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• FIGHTING CANCER - Inhibition of RANK/RANKL Signaling

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:
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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.

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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.

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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.

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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.
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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

Is your lab measuring FGF23?

 

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The FGF23 ELISA kits are developed and manufactured by

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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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#Acute pulmonary embolism (PE) is a common and potentially fatal disease. The cause is usually a blood clot in the leg that travels to the lung and blocks blood flow . #Angiopoietin-2 (Ang-2) is a signaling molecule that is upregulated in response to insufficient tissue oxygen supply. In a recent study scientists investigated the potential role of Ang2 as a #risk factor in patients with acute PE. The results indicate that Ang2 correlates with PE severity, right ventricular dysfunction, and need for #ICU admission. Thus, Ang-2 holds promise as a novel marker that can aid in risk stratification for this patient population.
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Systemic sclerosis (SSc) or Scleroderma is a chronic autoimmune disease characterized by thickening of the skin, fibrosis of various internal organs, and blood vessel abnormalities Though the cause of SSc remains still unknown dysregulation of the immune system is considered to play a significant role. Cardiovascular disease is one of the principal determinants of mortality in SSc and represents a diagnostic challenge. A team of researchers aimed to test the diagnostic and long term prognostic performance of the cardiac biomarkers NT-proANP and NT-proBNP in SSc patients. Both peptides are mainly secreted by the heart in response to increased myocyte stretch.
Read more: https://lnkd.in/e7ifHBX

The NT-proANP and NT-proBNP measurements were performed with Biomedica ELISA kits:
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Fibroblast growth factor 23 (FGF23) is a bone derived hormone involved in the regulation of phosphate and vitamin D metabolism. FGF23 is increased in patients with renal failure and has been shown to be a risk factor in cardiovascular mortality not only in kidney disease but also in the general population. FGF23 levels are elevated in obese people and increased energy intake is a potential predictor of plasma FGF23 concentrations. In a recent study, three groups of rats were fed diets with high, normal and low caloric content that resulted in different energy intake. The authors could demonstrate that FGF23 production is directly regulated by energy availability.
Read more: https://lnkd.in/eVZMvvF

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Osteoprotegerin (OPG) is a secreted protein that is implicated in heart and kidney disease. A recent study identifies OPG as a risk factor predicting death in stable renal transplant recipients.

Read more: Osteoprotegerin is an independent risk factor predicting death in stable renal transplant recipients. Zeng S et al., Clin Nephrol. 2021 May 27. 

Abstract

Background: Vascular calcification is common in chronic kidney disease and is associated with significant cardiovascular morbidity and mortality. One of the important factors regulating vascular calcification is osteoprotegerin (OPG). There are, however, limited data on the impact of OPG on all-cause mortality and graft loss in kidney transplant recipients so far. Given its impact on vascular calcification, the aim of our study is to analyze whether OPG was a risk factor of all-cause mortality and graft loss in 600 stable kidney transplant recipients.

Materials and methods: 600 stable renal transplant recipients (367 women, 233 men) were followed for all-cause mortality and graft loss for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, estimated glomerular filtration rate (eGFR), cold ischemia time, HbA1c, phosphorus, calcium, and albumin.

Results: 65 patients died, and 38 patients had graft loss during the observation period. The OPG baseline concentrations had no effect on graft loss, whereas Kaplan-Meier survival curve showed that baseline plasma OPG concentrations were associated with all-cause mortality in stable kidney transplant recipients (p < 0.0001, log-rank test). After multiple Cox regression analysis adjusting for age, eGFR, cold ischemia time, HbA1c, phosphorus, calcium, and albumin, plasma levels of OPG remained an independent predictor of all-cause mortality (HR, 1.181; 95%CI 1.035 – 1.347; p = 0.014).

Conclusion: Baseline plasma OPG is an independent risk factor for all-cause mortality but not graft loss in patients after kidney transplantation.

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Accurate, early diagnosis of acute appendicitis continues to be a major diagnostic challenge and cannot be detected by current inflammatory biomarkers. Leucine-rich alpha-2-glycoprotein (LRG) is a novel marker and functions as an acute-phase protein that is secreted by neutrophils. As neutrophils act as first responders to infection LRG may be useful to diagnose acute appendicitis.

Read more:
• Serum and Urine Biomarker Leucine-Rich Alpha-2 Glycoprotein 1 Differentiates Pediatric Acute Complicated and Uncomplicated Appendicitis. https://buff.ly/3cw3Vkg
• A novel noninvasive appendicitis score with a urine biomarker. https://buff.ly/3v4h4Yg

LRG can reliably be measured by ELISA in human serum, plasma and urine samples with a fully validated assay. Only 5 µl of sample volume is required!

LRG ELISA Assay Highlights https://buff.ly/31vlD26 :
√SPECIFIC – Characterized, epitope mapped antibodies
√CONVENIENT – Assay range optimized for clinical samples
√RELIABLE – Rigorously validated according to FDA/EMEA/ICH guidelines
√EASY -Results in 3 h, all reagents included

Chronic allergic itch is a common symptom affecting millions of people, but its pathogenesis is not fully understood. Periostin is an extracellular matrix protein that is highly expressed in the skin. Researchers have identified that Periostin can directly activate itch-associated neurons in the skin. Blocking the Periostin receptors on these neurons reduced the itch response in a mouse model.

Related publications: Periostin, an Emerging Player in Itch Sensation.
https://lnkd.in/g8dwQ3z
Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch.
https://lnkd.in/gMyJM3X

PERIOSTIN can reliably be measured by ELISA . Only 10 µl of sample volume is required! https://buff.ly/35zhkBz

Biomedica Periostin ELISA – Features & Benefits
√ CONVENIENT – Assay range optimized for clinical samples
√ RELIABLE – Full validation package
√ SPECIFIC – Characterized, epitope mapped capture and detection antibodies
√ HIGH QUALITY GUARANTEED–  https://lnkd.in/gmGhJgR

Neuropilin-1 (NRP1) is an essential cell surface receptor with an established role in development and immunity. Due to alternative splicing or shedding, the extracellular region can be released into circulation as soluble Neuropilin-1 (sNRP1). Researchers in Germany have shown that sNRP1 is an independent prognostic marker for breast cancer-specific survival. The study included 506 patients diagnosed with primary, non-metastatic breast cancer.
Read the full article here: https://buff.ly/3uvOBuh
Soluble NRP1 was measured with Biomedica´s ELISA kit.: https://buff.ly/38HbbWI

Features & Benefits
√ Low sample volume – only 10 µl required
√ Ready to use calibrators and controls
√ Full VALIDATION package
√ HIGH QUALITY GUARANTEED
Find out more: https://buff.ly/2oXzsWh

Proteins are particularly useful molecules to use as biomarkers. They are biochemical indicators that can provide vital information in determining disease prognosis and progression and in predicting the response to therapies. Biomarkers can be used in clinical trials or can be applied in toxicology, including preclinical drug safety assessment*.

Features & Benefits
√ Full VALIDATION package
√ WIDELY CITED +1500 publications
√ Automatable
√ HIGH QUALITY GUARANTEED

Find out more: https://buff.ly/2oXzsWh

*check out our NT-proANP kit – biomarker of cardiac hypertrophy in preclinical toxicology

Infertility is a frequent problem affecting up to 26% of all couples globally. Impaired semen quality is often the cause, but few treatment options exist. The RANKL system is an essential regulator of bone resorption. This current study by Blomberg Jensen M. and colleagues provides insights into a yet unrecognized regulatory role of RANKL in male reproductive function. These findings may ultimately be of clinical relevance since an approved specific RANKL inhibitor is in use to treat osteoporosis in women and men. Read more: https://buff.ly/3tV49aF

Biomedica ELISA kits were used in this study to measure soluble RANKL and OPG in serum and seminal fluid.

ELISA kit highlights:
• CE marked – widely cited in clinical studies
• Reliable – validated according to international guidelines
• High sensitivity – measurable concentrations in healthy subjects
• HIGH quality guaranteed https://buff.ly/3etWGHH

Proinflammatory cytokine IL-6 concentrations increase with age but elevated levels are also linked to underlying medical and psychological conditions. IL-6 is known to affect the brain and studies have implicated a specific role of IL-6 in stress- related pathophysiology.

Read more: The Link between Stress and IL-6 Is Heating Up. Darcy J, Tseng YH, Cell Metab. 2020 4;32(2):152-153. Full text: https://buff.ly/3tA3DP9

IL-6 can reliably be measured with Biomedica´s high quality IL-6 ELISA kit offering EXTRAORDINARY SENSITIVITY with a WIDE DYNAMIC RANGE:

• EASY ready to use calibrators & controls included
• HIGH SENSITIVITY measurable values in serum and plasma, CC and urine
• RELIABLE validated according to international quality guidelines
• HIGHLY SPECIFIC characterized recombinant epitope-mapped antibodies

Complete ready to use IL-6 ELISA kit for superior performance and reproducibility

May is “Osteoporosis Month” raising awareness on bone health. Osteoporosis is estimated to affect 200 million people worldwide. Taking action for prevention, diagnosis and treatment can reduce the risk and the burden of osteoporosis.

Biomedica offers a wide range of  bone biomarker ELISA kits for the accurate measurement of FGF23, Sclerostin, Osteoprotegerin, soluble RANKL, DKK-1, IL-6, and others.

Assay Highlights:
• EASY – ready to use calibrators & controls included
• RELIABLE – validated according to international quality guidelines
• WIDELY CITED in 1500 + publications
• COMPETENT CUSTOMER SERVICE

Complete ready-to-use ELISA kits for superior performance and reproducibility: https://buff.ly/2N3xY97

 

Effect of Sclerostin Inhibition on Cardiovascular Safety for the Treatment of Severe Osteoporosis

Osteoporosis is a skeletal disorder characterized by diminished bone strength that is responsible for an increased fracture risk. The glycoprotein sclerostin acts as an inhibitor of bone formation. Therapies directed against this molecule have been developed. A humanized antibody against sclerostin has been approved for the treatment of severe osteoporosis in postmenopausal women in many parts of the world. A recent review by Langdahl BL and colleagues sumarizes the current knowledge of the effect of sclerostin inhibition on cardiovascular safety.

Cardiovascular Safety and Sclerostin Inhibition – a mini-review.
Langdahl BL, Hofbauer LC, Forfar JC. J Clin Endocrinol Metab. 2021 Mar 23:dgab193. doi: 10.1210/clinem/dgab193. Epub ahead of print. PMID: 33755157. 

Biomedica´s Sclerostin ELISA kit:
• The internationally most referenced Sclerostin ELISA!
• Rigorously validated according to FDA/ICH/EMEA guidelines
• Low sample volume

 

RELATED Publications – Sclerostin Inhibition and Cardiovascular Safety

 

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Bovijn J, Krebs K, Chen CY, Boxall R, Censin JC, Ferreira T, Pulit SL, Glastonbury CA, Laber S, Millwood IY, Lin K, Li L, Chen Z, Milani L, Smith GD, Walters RG, Mägi R, Neale BM, Lindgren CM, Holmes MV. Sci Transl Med. 2020 Jun 24;12(549):eaay6570. doi: 10.1126/scitranslmed.aay6570. PMID: 32581134; PMCID: PMC7116615.

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a crucial role in regulating the acute phase response, inflammation, hematopoiesis, glucose metabolism, bone metabolism and cancer progression.

Biomedica´s high quality IL-6 ELISA kit offers EXTRAORDINARY SENSITIVITY with a WIDE DYNAMIC RANGE: https://buff.ly/3u139m1
Check out our new human IL-6 ELISA kit – developed and manufactured by Biomedica!

Why use Biomedica´s IL-6 ELISA kit?

• EASY ready to use calibrators & controls included
• HIGH SENSITIVITY measurable values in serum and plasma, CC and urine • RELIABLE validated according to international quality guidelines
• HIGHLY SPECIFIC characterized recombinant epitope-mapped antibodies

Complete ready to use IL-6 ELISA kit for superior performance and reproducibility Review:

Interleukin-6 signaling in health and disease. Rose-John S, 2020. F1000Res, 20;9:F1000 Faculty Rev-1013.

SARS-CoV-2 and COVID-19: Is interleukin-6 (IL-6) the ‘culprit lesion’ of ARDS onset? What is there besides Tocilizumab? SGP130Fc. Magro G., 2020. Cytokine X,2(2):100029. 

Researchers have identified the c-terminal fragment of the phosphate regulating hormone FGF23 (cFGF23) to better predict the risk of graft loss in kidney transplant recipients (KTRs) than its biologically active form (intact FGF23). The prospective observational cohort study included 562 maintenance KTRs with a median follow-up of 4 years.

C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. Chu C et al.,BMC Nephrology (2021) 22:125.

FGF23 (intact) and FGF23 (C-terminal) can reliably be measured by ELISA
√ CE-marked – for IVD use in the EU
√ CORRELATE with existing ELISA methods
√ Excellent stability in all matrices
√ For plasma & serum
√ HIGH QUALITY – fully validated according to international guidelines (ICH/FDA/EMEA)

The proinflammatory cytokine Angiopoietin-2 plays a key role in endothelial cell disruption and associated events. A recent study demonstrates that a three day change in Angiopoeitin-2 levels predicts the clinical course in hospital-mortality of patients with SARS-CoV-2. Angiopoietin-2 is a relevant part of disease pathogenesis and could be a target for new specific treatments in these patients.

Read more: Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with … Villa E et al., Blood Adv. 2021 Feb 9;5(3):662-673.

Angiopoietin-2 (ANG-2) can reliably be measured by ELISA in human serum, plasma and urine samples with Biomedica’s fully validated assay kit. Only 20 µl of sample volume is required! The kit incorporates ready to use standards and controls. The assay range is optimized for clinical samples- no sample dilution required!

Features & Benefits

√ Immediate results: no sample dilution required
√ Full validation package – the assay is optimized for clinical samples
√ Kit includes ready to use standards and controls
√ Automatable
√ HIGH QUALITY GUARANTEED – https://buff.ly/3etWGHH

Find out more: Angiopoietin-2 ELISA

Extracellular vesicles (EVs) are cell-derived membranous structures that contain lipids, proteins, and nucleic acids of the source cell. They are released into the extracellular space and act as intercellular communicators. Receptor activator of NF-κB ligand RANKLL) and its receptor RANK are bone-cell derived key proteins that are crucial in regulating bone remodeling. EVs containing RANKL and RANK have recently been identified as intercellular regulators in bone biology and are attractive as drug targets and as biomarkers.

Read more Free soluble RANKL can reliably be measured by ELISA in serum and plasma. 

Assay Highlights

• High sensitivity – measurable concentrations in healthy subjects

• Only ELISA that measures free, uncomplexed soluble RANKL

• CE marked – widely cited in clinical studies

Acute kidney injury (AKI) is an abrupt loss of kidney function and is independently associated with high mortality in critically ill patients. Endostatin, the C-terminal proteolytic fragment of collagen XVIII, is expressed during the progression of renal fibrosis. A team of researchers recently demonstrated that serial measurement of plasma endostatin has useful predictive value for 30-day mortality in AKI patients.

Read more: Prognostic value of dynamic plasma endostatin for the prediction of mortality in acute kidney injury: A prospective cohort study. Jia HM et al., J Int Med Res. 2020 48(7):300060520940856. Full text

Endostatin can reliably be measured by ELISA in human serum, plasma and urine samples. Only 20 µl of sample volume is required!

Endostatin ELISA Assay Highlights: https://www.bmgrp.com/product/cardiovascular/human-endostatin-elisa-biomedica/

•  SPECIFIC – no cross-reactivity with COL15A1
•  CONVENIENT – Assay range optimized for clinical samples
•  RELIABLE – Validated according to international quality guidelines
•  EASY – Results in 4,5 h, all reagents included

Osteoporosis is the most common bone disease and its prevalence increases with age affecting approximately 200 million people worldwide. Most osteoporosis therapies aim at inhibiting bone resorption, while only a few are capable of actively promoting the generation of new bone tissue. Osteoporosis treatment with anti-Sclerostin antibodies is an newer osteo-anabolic therapy that stimulates bone formation and inhibits at the same time bone resorption. This recent review by Rauner M. and colleagues highlights the advances in the application of this newer drug in the treatment of osteoporosis and other bone diseases.

Osteoporosis Treatment with Anti-Sclerostin Antibodies—Mechanisms of Action and Clinical Application. Rauner M, Taipaleenmäki H, Tsourdi E, Winter EM. Journal of Clinical Medicine. 2021; 10(4):787. https://lnkd.in/eyU3kPN

Biomedica´s Sclerostin ELISA kit https://buff.ly/2N4iVsK

• The internationally most referenced Sclerostin ELISA!
• Rigorously validated according to FDA/ICH/EMEA guidelines
• Low sample volume

High expression of leucine-rich alpha-2-glycoprotein (LRG) is closely related to angiogenesis, which may play an important role in promoting invasion and metastasis. In a retrospective study in 330 cases of early breast cancer, researchers have identified the use of LRG as a potential prognosis biomarker for early breast cancer analysis. LRG expression was associated with the tumor stage and lymphatic metastasis, and high LRG expression predicted poor survival. Analysis of serum samples from the patients may further assist in verifying the findings of this report.

Prognostic Value of LRG1 in Breast Cancer: A Retrospective Study. Zhang YS et al., 2021. Oncol Res Treat 44(1-2):36-42.

LRG can reliably be measured by ELISA in human serum, plasma and urine samples with a fully validated assay. Only 5 µl of sample volume is required!

LRG ELISA Assay Highlights https://buff.ly/31vlD26 :

• SPECIFIC – Characterized, epitope mapped antibodies

• CONVENIENT – Assay range optimized for clinical samples

• RELIABLE – Rigorously validated according to FDA/EMEA/ICH guidelines

• EASY -Results in 3 h, all reagents included

Leucine-rich alpha-2-glycoprotein (LRG) ELISA | BI-LRG

 

Osteoprotegerin (OPG) is a secreted protein that affects bone turnover and is implicated in heart and kidney disease. A recent study identifies OPG as an independent risk factor for all-cause mortality in patients after kidney transplantation. 982 prevalent kidney transplant (KT) recipients were followed up for all-cause mortality for 6 years. The researchers observed that each 1 pmol/L higher-serum OPG level was associated with a 49% higher risk of mortality.

Biomedica´s OPG ELISA was used in this recent study and is part of our Clinical Nephrology Biomarker ELISA line of reliable and widely cited assays.

Check out the Biomedica OPG ELISA:

CE marked
Reliable – validated according to international guidelines
Most referenced human OPG ELISA
Only 20µl sample volume required 

Association between serum osteoprotegerin level and mortality in kidney transplant recipients. Gupta V et al., 2021. Transpl Int 19. doi: 10.1111/tri.13847. Epub ahead of print. PMID: 33606319

Big Endothelin-1 (Big ET-1) is a valuable tool for risk stratification in patients with cardiomyopathy

Big Endothelin-1 (Big ET-1) is a protein that is mainly produced by vascular endothelial and smooth muscle cells and cardiomyocytes. Big ET-1 has been identified as a risk factor for a poor prognosis in patients with atrial fibrillation or coronary artery disease. This current study revealed that plasma Big ET-1 is a valuable tool for risk stratification in patients with LVNC.

Big ET-1 useful for risk stratification in cardiomyopathy

Prognostic value of plasma big endothelin-1 in left ventricular non-compaction cardiomyopathy.  Fan P et al., 2020. Heart. 2020. 

 

Biomedica Big-ET-1 ELISA kit highlights (BI-20082H)

 

√  Direct measurement

√ Fully validated according to international guidelines

√ Published cut-off values

√ cited in +70 publications

 

CITATIONS with the Biomedica Big Endothelin-1 (Big ET-1) ELISA, cat. no. BI-20082W

 

Prognostic value of plasma big endothelin-1 in left ventricular non-compaction cardiomyopathy. Fan P, Zhang Y, Lu YT, Yang KQ, Lu PP, Zhang QY, Luo F, Lin YH, Zhou XL, Tian T. Heart. 2021 May;107(10):836-841. doi: 10.1136/heartjnl-2020-317059. Epub 2020 Oct 14. PMID: 33055147; PMCID: PMC8077223.

Abstract