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Concept: Chromogranin

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Chromogranin A (CgA) is the major soluble protein co-stored and co-released with catecholamines and can function as prohromone giving rise to several bioactive peptides. This review focuses on these molecules summarizing their physiological functions, their pathogenetic implications and their recent use as biomarkers in several pathological conditions. A thorough literature search of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized key-words such Chromogranin A, Vasostatin-1 and 2, Chromofungin, Chromacin, Pancreastatin, Catestatin, WE-14, Chromostatin, GE-25, Parastatin and Serpinin, and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular and the immune systems and by affecting the glucose or calcium homeostasis. Since some peptides exert similar effects, but other elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenetic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumours, but also in cardiovascular, inflammatory and neuropsychiatric diseases.

Concepts: Immune system, Medicine, Cancer, Biology, Pathology, Physiology, Chromogranin A, Chromogranin

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The discovery in 1953 of the chromaffin granules as co-storage of catecholamines and ATP was soon followed by identification of a range of uniquely acidic proteins making up the isotonic vesicular storage complex within elements of the diffuse sympathoadrenal system. In the mid-1960s, the enzymatically inactive, major core protein, chromogranin A was shown to be exocytotically discharged from the stimulated adrenal gland in parallel with the co-stored catecholamines and ATP. A prohormone concept was introduced when one of the main storage proteins collectively named granins was identified as the insulin release inhibitory polypeptide pancreastatin. A wide range of granin-derived biologically active peptides have subsequently been identified. Both chromogranin A and chromogranin B give rise to antimicrobial peptides of relevance for combat of pathogens. While two of the chromogranin A-derived peptides, vasostatin-I and pancreastatin, are involved in modulation of calcium and glucose homeostasis, respectively, vasostatin-I and catestatin are important modulators of endothelial permeability, angiogenesis, myocardial contractility, and innate immunity. A physiological role is now evident for the full-length chromogranin A and vasostatin-I as circulating stabilizers of endothelial integrity and in protection against myocardial injury. The high circulating levels of chromogranin A and its fragments in patients suffering from various inflammatory diseases have emerged as challenges for future research and clinical applications.

Concepts: Immune system, Protein, Glucose, Hormone, Epinephrine, Adrenal medulla, Chromogranin A, Chromogranin

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To investigate whether chromogranin A (CgA) is secreted from the heart into circulation.

Concepts: Cell, Physiology, Secretion, Heart, Reptile, Mammal, Chromogranin A, Chromogranin

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The granin family comprises altogether 7 different proteins originating from the diffuse neuroendocrine system and elements of the central and peripheral nervous systems. The family is dominated by three uniquely acidic members, namely chromogranin A (CgA), chromogranin B (CgB) and secretogranin II (SgII). Since the late 1980ies it has become evident that these proteins are proteolytically processed, intragranularly and/or extracellularly into a range of biologically active peptides; a number of them with regulatory properties of physiological and/or pathophysiological significance. The aim of this comprehensive overview is to provide an up-to-date insight into the distribution and properties of the well established granin-derived peptides and their putative roles in homeostatic regulations. Hence, focus is directed to peptides derived from the three main granins, e.g. to the chromogranin A derived vasostatins, betagranins, pancreastatin and catestatins, the chromogranin B-derived secretolytin and the secretogranin II-derived secretoneurin (SN). In addition, the distribution and properties of the chromogranin A- derived peptides prochromacin, chromofungin, WE14, parastatin, GE-25 and serpinins, the CgB-peptide PE-11 and the SgII-peptides EM66 and manserin will also be commented on. Finally, the opposing effects of the CgA- derived vasostatin-I and catestatin and the SgII-derived peptide SN on the integrity of the vasculature, myocardial contractility, angiogenesis in wound healing, inflammatory conditions and tumors will be discussed.

Concepts: Protein, Amino acid, Wound healing, Physiology, Peptide bond, Peptide, Chromogranin A, Chromogranin

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Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.

Concepts: Epidemiology, Cancer, Diagnosis, Tumor, Neoplasm, Enolase 2, Chromogranin A, Chromogranin

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The objective of present study was to investigate changes in salivary components during restraint to identify potential markers of stress. Pigs were subjected to a nasal snare stress (Experiment 1) or an immobilization stress (Experiment 2) by being enclosed in a steel cage. Saliva was collected before, during and after the stress, respectively. Salivary cortisol, serum amyloid A (SAA), haptoglobin (HP), chromogranin A (CgA), amylase, K(+), Ca(2+) and lactoferrin content were detected. The results showed that in Experiment 1, HP and CgA content increased significantly at 10min during the restraint (P<0.05, P<0.05), in agreement with the significantly increased cortisol and SAA levels (P<0.01, P<0.05), while amylase, K(+) and lactoferrin concentrations did not significantly change. In Experiment 2, salivary HP and CgA concentrations also changed significantly during the restraint (P<0.01, P<0.01), yet cortisol, SAA, amylase, K(+) and lactoferrin levels did not show obvious change. The results confirmed that salivary HP and CgA content may be useful candidate biomarkers to monitor the physical state in pigs during stress.

Concepts: Saliva, Change, English language, Acute-phase protein, Chromogranin A, Salvia divinorum, Serum amyloid A, Chromogranin

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The neuroendocrine glycoprotein chromogranin A is a useful biomarker in humans for neuroendocrine tumors and stress. Chromogranin A can be measured in both blood and saliva. The objective of this study was to investigate concentrations of and correlation between the chromogranin A epitopes catestatin and vasostatin in healthy dogs accustomed to the sample collection procedures. Blood and saliva samples were collected from 10 research Beagle dogs twice daily for 5 consecutive days, and from 33 privately-owned blood donor dogs in association with 50 different blood donation occasions. All dogs were familiar with sample collection procedures. During each sampling, stress behavior was scored by the same observer using a visual analog scale (VAS) and serum cortisol concentrations. Catestatin and vasostatin were analyzed using radioimmunoassays for dogs.

Concepts: HIV, Antibody, Blood, Blood plasma, Blood donation, Blood bank, Chromogranin A, Chromogranin

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Better prognostication of clinically localized prostate cancer (PCA) is urgently needed. Former studies using different study end-points provided controversial results regarding the prognostic value of serum chromogranin A (CGA) in clinically localized PCA. However, serum CGA was not tested for correlation with the most significant study end-point of long-term disease-specific survival (DSS). CGA and matrix metalloproteinase-7 (MMP7) levels were measured by the BRAHMS KRYPTOR in two independent patient groups with 127 serum and 110 plasma samples. CGA and MMP7 concentrations were correlated with clinicopathological and survival data. In addition, we tested the combinations of CGA with PSA and with a currently identified prognostic factor, MMP7, for their prognostic value. CGA concentrations were significantly elevated in advanced compared to clinically localized cases both in serum and plasma samples (45 vs. 23 ng/ml, p < 0.001 and; 41 vs. 22 ng/ml; p = 0.002 respectively). In accordance, high CGA levels were correlated with poor DSS. In clinically localized cases, CGA levels alone were not prognostic, but its dichotomized combinations with PSA or MMP7 were independently associated with DSS (HR: 4.88, 95% CI: 1.35-17.71, p = 0.016, HR: 7.46, 1.65-33.63, p = 0.009, respectively). Elevated serum CGA levels in progressed PCA and its prognostic value suggest a potential for CGA in disease monitoring. Our results revealed no independent prognostic value for CGA as a single serum marker in clinically localized cases. However, when combining with PSA or MMP7, CGA may improve both marker's performance in distinguishing between clinically significant and indolent PCAs.

Concepts: Cancer, Metastasis, Prostate cancer, Correlation and dependence, Prognosis, Chromogranin A, Chromogranin

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The complexity of the clinical management of neuroendocrine neoplasia (NEN), is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies, inter-/intra-facility device variability, and that RECIST (Response Evaluation Criteria in Solid Tumours) criteria are not optimal for NEN. Limitations of currently utilized biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase, pancreastatin), monoanalyte measurements, and lack sensitivity, specificity and predictive capacity. None meet NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n=33) assessed current imaging strategies as well as biomarkers in NEN management. Consensus (>75%) was achieved for 78% of 142 questions. The panel concluded that morphological imaging has diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring disease status and predicting therapeutic efficacy. RECIST remains sub-optimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group concluded that circulating mRNA was a more effective tool than current monoanalyte NEN biomarkers and clinical data were auspicious. It resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumour spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Concepts: Medicine, Cancer, Oncology, Futurology, Tumor, Neoplasm, Efficacy, Chromogranin

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The stress reaction induced by surgery and associated pain may be detrimental for patient recovery and should be minimized. The neuropeptide chromogranin A (CGA) has shown promise as a sensitive biomarker for stress in humans. Little is known about CGA and its derived peptides, catestatin (CST) and vasostatin (VS), in dogs undergoing surgery. The objectives of this study were to investigate and compare concentrations of CGA epitopes CST and VS, cortisol, body temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale (CMPS-SF) and visual analog scales (VAS) for stress and pain behavior in dogs before and after ovariohysterectomy.

Concepts: Blood, Medical signs, Psychometrics, Force, Visual analogue scale, Chromogranin A, Market research, Chromogranin