penKid – Prediction of Acute Kidney Injury

Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study.

Ng LL, Squire IB, Jones DJ, Cao TH, Chan DC, Sandhu JK, Quinn PA, Davies JE, Struck J, Hartmann O, Bergmann A, Mebazaa A, Gayat E, Arrigo M, Akiyama E, Sabti Z, Lohrmann J, Twerenbold R, Herrmann T, Schumacher C, Kozhuharov N, Mueller C, GREAT Network.

J Am Coll Cardiol. 2017. 69(1):56-69.

Proenkephalin levels reflect the cardiorenal status in acute heart failure and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up


High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD.

Schulz CA, Christensson A, Ericson U, Almgren P, Hindy G, Nilsson PM, Struck J, Bergmann A, Melander O, Orho-Melander M.

J Am Soc Nephrol. 2017. 28(1):291-303.

Plasma Proenkephalin level predicts incident CKD and helps to identify subjects in need of primary preventive regimens.


Diagnostic and short-term prognostic utility of plasma pro-enkephalin (pro-ENK) for acute kidney injury in patients admitted with sepsis in the emergency department.

Marino R, Struck J, Hartmann O, Maisel AS, Rehfeldt M, Magrini L, Melander O, Bergmann A, Di Somma S.

J Nephrol. 2015. 28(6):717-24.

Accurate and quick detection of acute kidney injury (AKI) in critically ill patients is hampered by the influence of systemic inflammation and other confounding factors and/or requires urine as sample matrix. In septic patients admitted to the emergency department, plasma pro-enkephalin was increased with the presence and severity of (AKI), and was associated with short-term mortality, but essentially not elevated when sepsis was not accompanied with AKI.


Proenkephalin predicts acute kidney injury in cardiac surgery patients.

Shah KS, Taub P, Patel M, Rehfeldt M, Struck J, Clopton P, Mehta RL, Maisel AS.

Clin Nephrol. 2015. 83(1): 29-35.

Patients undergoing cardiac surgery frequently develop acute kidney injury (AKI). Plasma levels of proenkephalin were significantly elevated in patients developing AKI and increased faster than creatinine in such patients following surgery.


Proenkephalin and prognosis after acute myocardial infarction.

Ng LL, Sandhu JK, Narayan H, Quinn PA, Squire IB, Davies JE, Bergmann A, Maisel A, Jones DJ.

J Am Coll Cardiol. 2014. 63(3): 280-9.

Plasma proenkephalin was measured in 1,141 patients with myocardial infarction. Increased levels were associated with major adverse cardiac events and death. Kidney function (eGFR) was shown to be by far the strongest independent determinant of proenkephalin.


Proenkephalin A 119-159, a stable proenkephalin precursor fragment identified in human circulation.

Ernst A, Köhrle J, Bergmann A.

Peptides. 2006. 27(7):1835-40.

A stable fragment of Proenkephalin (PENK or pro-ENK) has been identified as suitable surrogate marker for the unstable enkephalin peptides.


Proenkephalin expression and enkephalin release are widely observed in non-neuronal tissues.

Denning GM, Ackermann LW, Barna TJ, Armstrong JG, Stoll LL, Weintraub NL, Dickson EW.

Peptides. 2008. 29(1):83-92.

Tissue-specific expression of enkephalin and enkephalin receptors was assessed by several methods in various species. Widespread expression was observed and the kidney was found to be one of the major expression sites.

bio-ADM – Prediction of Shock & Vasopressor Demand

Plasma adrenomedullin in critically ill patients with sepsis after major surgery: A pilot study.

Simon TP, Martin L, Doemming S, Humbs A, Bruells C, Kopp R, Hartmann O, Struck J, Bergmann A, Marx G, Schuerholz T.

J Crit Care. 2016. 38:68-72. doi: 10.1016/j.jcrc.2016.10.017.

First study investigating adrenomedullin in patients with sepsis following major surgery. Higher adrenomedullin on admission is associated with increased vasopressor need and mortality after 90 days.

Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis.

Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S.

Crit Care. 2014. 18(1):R34. doi: 10.1186/cc13731.

Patients admitted with sepsis are at a high risk of developing shock. Adrenomedullin is a key mediator in this process and was measured here in a typical emergency department cohort of patients with sepsis, severe sepsis or septic shock with a new assay. This specifically detects the biologically active molecule. Strong associations were found with the need for vasopressor therapy, severity of disease and 28-day mortality.

pro-NT – Prediction of Obesity Risk

An obligatory role for neurotensin in high-fat-diet-induced obesity

Li J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K, Starr ME, Kim JT, Harris JW, Yiannikouris FB, Katz WS, Nilsson PM, Orho-Melander M, Chen J, Zhu H, Fahrenholz T, Higashi RM, Gao T, Morris AJ, Cassis LA, Fan TW, Weiss HL, Dobner PR, Melander O, Jia J, Evers BM

Nature. 2016. 533(7603):411-5.

Obesity and its associated comorbidities contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin, a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

pro-NT – Prediction of Breast Cancer Risk

Plasma Proneurotensin and Incidence of Diabetes, Cardiovascular Disease, Breast Cancer, and Mortality.

Olle Melander, Alan S. Maisel, Peter Almgren, Jonas Manjer, Mattias Belting, Bo Hedblad, Gunnar Engström, Ute Kilger, Peter Nilsson, Andreas Bergmann, Marju Orho-Melander.

JAMA. 2012. 308(14):1469-75.

Results from the first epidemiological study on fasting concentration of proneurotensin show that high concentrations of the satiety hormone neurotensin are significant associated with the future development of breast cancer in women resulting in a HR of 1.44 per SD increment of log-transformed proneurotensin. It is known from experimental studies that expression of neurotensin and Nstr1 is increased in breast tumors. Further pharmacological blockade or RNA silencing of Ntsr 118,19 result in reduced tumor growth. Both observations indicate a direct mechanistic relationship between high-fasting proneurotensin and breast cancer development.


Validation of plasma proneurotensin as a novel biomarker for the prediction of incident breast cancer.

Melander O, Belting M, Manjer J, Maisel AS, Hedblad B, Engström G, Nilsson P, Struck J, Hartmann O, Bergmann A, Orho-Melander M.

Cancer Epidemiol Biomarkers Prev. 2014. 23(8):1672-6.

Data from the Malmö Prevention Project (MPP) Study confirms the results initially found in the Malmö Diet And Cancer (MDC) Study. Fasting plasma proneurotensin concentration was significantly associated with the development of breast cancer showing an odds ratio (OR) per standard deviation (SD) increment of LN-transformed proneurotensin of 2.09 (95% confidence interval). The effect of proneurotensin, which is independent of other factors like age, body mass index (BMI), smoking, and hormone replacement therapy, was even greater than was found in the MDC Study.


Proneurotensin 1-117, a stable neurotensin precursor fragment identified in human circulation.

Ernst, A, Helmich, S und Bergmann, A.

Peptides. 2006. 27(7):1787-93.

A sandwich immunoassay for the detection of proneurotensin which is the common precursor of two biologically active peptides, neurotensin (NT) and neuromedin N (NMN), has been developed. The in-vitro stability of proneurotensin was shown for at least 48 h at room temperature. As proneurotensin is produced in stoichiometric amounts relative to NT and NMN, proneurotensin can function as a surrogate marker for the release of these bioactive peptides.


The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression.

Dupouy S, Viardot-Foucault V, Alifano M, Souazé F, Plu-Bureau G, Chaouat M, Lavaur A, Hugol D, Gespach C, Gompel A, Forgez P.

PLoS ONE. 2009. 4(1):e4223.

Expression of neurotensin and Nstr1 has been compared in normal human breast tissue and in invasive ductal breast carcinomas (IDCs). Neurotensin has been found to be expressed in the ductal and invasive components of IDCs. High expression of NTSR1 correlated with Scarff-Bloom-Richardson (SBR) grade as well as with tumor size and number and the number of metastatic lymph nodes. All data support the model of activation of neurotensinergic deleterious pathways in breast cancer progression.


Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression.

Souazé F, Dupouy S, Viardot-Foucault V, Bruyneel E, Attoub S, Gespach C, Gompel A, Forgez P.

Cancer Res. 2006. 66(12):6243-9.

Neurotensin acts as a trophic and antiapoptotic factor in several human solid tumors via interaction with the high-affinity neurotensin receptor (NT1 receptor). This could have been shown while functionally expressed NT1 receptor coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. When signaling pathway of the NT1 receptor was blocked the reversion of these transforming functions and tumor growth resulted.


Involvement of neurotensin in cancer growth: Evidence, mechanisms and development of diagnostic tools.

Carraway, Robert E. and Plona, Ann M.

Peptides. 2006. 27(10):2445-60.

Cancers that overexpress NT receptors are described as well as signaling events involved in the direct effects of NT on cancer cells in vitro. Data illustrates different potential possibilities to regulate cancer growth that neurotensin might influence.


The Anti-Apoptotic Role of Neurotensin.

Christelle Devader, Sophie Béraud-Dufour, Thierry Coppola, Jean Mazella

Cells. 2013. 2(1):124–135.

The anti-apoptotic action of NT has been reviewed and assessed. When it comes to the protection of cells or tissues against cytotoxic agents (IL-1β, proNGF, proBDNF) , it is beneficial but deleterious on the other hand when it comes to the growth of neoplastic cells. The necessity of blocking of NT receptors, which are overexpressed in tumors, is discussed.


Role of nutrients in the gastrointestinal release of immunoreactive neurotensin.

Go, Vay Liang W. and Demol, Pierre.

Peptides. 1981. 2(Suppl 2): 267-9.

The satiety hormone neurotensin is released into the circulation upon ingestion of a meal. Uptake of fatty acid is the most potent in stimulating immunoreactive neurotensin release. This response itself is dose dependent.

vr-hGH – Prediction of CVD Risk in men

Plasma growth hormone is a strong predictor of risk at 1 year in acute heart failure.

Bhandari SS, Narayan H, Jones DJ, Suzuki T, Struck J, Bergmann A, Squire IB, Ng LL.

Eur J Heart Fail. 2016. 18(3):281-9. doi: 10.1002/ejhf.459.

hGH and NTproBNP levels were measured in 537 patients with acute HF (HFrEF n = 415; HFpEF n = 122). hGH offers incremental prognostic information over the ADHERE score
clinical predictors and NT-proBNP for risk stratification of acute HF patients.


Fasting levels of high-sensitivity growth hormone predict cardiovascular morbidity and mortality: the Malmö Diet and Cancer study.

Hallengren E, Almgren P, Engström G, Hedblad B, Persson M, Suhr J, Bergmann A, Melander O.

J Am Coll Cardiol. 2014. 64(14):1452-60.

Using an ultrasensitive assay, the plasma growth hormone was measured in a large Swedish general population study (4,323 participants, mean age 58 years, median follow-up 16.2 years). Samples were gained in the morning from fasting subjects. Independent from known risk factors, relatively elevated levels of growth hormone were associated with an increased risk of incident cardiovascular events and mortality, especially in males.


Growth hormone for risk stratification and effects of therapy in acute myocardial infarction.

Ng LL, Bhandari SS, Sandhu JK, Quinn PA, Squire IB, Davies JE, Struck J, Bergmann A, Jones DJ.

Biomarkers. 2015. 20(6-7):371-5. doi:10.3109/1354750X.2015.1093031.

hGH levels post-AMI are prognostic for MACE and indicate those patients who benefit from beta blocker and ACE/ARB therapy.


Growth hormone as a risk for premature mortality in healthy subjects: data from the Paris prospective study.

Maison P, Balkau B, Simon D, Chanson P, Rosselin G, Eschwège E.

BMJ. April 11, 1998;316(7138): 1132-3

The prospective study of French policemen, which began in the late 1960s and early 1970s with an 18-year follow-up, showed that higher fasting GH levels are associated with elevated risks of premature all-cause mortality and for cardiovascular mortality.

pro-ENK – Prediction of Breast Cancer Risk

Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk

O. Melander, M. Orho-Melander, J. Manjer, T. Svensson, P. Almgren, P. M. Nilsson, G. Engström, B. Hedblad, S. Borgquist, O. Hartmann, J. Struck, A. Bergmann, M. Belting

Jornal of Clinical Oncology. 2015. 33(24):2632-8. doi:10.1200/JCO.2014.59.7682.

Data from two large studies (Malmö Diet and Cancer study and Malmö Preventive Project) using fasting plasma samples from approx. 3,500 healthy women (mean age, 57.6 ± 5.9 years and mean age, 70.0 ± 4.4 years respectively) show the significant association of plasma pro-ENK, a surrogate for mature ENK, with the risk of incident breast cancer. Coincidently with the known negative regulation of breast cancer development of enkephalins (ENKs) and related opioids by enhancing immune-mediated tumoral defense as well as directly inhibiting cancer cells pro-ENK was found to be inversely related to the risk of incident breast cancer in middle-aged and postmenopausal women.


Plasma Pro-Enkephalin, a stable peptide of the precursor to the endogenous opioid Enkephalin, predicts breast cancer risk.

O. Melander, M. Orho-Melander, P. Almgren, J. Manjer, B. Hedblad, G. Engström, J. Struck, P. Nilsson, A. Bergmann, M. Belting

Oncol Res Treat. 2014. 37(suppl 1):4.

Results of two large-scale general population studies indicate a strong association between fasting plasma concentration of pro-ENK and risk of future breast cancer development in middle-aged and post-menopausal women.


Plasma Pro-Enkephalin adds value to Proneurotensin for the risk prediction of incident breast cancer.

O. Melander, M. Orho-Melander, P. Almgren, J. Manjer, B. Hedblad, G. Engström, J. Struck, P. Nilsson, A. Bergmann, M. Belting

Oncol Res Treat. 2014. 37(suppl 1):6.

Data from the Malmö Diet And Cancer (MDC) Study shows that biomarker-based risk prediction for the development of breast cancer is significantly improved by combining determination of plasma pro-ENK and pro-NT.


Proenkephalin A 119-159, a stable proenkephalin A precursor fragment identified in human circulation.

Ernst A, Köhrle J, Bergmann A.

Peptides. 2006. 27(7):1835-40.

A sandwich immunoassay for the detection of pro-Enkephalin A 119-159, which is a fragment of the pro-Enkephalin A precursor, has been developed. The in-vitro stability of pro-Enkephalin A 119-159 has been shown for at least 48 hours at room temperature compared to the low stability of the peptides methionine- and leucine-enkephalin derived from the same precursor. As pro-Enkephalin A 119-159 is produced in stoichiometric amounts relative to leucine-enkephalin (1:1) and methionine-enkephalin (1:4), it can function as a surrogate marker for the release of these two bioactive peptides.


Inhibition of Pulmonary Metastases and Enhancement of Natural Killer Cell Activity by Methionine-Enkephalin.

Robert E. Faith, Anthony J. Murgo

Brain Behav Immun. 1988. 2(2):114-22.

The effects of the endogenous opioid peptide methionine-enkephalin have been investigated on experimental metastasis of the murine B-16 melanoma and on murine splenic natural killer cell activity. As methionine-enkephalin was shown to significantly inhibit tumor metastasis and significantly enhance splenic natural killer cell activity, the suggestion was made that such endogenous opioids might be of a beneficial adjunct to the therapy of neoplastic disease.


Opioid therapy and tumor progression.

Michael Schäfer, Shaaban A. Mousa

Advances in Palliative Medicine. 2009. 8:53–56.

Review on the immunemodulatory effects of opioids, especially Metenkephalin, and in particular their impact on tumor growth and dissemination of metastases. The results available support the suggestion that opioids affect tumor progression and that Metenkephalin possibly seems to play a most prominent role.


Met-enkephalin induces cytolytic processes of apoptotic type in K562 human erythroid leukemia cells.

Mernenko OA, Blishchenko EY, Mirkina II, Karelin AA.

FEBS Lett. 1996. 383(3):230-2.

K562 human erythroid leukemia cells were used to study the cytolytic activity of Met-enkephalin. Results indicate an apoptotic mechanism due to observed cytolysis accompanied by internucleosomal DNA fragmentation.


Opioids induce while nicotine suppresses apoptosis in human lung cancer cells

Maneckjee R, Minna JD.

Cell Growth Differ. 1994. 5(10):1033-40.

Mechanistic comparision of apoptotic processes in lung cancer cells induced by opioids and nicotine confirm the apoptotic role of opioids.