Exploring the biology of vascular calcification in chronic kidney disease: What's circulating?

Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium × phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or ‘damage’ of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients

Effect of anti-osteoporotic treatments on circulating and bone microRNA patterns in osteopenic ZDF rats

Bone fragility is an adverse outcome of type 2 diabetes mellitus (T2DM). The underlying molecular mechanisms have, however, remained largely unknown. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression in health and disease states. The aim of this study was to investigate the genome-wide regulation of miRNAs in T2DM bone disease by analyzing serum and bone tissue samples from a well-established rat model of T2DM, the Zucker Diabetic Fatty (ZDF) model. We performed small RNA-sequencing analysis to detect dysregulated miRNAs in the serum and ulna bone of the ZDF model under placebo and also under anti-sclerostin, PTH, and insulin treatments. The dysregulated circulating miRNAs were investigated for their cell-type enrichment to identify putative donor cells and were used to construct gene target networks. Our results show that unique sets of miRNAs are dysregulated in the serum (n = 12, FDR < 0.2) and bone tissue (n = 34, FDR < 0.2) of ZDF rats. Insulin treatment was found to induce a strong dysregulation of circulating miRNAs which are mainly involved in metabolism, thereby restoring seven circulating miRNAs in the ZDF model to normal levels. The effects of anti-sclerostin treatment on serum miRNA levels were weaker, but affected miRNAs were shown to be enriched in bone tissue. PTH treatment did not produce any effect on circulating or bone miRNAs in the ZDF rats. Altogether, this study provides the first comprehensive insights into the dysregulation of bone and serum miRNAs in the context of T2DM and the effect of insulin, PTH, and anti-sclerostin treatments on circulating miRNAs

Pheochromocytoma - update on disease management

Contains fulltext : 109049.pdf (publisher's version ) (Open Access)Pheochromocytomas are rare endocrine tumors that can present insidiously and remain undiagnosed until death or onset of clear manifestations of catecholamine excess. They are often referred to as one of the 'great mimics' in medicine. These tumors can no longer be regarded as a uniform disease entity, but rather as a highly heterogeneous group of chromaffin cell neoplasms with different ages of onset, secretory profiles, locations, and potential for malignancy according to underlying genetic mutations. These aspects all have to be considered when the tumor is encountered, thereby enabling optimal management for the patient. Referral to a center of specialized expertise for the disease should be considered wherever possible. This is not only important for surgical management of patients, but also for post-surgical follow up and screening of disease in patients with a hereditary predisposition to the tumor. While preoperative management has changed little over the last 20 years, surgical procedures have evolved so that laparoscopic resection is the standard of care and partial adrenalectomy should be considered in all patients with a hereditary condition. Follow-up testing is essential and should be recommended and ensured on a yearly basis. Managing such patients must now also take into account possible underlying mutations and the appropriate selection of genes for testing according to disease presentation. Patients and family members with identified mutations then require an individualized approach to management. This includes consideration of distinct patterns of biochemical test results during screening and the appropriate choice of imaging studies for tumor localization according to the mutation and associated differences in predisposition to adrenal, extra-adrenal and metastatic disease

[Diagnosis of pheochromocytoma and paraganglioma: the clonidine suppression test in patients with borderline elevations of plasma free normetanephrine]

Item does not contain fulltextBACKGROUND: Measurements of plasma free metanephrines provide a sensitive test for the diagnosis of pheochromocytoma/paraganglioma (P/PGL), with highly elevated levels diagnostic of the disease. However, there is less diagnostic certainty in patients with mild elevations of these catecholamine metabolites. PATIENTS AND METHODS: Here we report use of the clonidine suppression test (CST) as a second-tier diagnostic test in 24 patients with mild elevations of plasma free metanephrines and/or catecholamines. Blood samples before and 3 hours after clonidine were analyzed for plasma concentrations of metanephrines and catecholamines with a negative test result defined as either a clonidine-induced fall in normetanephrine or noradrenaline by more than 40 % and 50 % respectively or to below the upper cut-offs of reference intervals. RESULTS: P/PGLs were confirmed in 9 patients and excluded in 15 by independent criteria. More than half of the patients without P/PGL showed normalized plasma concentrations of normetanephrine at baseline before clonidine compared to initial screening; all showed appropriate clonidine-induced falls in normetanephrine and noradrenaline or levels after the drug below upper cut-offs, indicating a diagnostic specificity of 100 % (CI 78-100 %). However, similar responses for noradrenaline were noted in 7 patients with P/PGL, indicating a diagnostic sensitivity of only 22 % (CI 2,8-60 %) compared to 100 % (CI 66-100 %) for normetanephrine. CONCLUSION: These results support use of the CST in combination with measurements of normetanephrine for confirming or excluding P/PGL in patients with borderline elevated test results, which should, however, first be confirmed by sampling blood under standardized resting conditions

Serum Profile of microRNAs Linked to Bone Metabolism during Sequential Treatment for Postmenopausal Osteoporosis

Context: Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. Objective: To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. Design: Observational, open label, nonrandomized clinical trial. Setting: A single-center outpatient clinic. Patients and Interventions: Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). Main Outcome Measures: Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. Results: Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P &lt; 0.001) and 6 months (FC 0.34, P &lt; 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P &lt; 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P &lt; 0.001, respectively) and 6 months (FC 0.1, P &lt; 0.001; FC 0.52, P &lt; 0.001; FC 0.04, P = 0.006; and FC 0.2, P &lt; 0.001, respectively) only within the TPTD group. Conclusions: TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction. © 2020 Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected]

Oncologic Resection Achieving R0 Margins Improves Disease-Free Survival in Parathyroid Cancer

Background: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. Methods: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ 2 testing and Kaplan-Meier statistics. Results: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ 2 = 5.6; p &lt; 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (χ 2 = 8.1; p &lt; 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (χ 2 = 7.9; p = 0.005 and χ 2 = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients. Conclusions: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence

Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis

Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80+CD206+) were identified in PCa bone resident tumors in mice. Induced M2-like macrophages in vitro were more proficient at phagocytosis (efferocytosis) of apoptotic tumor cells than M1-like macrophages. Moreover, soluble factors released from efferocytic versus nonefferocytic macrophages increased PC-3 prostate cancer cell numbers in vitro. Trabectedin exposure reduced M2-like (F4/80+CD206+) macrophages in vivo. Trabectedin administration after PC-3 cell intracardiac inoculation reduced skeletal metastatic tumor growth. Preventative pretreatment with trabectedin 7 days prior to PC-3 cell injection resulted in reduced M2-like macrophages in the marrow and reduced skeletal tumor size. Together, these findings suggest that M2-like monocytes and macrophages promote PCa skeletal metastasis and that trabectedin represents a candidate therapeutic target