1 in malignancies.

Materials and methods: We measured sNRP-1 in the serum of 509 patients with primary early breast cancer (BC) at the time of diagnosis using ELISA.

Results: Mean serum values of sNRP-1 were 1.88 ± 0.52 nmol/l (= 130.83 ± 36.24 ng/ml). SNRP-1 levels weakly correlated with age, and were higher in peri- and postmenopausal patients compared to premenopausal patients, respectively (p < 0.0001). Low levels of sNRP-1 were associated with a significant survival benefit compared to high sNRP-1 levels at baseline (p = 0.005; HR 1.94; 95%CI 1.23-3.06). These findings remained significant after adjustment for tumor stage including lymph node involvement, grading, hormone receptor, HER2 status, and age (p = 0.022; HR 1.78; 95%CI 1.09-2.91).

Conclusion: Our findings warrant further investigations into the prognostic and therapeutic potential of sNRP-1 in BC.

 

LOVE YOUR BONES and PROTECT YOUR FUTURE

Osteoporosis is a “silent” disease that thins and weakens the bones. Your bones become fragile.

Check  out THE 5 STEPS TO HEALTHY BONES AND A FRACTURE-FREE FUTURE  link

Early intervention can delay the development of osteoporosis and novel biomarkers may help to identify people at risk.

World Osteoporosis Awareness Day October 20

BIOMEDICA – Bone Disease Biomarker ELISA kits for clinical research  

check out our Bone Biomarker Brochure

Assay Kit Highlights

√  EASY –ready to use calibrators & controls included (color-coded reagents)
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Biomedica – Complete ready-to-use ELISA kits for superior performance and reproducibility

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Osteoprotegerin (OPG) ELISA  , DKK-1 ELISA ,  Sclerostin ELISA

IL-6 ELISA  ,  VEGF ELISA ,  Angiopoietin-2 ELISA

Related links

International Osteoporosis Foundation

Related publications

 

Menopausal osteoporosis: screening, prevention and treatment. Yong EL, Logan S. Singapore Med J. 2021 Apr;62(4):159-166. doi: 10.11622/smedj.2021036. PMID: 33948669; PMCID: PMC8801823.

Abstract

Delirium is a common complication following cardiac surgery and is associated with increased long-term cognitive dysfunction. It is estimated to have an incidence up to 52%. Natriuretic peptides have shown to worsen the disruption of the blood-brain barrier and thus promote delirium. Using the Biomedica NT-proCNP ELISA a  team of researchers investigated atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) as prognostic markers for delirium in cardiac surgery. Learn more  .

Check out our human  NT-proCNP ELISA  – developed and manufactured by Biomedica.

√  CE marked

√  Protocols for urine, cell culture and non-human samples

 

And our NT-proANP ELISA    

√  CE marked

√  Small sample volume – 10 µl / well

√  Assay suitable for rat/mouse samples

 

Abstract:

Natriuretic Peptides as a Prognostic Marker for Delirium in Cardiac Surgery—A Pilot Study. Saller T, Peterss S, Scheiermann P, Eser-Valeri D, Ehler J, Bruegger D, Chappell D, Kofler O, Hagl C, Hofmann-Kiefer K. Medicina (Kaunas). 2020. 56(6):258. doi: 10.3390/medicina56060258. PMID: 32471143; PMCID: PMC7353880.

Background and Objectives: Delirium is a common and major complication subsequent to cardiac surgery. Despite scientific efforts, there are no parameters which reliably predict postoperative delirium. In delirium pathology, natriuretic peptides (NPs) interfere with the blood–brain barrier and thus promote delirium. Therefore, we aimed to assess whether NPs may predict postoperative delirium and long-term outcomes. Materials and Methods: To evaluate the predictive value of NPs for delirium we retrospectively analyzed data from a prospective, randomized study for serum levels of atrial natriuretic peptide (ANP) and the precursor of C-type natriuretic peptide (NT-proCNP) in patients undergoing coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (off-pump coronary bypass grafting; OPCAB). Delirium was assessed by a validated chart-based method. Long-term outcomes were assessed 10 years after surgery by a telephone interview. Results: The overall incidence of delirium in the total cohort was 48% regardless of the surgical approach (CABG vs. OPCAB). Serum ANP levels > 64.6 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 100% (75.3–100) and specificity of 42.9% (17.7–71.1). Serum NT-proCNP levels >1.7 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 92.3% (64.0–99.8) and specificity of 42.9% (17.7–71.1). Both NPs could not predict postoperative survival or long-term cognitive decline. Conclusions: We found a positive correlation between delirium and preoperative plasma levels of ANP and NT-proCNP. A well-powered and prospective study might identify NPs as biomarkers indicating the risk of delirium and postoperative cognitive decline in patients at risk for postoperative delirium.

Related publications:

The predictive value of preoperative natriuretic peptide concentrations in adults undergoing surgery: a systematic review and meta-analysis. Lurati Buse GA, Koller MT, Burkhart C, Seeberger MD, Filipovic M. Anesth Analg. 2011. 112(5):1019-33. doi: 10.1213/ANE.0b013e31820f286f. PMID: 21372274.

 

Related products:

NT-proBNP ELISA

Angiopoietin-2 ELISA

Big Endothelin ELISA

Chronic kidney disease is common in patients with heart failure and is associated with high mortality and morbidity. Biomarkers are needed that can accurately predict disease progression. Recent studies have provided evidence that circulating ENDOSTATIN increases significantly in patients with kidney and heart failure and may also contribute to disease progression.  Learn more in this latest published review: “Endostatin in Renal and Cardiovascular Diseases” full-text review link

Check out our fully validated human Endostatin ELISA  – developed and manufactured by Biomedica.

– For serum, plasma, and urine samples
– Easy – results in 4.5 h with only 20µl sample / well
– Fully validated assay according to international quality guidelines

Also available: Mouse/Rat Endostatin ELISA – only 5µl sample volume required

Related ELISA kits

Sclerostin,  Angiopoietin-2,  FGF23,  IL-6

Abstract

Endostatin, a protein derived from the cleavage of collagen XVIII by the action of proteases, is an endogenous inhibitor known for its ability to inhibit proliferation and migration of endothelial cells, angiogenesis, and tumor growth. Angiogenesis is defined as the formation of new blood vessels from pre-existing vasculature, which is crucial in many physiological processes, such as embryogenesis, tissue regeneration, and neoplasia. Summary: Increasing evidence shows that dysregulation of angiogenesis is crucial for the pathogenesis of renal and cardiovascular diseases. Endostatin plays a pivotal role in the regulation of angiogenesis. Recent studies have provided evidence that circulating endostatin increases significantly in patients with kidney and heart failure and may also contribute to disease progression. Key Message: In the current review, we summarize the latest findings on preclinical and clinical studies analyzing the impact of endostatin on renal and cardiovascular diseases.

Related publications

• Endostatin predicts mortality in patients with acute dyspnea – A cohort study of patients seeking care in emergency departments. Carlsson AC, Wessman T, Larsson A, Leijonberg G, Tofik R, Ärnlöv J, Melander O, Ruge T. Clin Biochem. 2020. 75:35-39.
• Endostatin Is an Independent Risk Factor of Graft Loss after Kidney Transplant. Chu C, Hasan AA, Gaballa MMS, Zeng S, Xiong Y, Elitok S, Krämer BK, Hocher B. Am J Nephrol. 2020;51(5):373-380.
• Endostatin in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events and survival. Kanbay M, Afsar B, Siriopol D, Unal HU, Karaman M, Saglam M, Gezer M, Taş A, Eyileten T, Guler AK, Aydin İ, Oguz Y, Tarim K, Covic A, Yilmaz MI. Eur J Intern Med. 2016. 33:81-7.
• Detection of pro angiogenic and inflammatory biomarkers in patients with CKD. Jalal D, Sanford B, Renner B, Ten Eyck P, Laskowski J, Cooper J, Sun M, Zakharia Y, Spitz D, Dokun A, Attanasio M, Jones K, Thurman JM. Sci Rep. 2021.11(1):8786.

 

Biomedica offers fully validated and reliable cytokine assays for your clinical research – High Quality and Ready to Use.

Save 30% on any of our new cytokine ELISA kits. Use promo code BI-CytELISA. Valid until 12/31/21

IL-6, VEGF, Angiopoietin-2 ELISA kits for accurate and reliable results.

• EASY ready to use calibrators & controls included
• HIGH SENSITIVITY measurable values in serum and plasma
• FULL VALIDATION PACKAGE – assays are optimized for clinical samples

 

Request your promotion discount now info@bmgrp.com

Related reviews:

IL-6 in inflammation, autoimmunity and cancer. Hirano T. Int Immunol. 2021. 33(3):127-148. Full text link.

Abstract:

IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6–STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6–STAT3 axis is a critical target for treating diseases.

 

VEGF inhibition in urothelial cancer: the past, present and future. Ghafouri S, Burkenroad A, Pantuck M, Almomani B, Stefanoudakis D, Shen J, Drakaki A. World J Urol. 2021. 39(3):741-749. Abstract link.

Abstract:

Purpose: To describe the role of anti-angiogenic agents that have been used as a treatment approach for locally advanced or metastatic urothelial cancers and to propose future directions.

Methods: PubMed/MEDLINE was searched for articles related to VEGF inhibition and locally advanced or metastatic urothelial cancer.

Results: Angiogenesis is a fundamental process for urothelial cancer initiation and progression. First-line therapy for locally advanced or metastatic urothelial cancer includes cisplatin-based chemotherapy combinations; subsequent systemic therapy includes taxanes, nanoparticle albumin-bound (nab) paclitaxel, or pemetrexed. More recently, several anti-PD-L1 and anti-PD-1 antibodies have shown promising activity in the first-line and post-platinum setting; however, immunotherapy remains ineffective in most patients. FGFR inhibitor erdafitinib was recently approved in the third-line setting. Studies on bevacizumab, pazopanib and ramucirumab have shown improved response rates when added to chemotherapy in selected patients, but have not led to overall survival (OS) benefit in randomized controlled studies.

Conclusion: Anti-angiogenic agents have shown promise in recent studies treating locally advanced or metastatic urothelial cancer. However, further work is needed to elucidate ideal treatment combinations in selected patient populations to maximize benefit, with the ultimate goal of being added to the FDA-approved treatment armamentarium for this disease.

 

Angiopoietin inhibitors: A review on targeting tumor angiogenesis. Parmar D, Apte M. Eur J Pharmacol. 2021. 5;899:174021. Abstract link.

Abstract:

Angiogenesis is the process of formation of new blood vessels from existing ones. Vessels serve the purpose of providing oxygen, nutrients and removal of waste from the cells. The physiological angiogenesis is a normal process and is required in the embryonic development, wound healing, menstrual cycle. For homeostasis, balance of pro angiogenic factors and anti angiogenic factors like is important. Their imbalance causes a process known as “angiogenic switch” which leads to various pathological conditions like inflammation, tumor and restenosis. Like normal cells, tumor cells also require oxygen and nutrients to grow which is provided by tumor angiogenesis. Hence angiogenic process can be inhibited to prevent tumor growth. This gives rise to study of anti angiogenic drugs. Currently approved anti angiogenic drugs are mostly VEGF inhibitors, but VEGF inhibitors have certain limitations like toxicity, low progression free survival (PFS), and resistance to anti VEGF therapy. This article focuses on angiopoietins as alternative and potential targets for anti angiogenic therapy. Angiopoietins are ligands of Tie receptor and play a crucial role in angiogenesis, their inhibition can prevent many tumor growths even on later stages of development. We present current clinical and preclinical stages of angiopoietin inhibitors. Drugs studied in the article are selective as well as non-selective inhibitors of angiopoietin 2 like Trebananib (AMG 386), AMG 780, REGN 910, CVX 060, MEDI 3617 and dual inhibitors of angiopoietin 2 and VEGF like Vanucizumab and RG7716. The angiopoietin inhibitors show promising results alone and in combination with VEGF inhibitors in various malignancies.

 

Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19. Patel S, Saxena B, Mehta P. Heliyon. 2021. 7(2):e06158. Full text link.

Abstract:

Clinical studies have identified a cytokine storm in the third stage of disease progression in critical ill patients with coronavirus disease 2019 (COVID-19). Hence, effectively suppressing the uncontrolled immune response of the host towards the invaded viruses in a cytokine storm is a critical step to prevent the deterioration of patient conditions and decrease the rate of mortality. Therapeutic monoclonal antibodies (mAbs) are found to be effective for the management of acute respiratory distress syndrome in patients with COVID-19. In this review, we compiled all therapeutic mAbs targeting cytokine storm, which are in clinical trials for its repurposing in the management of COVID-19. Compilation of clinical trial data indicated that therapeutic monoclonal antibodies targeting interleukins (IL-6, IL-1ra, IL-8, IL-1β, IL-17A, IL-33), interferon-gamma, tumor necrosis factor-alpha, P-selectin, connective tissue growth factor, plasma kallikrein, tumor necrosis factor superfamily 14, granulocyte macrophage colony stimulating factor, colony stimulating factor 1 receptor, C-C chemokine receptor type 5, cluster of differentiation 14 and 147, vascular endothelial growth factor, programmed cell death protein-1, Angiopoietin – 2, human factor XIIa, complementary protein 5, natural killer cell receptor G2A, human epidermal growth factor receptor 2, immunoglobulin-like transcript 7 receptor, complement component fragment 5a receptor and viral attachment to the human cell were under investigation for management of severely ill patients with COVID-19. Among these, about 65 clinical trials are targeting IL-6 inhibition as the most promising one and Tocilizumab, an IL-6 inhibitor is considered to be the potential candidate to treat cytokine storm associated with the COVID-19.

Vascular endothelial growth factor (VEGF) is a protein that stimulates the growth of blood vessels. A recent study in Science reports that VEGF signaling insufficiency in aged mice may be the driver of physiological aging in several organs. The researchers demonstrated that a modest increase of circulatory VEGF in “old mice” was sufficient to improve age-related effects and to extend their life span. View Abstract  .

Abstract:

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

Structured Abstract:

INTRODUCTION
All body cells rely on blood vessels (BVs) for the provision of oxygen and other blood-borne substances and, in certain settings, also for the provision of endothelial-derived paracrine factors. Like other organ systems, the vascular system undergoes aging, which leads to progressive functional deterioration. Given the centrality of BVs to organ homeostasis, it has been hypothesized that vascular aging is an upstream, founding factor in organismal aging, but experimental support for this proposition is limited. Vascular aging involves both large and small vessels, with the latter marked by capillary rarefaction, i.e., age-related failure to maintain adequate microvascular density (MVD). A key homeostatic mechanism preventing MVD reduction relies on the angiogenic activity of vascular endothelial growth factor (VEGF), which by virtue of its hypoxic inducibility, constantly acts to replenish lost vessels and match vascular supply to the tissue needs. The reason(s) that VEGF fails to do so during aging is unknown.

RATIONALE
Compromised vascular function is expected to perturb organ homeostasis in ways conducive for the development of age-related frailties and diseases. Accordingly, counteracting critical facets of vascular aging might be a useful approach for their alleviation. The presumption that insufficient vascular supply in aging is underlined by VEGF signaling insufficiency, primarily (but not exclusively) because of its indispensable role in preventing capillary loss, led us to investigate whether securing a young-like level of VEGF signaling might rectify capillary loss and its sequelae. On the premise that deteriorated vascular function is an upstream driver of multiorgan malfunctioning, it is envisioned that its rectification might confer comprehensive geroprotection.

RESULTS
Although VEGF production is not significantly reduced during mouse aging, longitudinal monitoring revealed that VEGF signaling was greatly reduced in multiple key organs. This was associated with increased production of soluble VEGFR1 (sVEGFR1) generated through an age-related shift in alternative splicing of VEGFR1 mRNA and its activity as a VEGF trap. A modest increase of circulatory VEGF using a transgenic VEGF gain-of-function system or adeno-associated virus (AAV)–assisted VEGF transduction maintained a more youthful level of VEGF signaling and provided protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function by conditional induction of transgenic sFlt1 in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.

CONCLUSION
The study provides compelling evidence for the proposition that vascular aging is a hierarchically high driver of overall organismal aging. It places VEGF signaling insufficiency at center stage to multiorgan aging and suggests that its undoing might confer comprehensive geroprotection.

 

Check out our human VEGF ELISA – developed and manufactured by Biomedica

√ SMALL SAMPLE VOLUME: only 10µl sample / well required

√ HIGH SENSITIVITY: measurable values in both serum and plasma

√ RELIABLE: rigorously validated according to FDA/ICH/EMEA guidelines

√ EASY: ready to use calibrators & controls included

 

Literature:

VEGF in Signaling and Disease: Beyond Discovery and Development. Apte RS et al., Cell. 2019; 176, 6: 1248–64.

Poster: “Highly sensitive quantification of human VEGF with an ELISA”

 

Related products:

Human Angiopoietin-2 ELISA

Rat/Mouse Angiopoietin-2 ELISA

Human IL-6 ELISA

RANKL inhibition is emerging as  a novel cancer immunotherapy.   

Fighting cancer – Inhibition of RANK/RANKL Signaling

RANKL (receptor activator of the nuclear factor-κB ligand) is a key mediator of bone remodeling. RANKL plays an important role in breast carcinogenesis,  as it initiates a pre-metastatic niche in bone. Therapeutical targeting of RANKL has become part of the standard care of diseases with bone loss including bone metastasis.  RANKL inhibition is emerging as  a novel cancer immunotherapy.  Clinical trials are exploring the use of RANKL blockage as a combined treatment with immune checkpoint inhibitors to fight cancer.

View abstract

Abstract

The Roadmap of RANKL/RANK Pathway in Cancer. Casimiro S, Vilhais G, Gomes I, Costa L Cells. 2021 Aug 4;10(8):1978.

The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

Inhibition of RANK/RANKL Signaling

Biomedica offers a highly sensitive ELISA to measure free soluble RANKL in serum

RANKL Kit highlights:
• CE marked – widely cited in clinical studies (+290 publications)
• Reliable – validated according to international guidelines
• High sensitivity – measurable concentrations in healthy subjects
• HIGH quality guaranteed 

Related products

Osteoprotegerin (OPG) ELISA  , DKK-1 ELISA ,  Sclerostin ELISA

IL-6 ELISA  ,  VEGF ELISA ,  Angiopoietin-2 ELISA

Related publications

Targeting the RANKL/RANK/OPG Axis for Cancer Therapy. Front Oncol. Ming J, Cronin SJF, Penninger JM.2020.10:1283.

The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL. Simatou A, Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV.Int J Mol Sci. 2020. 21(20):7570.

 

Glycan structures of therapeutic proteins must be characterized and controlled throughout product life cycle to ensure product quality, safety and efficacy, pharmacokinetics/pharmacodynamics (PK/PD), and immunogenicity. Commonly used methods include HPLC, HPAEC-PAD, MS and CE.

Glycotechnica’s lectin microarray LecChip™ is an alternative time-effective method, which uses a broad range of lectins for glycan profiling to determine a protein-specific glycan fingerprint. This proof-of-principle study published in 2016, Zhang et al. showed that the lectin-based microarray can effectively distinguish glycans on therapeutic antibodies with high sensitivity, thus offering a simple alternative for rapid glycan profiling of therapeutic glycoproteins.

Now a second lectin array was launched by our partner Glycotechnica which includes 15 Mannose specific lectins. Results are obtained in only 48 hours. Moreover, the lectin microarray allows the identification of N- and O-glycans.

Have a look at the LecChip versions and their specificities: https://buff.ly/3yVLFsK.

To learn more, visit https://buff.ly/33VHO13
To request your personal quote for a glycan profiling service, click here: https://buff.ly/3DTyexv.

Sepsis is a life-threatening organ dysfunction and has become the main cause of in-hospital death in severe trauma patients. It is caused by an extreme response of the body to an infection. The early recognition of sepsis is critical for timely initiation of treatment and new biomarkers may help for early diagnosis.  Researchers recently investigated the use of Vanin-1 as a possible predictive biomarker of traumatic sepsis. The study demonstrated that Vanin-1 increased among trauma patients and was independently associated with the risk of sepsis, especially in the first 3 days after injury.

View abstract:  Plasma Vanin-1 as a Novel Biomarker of Sepsis for Trauma Patients: A Prospective Multicenter Cohort Study. Lu H et al. , J Infect Dis Ther. 2021. 10(2):739-751.

Abstract:
Introduction: Vanin-1 plays a pivotal role in oxidative stress and the inflammatory response. However, its relationship with traumatic sepsis remains unknown. The aim of our study was to evaluate whether plasma vanin-1 could be used for the early prediction of traumatic sepsis.

Methods: In this three-stage prospective cohort study, severe trauma patients admitted from January 2015 to October 2018 at two hospitals were enrolled. Plasma vanin-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). The associations among variables and traumatic sepsis were identified by logistic regression models and the receiver operating characteristic (ROC) curve was analyzed to evaluate the diagnostic efficiency.

Results: A total of 426 trauma patients (22 in the discovery cohort, 283 in the internal test cohort, and 121 in the external validation cohort) and 16 healthy volunteers were recruited. The plasma vanin-1 of trauma patients was significantly higher than that of healthy volunteers (P < 0.05). Patients with sepsis had higher plasma vanin-1 than patients without sepsis in the discovery trauma cohort (P < 0.05). In the internal test cohort, plasma vanin-1 at day 1 after trauma was significantly associated with the incidence of sepsis (OR = 3.92, 95% CI 2.68-5.72, P = 1.62 × 10^-12). As a predictive biomarker, vanin-1 afforded a better area under the curve (AUC) (0.82, 95% CI 0.77-0.87) than C-reaction protein (CRP) (0.62, 95% CI 0.56-0.68, P < 0.0001), procalcitonin (PCT) (0.66, 95% CI 0.60-0.71, P < 0.0001), and Acute Physiology and Chronic Health Evaluation II (APACHE II) (0.71, 95% CI 0.65-0.76, P = 6.70 × 10^-3). The relevance was further validated in the external validation cohort (OR = 4.26, 95% CI 2.22-8.17, P = 1.28 × 10^-5), with an AUC of 0.83 (95% CI 0.75-0.89). Vanin-1 could also improve the diagnostic efficiency of APACHE II (AUC = 0.85).

Conclusions: Our study demonstrated that plasma vanin-1 increased among trauma patients and was independently associated with the risk of sepsis. Vanin-1 might be a potential biomarker for the early prediction of traumatic sepsis.

Human VANIN -1  can reliably be measured in urine samples by ELISA

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Related products:

Mouse/rat Vanin-1 ELISA

Nephrology: FGF23, Endostatin, Anti C4d
Cardiology: NT-proBNP, Endothelins, proANP, NT-proCNP

Marathon running has become very popular among amateurs. The impact of intensive training on their cardiovascular system is yet unknown. The following study analyses changes in biomarkers reflecting cardiac injury and overload in male amateur runners. Measurements were assessed at baseline, immediately post-marathon and two weeks after the marathon. The data reveal that completing a marathon by an amateur led to an acute, significant cardiac volume and pressure overload, as indicated by significant increases in BNP, NT-proANP and GDF-15 levels.

Although numerous studies have demonstrated that regular physical activity is beneficial, a medical check-up including medical history and cardiovascular risk profile and resting ECG  in individuals who are planning to practice intensive endurance sports could diminish potential negative effects on the heart.

View abstract:  Myocardial Injury and Overload among Amateur Marathoners as Indicated by Changes in Concentrations of Cardiovascular Biomarkers. Kaleta-Duss AM et al., Int J Environ Res Public Health. 2020.  26;17(17):6191.  

Abstract:
Marathons continue to grow in popularity among amateurs. However, the impact of intensive exercise on the amateur’s cardiovascular system has not yet been studied. Analysis of the influence of the marathon on kinetics of biomarkers reflecting cardiac injury and overload may bring new insights into this issue. We investigated the effect of running a marathon on the concentrations of high sensitivity cardiac troponin I (hs-cTnI), heart-type fatty acid binding protein (H-FABP), N-terminal proatrial natriuretic peptide (NT-proANP), B-type natriuretic peptide (BNP), growth differentiation factor 15 (GDF-15) and galectin 3 (Gal-3) in the population of male amateur runners. The study included 35 amateur marathoners and followed 3 stages: S1—two weeks prior to the marathon, S2—at the finish line and S3—two weeks after. Blood samples were collected at each stage and analyzed for biomarkers and laboratory parameters. Concentrations of all studied biomarkers were significantly higher at S2, whereas at S3 did not differ significantly compared to S1. Running a marathon by an amateur causes an acute rise in biomarkers of cardiac injury and stress. Whether repetitive bouts of intensive exercise elicit long-term adverse cardiovascular effects in amateur marathoners needs further research.

The cardiac biomarkers NT-proANP and NT-proBNP  can reliably be measured with Biomedica´s ELISA kits: 

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Cytokines are small proteins released by cells that act as molecular messengers. They are part of the immune system and regulate various inflammatory responses as the regulation of the body’s response to disease and infection.

Cytokine ELISAs are sensitive immunoassays that can specifically detect and quantitate the concentration of soluble cytokine proteins in biological fluids. The assays accurately measure the levels of specific cytokines which can provide valuable insight into the changes associated with different disease states.
Biomedica offers fully validated and reliable cytokine assays for your clinical research – High Quality and Ready to Use. https://buff.ly/3r9uh1p

Save 30% on any of our new cytokine ELISA kits. Use promo code BI-CytELISA. Valid until 12/31/21

IL-6, VEGF, Angiopoietin-2 ELISA kits for accurate and reliable results
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Background:  

Fibroblast growth factor 23 (FGF23) is a key regulator of Vitamin D and phosphate metabolism. Preclinical studies have linked FGF23 with left ventricular hypertrophy. In a recent large prospective study, researchers identified that biologically active intact FGF23 is independently associated with all-cause and cardiovascular mortality. This finding opens the possibility for consideration of trials targeting FGF23 lowering in community-living individuals, as are being evaluated in other study populations. Read more

Fibroblast growth factor 23 (FGF23) is a 251 amino acid (AA) protein mainly produced by bone cells and functions as a central endocrine hormone regulating phosphate balance. The full-length protein comprises 251 AA including a 24 AA signal peptide. A proportion of FG23 is proteolytically processed between arginine179 and serine180 to generate N-terminal and C-terminal fragments. Therefore, the major forms of FGF23 present in human circulation are hormonally intact FGF23 and inactive N-terminal and C-terminal fragments. Depending on the epitope specificity of the antibodies utilized in commercial FGF23 assays, quantification of circulating FGF23 is based on two distinct approaches: Intact FGF23 (iFGF23) assays utilize a capture antibody that flanks the proteolytic cleavage site of FGF23, thus measuring exclusively biologically active intact FGF23 (AA 25 –251).  By contrast, C-terminal FGF23 (cFGF23) assays detect both c-terminal inactive fragments of FGF23 (AA 180-251) as well as the biologically active intact FGF23. The epitopes of the antibodies utilized in these assays lie within the c-terminal region of FGF23.

Most of the existing epidemiological studies on the association of FGF23 with clinical events related to mortality, cardiovascular disease and inflammation, measured FGF23 with a C-terminal FGF23 assay that detects both the biologically active intact hormone (iFGF23) as well as the inactive C-terminal fragments (cFGF23). These studies were performed both in the general population and in patients with kidney disease. Newer research however demonstrates that iron deficiency and inflammation induce FGF23 cleavage, increasing mainly cFGF23 degradation fragment levels whereas iFGF23 levels remain mostly unchanged.  Thus, it remains uncertain if the observed clinical associations are related to the biologically intact FGF23 hormone or if the effects of iron and inflammation on cFGF23 levels, influence the findings.

To closer evaluate the relationship of active FGF23 and its biological functions, a group of researchers recently investigated its association with mortality in a large prospective cohort of community-dwelling well-functioning older adults. The study published by Sharma et al.  included 2,763 individuals between 70-79 years who were followed up for more than 8 years. The results of the study indicate that intact FGF23 is independently associated with all-cause and cardiovascular mortality in community-living older individuals.  The authors concluded that the association seems to be restricted to certain death sub-types, in particular cardiovascular disease.  In summary, the findings suggest that the associations of FGF23 with the clinical outcomes are specific and provide insights into the biological mechanisms of FGF23. 

Click here to read full text: FGF23 and Cause-Specific Mortality in Community-Living Individuals-The Health, Aging, and Body Composition Study. Sharma S et al., 2021. Am Geriatr Soc, 69(3):711-717.

Abstract

Objectives: Fibroblast growth factor (FGF)-23 is a key regulator of mineral metabolism and has been linked with left ventricular hypertrophy in animal models. Most existing epidemiologic studies evaluated a C-terminal FGF23 assay which measures both the intact (active) hormone and inactive fragments. The relationship of intact FGF23 with cause-specific mortality is unknown.

Design: Prospective analyses of data from Health, Aging, & Body Composition (HABC) study

Setting: Community-living adults aged 70–79 years with longitudinal follow up.

Participants: 2763 older adults who participated in the HABC study

Measurements: Plasma intact FGF23 levels were measured from samples drawn in 2000 and 2001, and participants were followed through 2012. Mortality and its causes were determined by an adjudication committee. Associations of FGF23 with all-cause and cause-specific mortality were evaluated using Cox proportional hazards models adjusted for demographics, prevalent cardiovascular disease (CVD) and its risk factors, and kidney function.

Results: Median baseline intact FGF23 was 47 (IQR 37, 60) pg/ml and mean estimated glomerular filtration rate (eGFR) was 72 ± 18 ml/min/1.73m². During 8.3 years (median) follow-up, there were 821 deaths. In adjusted analysis, each two-fold higher FGF23 was associated with risk for all-cause mortality (HR 1.24 [95% CI 1.12, 1.37]). When evaluating cause-specific mortality, higher FGF23 was associated with cardiovascular mortality (HR 1.31 [95% CI 1.11, 1.54]), but not significantly with cancer (HR 1.01 [95% CI 0.83, 1.23]), gastrointestinal bleed (HR 2.49 [95% CI 0.86, 7.21]), and kidney failure (HR 1.25 [95% CI 0.77, 2.03]), dementia (HR 0.84 [95% CI 0.56, 1.26]), sepsis (HR 0.73 [95% CI 0.31, 1.73]) or pulmonary disease related mortality (HR 1.40 [95% CI 0.87, 2.27]).

Conclusion: Although higher intact FGF23 concentrations are associated with all-cause mortality in community-living individuals, the association appears limited to certain death sub-types, particularly CVD. Future studies are needed to evaluate potential mechanisms linking FGF23 concentrations with specific causes of death.

Did you know? 

Intact and c-terminal FGF23 can reliably be measured by ELISA in human serum and plasma with Biomedica’s fully validated kits. Only 50 µl of sample volume is required. The kits incorporate characterized epitope mapped antibodies and ready to use standards and controls. The assay range is optimized for clinical samples.

Biomedica´s Intact FGF23 and C-terminal FGF23 ELISA kits

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Literature:

C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. Chu C, Elitok S, Zeng S, Xiong Y, Hocher CF, Hasan AA, Krämer BK, Hocher B. BMC Nephrol. 2021 Apr 8;22(1):125. doi: 10.1186/s12882-021-02329-7. PMID: 33832449; PMCID: PMC8033679.

FGF23 and Cause-Specific Mortality in Community-Living Individuals-The Health, Aging, and Body Composition Study. Sharma S, Katz R, Dubin RF, Drew DA, Gutierrez OM, Shlipak MG, Sarnak MJ, Ix JH. J Am Geriatr Soc. 2021 Mar;69(3):711-717. doi: 10.1111/jgs.16910. Epub 2020 Nov 10. PMID: 33170519; PMCID: PMC8175094.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes? Sharma S, Katz R, Bullen AL, Chaves PHM, de Leeuw PW, Kroon AA, Houben AJHM, Shlipak MG, Ix JH. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4875–85. doi: 10.1210/clinem/dgaa665. PMID: 32951052; PMCID: PMC7571450.

FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Edmonston D, Wolf M. Nat Rev Nephrol. 2020 Jan;16(1):7-19. doi: 10.1038/s41581-019-0189-5. Epub 2019 Sep 13. PMID: 31519999.

Renal and extrarenal effects of fibroblast growth factor 23. Vervloet M. Nat Rev Nephrol. 2019 Feb;15(2):109-120. doi: 10.1038/s41581-018-0087-2. PMID: 30514976.

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator? Stöhr R, Schuh A, Heine GH, Brandenburg V. Front Endocrinol (Lausanne). 2018 Jun 27;9:351. doi: 10.3389/fendo.2018.00351. Erratum in: Front Endocrinol (Lausanne). 2018 Jul 18;9:422. PMID: 30013515; PMCID: PMC6036253.

Physiological Actions of Fibroblast Growth Factor-23. Front Endocrinol (Lausanne). Erben RG. 2018 May 28;9:267. doi: 10.3389/fendo.2018.00267. PMID: 29892265; PMCID: PMC5985418.

Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Wolf M, White KE. Curr Opin Nephrol Hypertens. 2014 Jul;23(4):411-9. doi: 10.1097/01.mnh.0000447020.74593.6f. PMID: 24867675; PMCID: PMC4322859.

Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. Beben T, Ix JH, Shlipak MG, Sarnak MJ, Fried LF, Hoofnagle AN, Chonchol M, Kestenbaum BR, de Boer IH, Rifkin DE. J Am Geriatr Soc. 2016 Feb;64(2):270-6. doi: 10.1111/jgs.13951. PMID: 26889836; PMCID: PMC5510331.

Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M. Kidney Int. 2016 Jan;89(1):135-46. doi: 10.1038/ki.2015.290. Epub 2016 Jan 4. PMID: 26535997; PMCID: PMC4854810.

Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: a meta-analysis of prospective cohort studies. Xiao Y, Luo X, Huang W, Zhang J, Peng C. Int J Cardiol. 2014 Jul 1;174(3):824-8. doi: 10.1016/j.ijcard.2014.04.138. Epub 2014 Apr 22. PMID: 24820751.

Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Ärnlöv J, Carlsson AC, Sundström J, Ingelsson E, Larsson A, Lind L, Larsson TE. Kidney Int. 2013 Jan;83(1):160-6. doi: 10.1038/ki.2012.327. Epub 2012 Sep 5. PMID: 22951890.

After corticoids, the WHO has updated its patient care guidelines to include the use of interleukin-6 (IL-6) antagonists for the treatment of patients with COVID-19. This is based on the results of a meta-analysis recently published in the Journal of the American Medical Association (JAMA 2021: DOI: 10.1001 / jama.2021.11330).

Background:

Interleukin-6 antagonists have been developed to treat rheumatic diseases. They block the cytokine IL-6, which is central to the inflammatory response that leads to the destruction of the joints. Excessive systemic inflammation, characterized by increased levels of IL-6, is a key feature of COVID-19 infection. This led to numerous clinical studies investigating the overall mortality benefit from IL-6 antagonists in hospitalized patients with COVID-19. Due to the ambiguity of the results, the WHO initiated a meta-analysis, where over 10 000 patients enrolled in 27 clinical trials were included. 

Abstract

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data extraction and synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main outcomes and measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions and relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Find the full text here.

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Higher levels of IL-6 early after tocilizumab distinguish survivors from nonsurvivors in COVID-19 pneumonia: A possible indication for deeper targeting of IL-6. 

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study.  

 

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