Circulating Chromogranin B Is Associated With Left Ventricular Functional Recovery After Successful Recanalization of Chronic Total Occlusion

Background: Chromogranin B (CgB) is increased in heart failure and proportionate to disease severity. We investigated whether circulating CgB level is associated with left ventricular (LV) functional recovery potential after successful recanalization of chronic total occlusion (CTO).Methods: Serum levels of CgB were assayed in 53 patients with stable angina with LV functional recovery [an absolute increase in LV ejection fraction (EF) of ≥5%] and 53 age- and sex-matched non-recovery controls after successful recanalization of CTO during 12-month follow-up.Results: We found that CgB level was significantly lower in the recovery group than in the non-recovery group (593 [IQR 454–934] vs. 1,108 [IQR 696–2020] pg/ml, P < 0.001), and that it was inversely correlated with changes in LVEF (Spearman's r = −0.31, P = 0.001). Receiver operating characteristic (ROC) analysis showed that the area under the curve of CgB for predicting LVEF improvement was 0.76 (95% CI 0.664–0.856), and that the optimal cutoff value was 972.5 pg/ml. In multivariate analyses, after adjusting for confounding factors, high CgB level remained an independent determinant of impaired LV functional recovery after CTO recanalization. LV functional improvement appeared to be more responsive to CgB in patients with poor than with good coronary collaterals.Conclusions: Elevated circulating CgB level confers an increased risk of impaired LV functional recovery after successful recanalization of CTO in patients with stable coronary artery disease.

Activation of Gαq sequesters specific transcripts into Ago2 particles

Hormones and neurotransmitters can activate the Gαq / phospholipase Cβ1 (PLCβ1) signaling system eliciting cellular calcium responses. PLCβ1 also prevents the aggregation of ribosomal and RNA proteins into stress granules, which are halted translation complexes that form in response to cellular stress. Activation of Gαq promotes PLCβ1association releasing bound proteins and promoting the formation of stress granules. However, the cellular impact of stress granules formed from routine Gαq protein signaling is unknown. Here, we have characterized Ago2 stress granules formed in response to Gαq activation in a neuronal-like cell line. We find these stress granule have a distinct protein composition, and unlike stress granules formed under heat stress, contain only two mRNA transcripts, chromogranin B, which is involved in secretory function, and ATP synthase 5f1b, which is required for ATP synthesis. Our studies show an unexpected pathway where Gαq/PLCβ regulates the translation of specific proteins.

Acromegaly in a Young Women With Pituitary Hyperplasia Secondary to a Neuroendocrine Tumor

Acromegaly is rarely due to an excess of the GH-releasing hormone (GHRH) and pituitary hyperplasia on histology should alert to its presence. Clinical Case: A 35-year-old was referred to surgery with a confirmed diagnosis of symptomatic acromegaly. Her GH failed to suppress during an oral glucose tolerance test (OGTT), her IGF-1 and prolactin was high. Her serum calcium was normal and her chromogranin B was high. MRI scan suggested microadenoma. Her surgery was deferred because of Covid 19, and she was treated with somatostatin analog (SSA). She finally had surgery in July. The histology and immunocytochemistry suggested pituitary hyperplasia with diffuse positivity for chromogranin and synaptophysin. GH was positive in the majority of the cells with many cells positive for Prolactin and ACTH. FSH and LH were positive in scattered cells with patchy positivity of TSH. A solitary nodule was noted in her neck during an examination. We arranged to look for conditions associated with pituitary hyperplasia resulting in GHRH production, including the genetic tests for inherited conditions. Her calcitonin level was normal. She had an ultrasound scan guided fine needle aspiration of the thyroid nodule, this showed Thy3f oncocytic nodule with no features of medullary thyroid carcinoma. She had an NMGa68DOTATATE whole body PET CTand the scan showed a large DOTATAE avid mass from the right adrenal gland compatible with Pheochromocytoma. Her 24 hours total urinary metadrenaline and normetadrenalin was high. Her genetic test for MEN1, CDKN1B, and MEN2 are negative. We have requested the GHRH measurement. After a pituitary surgery, her GH suppressed adequately on OGTT. Her IGF-1 and prolactin is low and her hypogonadism is resolved. Conclusion: Excess production GHRH can result from neuroendocrine tumors of the lung, pancreas, thyroid (medullary thyroid cancer), or pheochromocytomas and hypothalamic gangliocytomas. Several familial syndromes, multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA), Carney complex, and sporadic germline mosaic disorder McCune-Albright disease predispose to pituitary hyperplasia. GHRH acromegaly should be suspected in a patient with biochemical/clinical features of acromegaly in the presence of co-existing neuroendocrine tumors when there is diffuse pituitary enlargement on imaging or resolution of acromegaly after the surgical resection of the primary neuroendocrine tumour or persistent acromegaly after surgery if there is histological evidence of somatotroph hyperplasia. References: Akirov A, ASA SL, AMER L Shimon I and Ezzat S. The clinicopathological spectrum of acromegaly. J. Clin. Med. 8(11), 1962 (2019) J. Clin. Med. 2019; 8: 11, 1962

Histopathological Chromogranin A-Positivity Is Associated with Right-Sided Colorectal Cancers and Worse Prognosis

Background: Colorectal cancer (CRC) is known to be affected by paraneoplastic thrombocytosis and chromogranin A-positive neuroendocrine-cell differentiation (CgA+). Their combined effect has never been previously investigated. Methods: A prospective cohort pilot study of 42 CRC patients and 42 age- and sex-matched controls was carried out. Plasma interleukin-6, thrombopoietin, and serum chromogranin A and -B were measured; furthermore, tumor tissue was immunohistochemically stained for CgA+. Results: Twenty-seven and 15 patients were assigned to the chromogranin A-negative (CgA−) and CgA+ groups, respectively. Within the CgA+ group, right-sided tumors were more frequent (18.5% vs. 53.3%), no stage I cancer was found, and patients of this group were in worse general condition. Compared to control subjects, chromogranin A level was higher in the CgA+ group (p = 0.0086), thrombopoietin (p = 0.0040) and chromogranin B (p = 0.0070) in the CgA− group, while interleukin-6 was high in both tumor groups (p ≤ 0.0090). Survival was significantly worse in the CgA+ group (hazard ratio: 5.73; p = 0.0378). Conclusions: Different thrombopoietin levels indicated distinct thrombocytosis types. Within the two CRC groups, serum levels of chromogranins changed in different directions suggesting two well-distinguishable pathophysiologies. Based on these observations we propose a new subtype of CRC, which can be characterized by chromogranin A-positive neuroendocrine-cell differentiation.

Chromogranin B is associated with impaired coronary collateralization and heart failure in patients with stable angina and chronic total occlusion

Background Chromogranin B (CgB) is a member of granin family that can be cleaved into a number of bioactive peptides. Previous studies showed that CgB is produced in cardiomyocytes and is increased in heart failure animals and patients in proportion to disease severity. Chronic total occlusion (CTO) of coronary artery leads to sustained myocardial ischemia which predisposes to adverse cardiovascular outcomes including heart failure. Purpose In this study, we sought to investigate the association between CgB and coronary collateralization formation and heart failure in patients with stable angina and CTO. Methods A total of 720 subjects with stable angina and CTO of at least one major coronary artery were enrolled in this study. CgB was assayed using an ELISA kit and the degree of coronary collaterals supplying the distal aspect of a total occlusion from the contralateral vessel was graded according to Rentrop classification. Results These was a stepwise decrease in levels of CgB with increasing Rentrop grades of coronary collateralization (P=0.001). Compared with the good collateralization (Rentrop grade 2–3) group, CgB was significantly higher in subjects with poor coronary collateralization (Rentrop grade 0–1; 1222.95 [IQR 506.24–2710.24] pg/mL vs. 776.17 [IQR 276.24–2209.39] pg/mL, P<0.001). Consistent results were found across subgroups of age, sex and the presence of diagnosed diabetes. In subjects with poor collateralization, CgB was positively correlated to N-terminal–pro-brain natriuretic peptide (NT-proBNP) levels (both log-transformed; Pearson's r=0.280, P=0.005). This correlation was markedly enhanced (Pearson's r=0.501, P<0.001) in the poorly-collateralized heart failure subgroup with left-ventricular ejection fraction (LVEF) <50%. Consistently, an inverse correlation was present between log-transformed CgB and LVEF (Pearson's r=−0.528, P<0.001) in the same subgroup. After adjusting for conventional confounding factors and LVEF, CgB remained significantly associated with impaired coronary collateralization (odds ratio: 1.314 [95% CI 1.097–1.590], P=0.004). Inclusion of CgB led to a better diagnostic accuracy as confirmed by net reclassification improvement (NRI) of 17.70% (95% CI 8.08–27.32%, P<0.001) and integrated discrimination improvement (IDI) of 1.98% (95% CI 0.63–3.34%, P=0.004). Conclusions CgB is an independent predictor of poor coronary collateralization and is related to worse heart function in patients with stable angina and CTO. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China

Promising immunohistochemical and circulating markers of insulinoma

Insulinoma is the most common functioning pancreatic neuroendocrine tumor. The review examines the currently used immunohistochemical and circulating markers for its diagnosis, and discusses the sensitivity and specificity of these parameters. At the same time, the relevance of searching for new biochemical indicators of the presence of insulinoma and its characteristics, as well as studying the mechanisms of tumor growth and hormonal hypersecretion is emphasized. One of the primary methods for solving these problems is immunohistochemical testing with the determination of circulating markers. The results of recent studies of alternative secretory products, in particular, cocaine - and amphetamine - regulated transcript (CART), chromogranin B, and neuroendocrine secretory protein 55 (NESP55) are presented. In addition, the question of expression of various receptors in the insulinoma tissue is considered, including in the context of determining molecular targets for its visualization or radiotherapy. In particular, the expression of receptors for glucagon-like peptide 1 in the tumor tissue is characterized. The possible role of melatonin receptors MT1 (MTNR1a) and MT2 (MTNR1b) in the pathogenesis of insulinoma is clarified. The article also discusses the possible use of tumor protein D52 (TPD52) as a new predictive biomarker for the differential diagnosis of benign and malignant insulinoma.

Chromogranin A and chromogranin B in pancreatic neuroendocrine tumors

For the first time in Russia a comparative study of chromogranin A (CgA) and chromogranin B (CgB) in neuroendocrine tumors (NETs) of the pancreas was performed. We examined 50 primary patients with pancreatic NETs and 42 healthy people. The determination of CgA and CgB was performed in blood serum using standard enzyme-linked immunoassay test-systems (Chromogranin A NEOLISA, Eurodiagnostica; Human Chromogranin B, USCN). The levels of CgA and CgB in pancreatic NETs significantly differed from the control group. There was found the association between CgA levels and the dissemination of the process, while CgB demonstrated the properties of a marker independent from the tumor dissemination. The diagnostic sensitivity of CgA was 76 %, CgB – 68 %. Complex determination of CgA and CgB enhanced the diagnostic sensitivity to 84 %. Our data indicate the potential usefulness of complex CgA and CgB in the diagnosis of pancreatic NETs.

A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles

In recent years erythropoietin (EPO) has emerged as a useful neuroprotective and neurotrophic molecule that produces antidepressant and cognitive enhancing effects in psychiatric disorders. However, EPO robustly induces erythropoiesis and elevates red blood cell counts. Chronic administration is therefore likely to increase blood viscosity and produce adverse effects in non-anemic populations. Carbamyolated erythropoietin (CEPO), a chemically engineered modification of EPO, is non-erythropoietic but retains the neurotrophic and neurotrophic activity of EPO. Blood profile analysis after EPO and CEPO administration showed that CEPO has no effect on red blood cell or platelet counts. We conducted an unbiased, quantitative, mass spectrometry-based proteomics study to comparatively investigate EPO and CEPO-induced protein profiles in neuronal phenotype PC12 cells. Bioinformatics enrichment analysis of the protein expression profiles revealed the upregulation of protein functions related to memory formation such as synaptic plasticity, long term potentiation (LTP), neurotransmitter transport, synaptic vesicle priming, and dendritic spine development. The regulated proteins, with roles in LTP and synaptic plasticity, include Neudesin, Chromogranin b, Cortactin, Elongation initiation factor 3a and Proteasome 26s subunit, ATPase. We examined the expression of a subset of regulated proteins by immunohistochemical analysis in mouse brain. The results of our study sheds light on potential mechanisms whereby EPO and CEPO produce cognitive enhancing effects in clinical and preclinical studies.