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PloS One 2018Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision... (Comparative Study)
Comparative Study
BACKGROUND
Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision and radiotherapy remains the mainstay therapy but medical treatments are limited. We explore new drug candidates using computational drug repurposing based on the gene expression signature of atypical meningioma tissue with subsequent analysis of drug-generated expression profiles. We further explore possible mechanisms of action for the identified drug candidates using ingenuity pathway analysis (IPA).
METHODS
We extracted gene expression profiles for atypical meningiomas (12 samples) and normal meningeal tissue (4 samples) from the Gene Expression Omnibus, which were then used to generate a gene signature comprising of 281 differentially expressed genes. Drug candidates were explored using both the Board Institute Connectivity Map (cmap) and Library of Integrated Network-Based Cellular Signatures (LINCS). Functional analysis of significant differential gene expression for drug candidates was performed with IPA.
RESULTS
Using our integrated approach, we identified multiple, already licensed, drug candidates such as emetine, verteporfin, phenoxybenzamine and trazodone. Analysis with IPA revealed that these drugs target signal cascades potentially relevant in pathogenesis of meningiomas, particular examples are the effect on ERK by trazodone, MAP kinases by emetine, and YAP-1 protein by verteporfin.
CONCLUSION
Gene expression profiling and use of drug expression profiles have yielded several plausible drug candidates for treating atypical meningioma, some of which have already been suggested by preceding studies. Although our analyses suggested multiple anti-tumour mechanisms for these drugs, further in vivo studies are required for validation.
IMPORTANCE OF THE STUDY
To our knowledge this is the first study which combines relatively new, yet established computational techniques to identify additional treatments for a difficult to manage cerebral neoplasm. Beyond proposing already approved drug candidates in the management of atypical meningioma the study highlights the promise held by computational techniques in improving our management strategies.
Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Discovery; Drug Repositioning; Drug Screening Assays, Antitumor; Emetine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Meningeal Neoplasms; Meningioma; Metabolic Networks and Pathways; Microarray Analysis; Porphyrins; Systems Integration; Transcriptome; Verteporfin
PubMed: 29558515
DOI: 10.1371/journal.pone.0194701 -
Protein & Cell Mar 2019Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the...
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HTR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HTR and clinically available 5-HTR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDA-approved 5-HTR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.
Topics: Animals; Antiviral Agents; Claudin-1; HEK293 Cells; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Mice; Phenoxybenzamine; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Virus Internalization
PubMed: 29542010
DOI: 10.1007/s13238-018-0521-z -
Oncotarget Oct 2017This retrospective analysis of patients who underwent adrenalectomy for pheochromocytoma aimed to determine preoperative risk factors for intraoperative massive blood...
BACKGROUND
This retrospective analysis of patients who underwent adrenalectomy for pheochromocytoma aimed to determine preoperative risk factors for intraoperative massive blood loss. Preoperative identification of patients at high-risk of massive blood loss may be helpful in anesthesia management and preoperative preparation.
MATERIALS AND METHODS
The study involved data of 268 patients who had undergone pheochromocytoma surgery at the Peking Union Medical College Hospital between January 1, 2013 and October 31, 2016. For analysis, the patients were grouped according to intraoperative blood loss: ≥ 20% of estimated blood volume (group A, 38) and < 20% of estimated blood volume (group B, 230). Perioperative characteristics were compared between the two groups. Significant variables were selected for a forward stepwise binary logistic regression analysis to determine the independent risk factors for massive blood loss.
RESULTS
The two groups showed significant differences in tumor location, tumor size, operative approach, preoperative 24-hour urine level of total noradrenaline, preoperative hemoglobin concentration, phenoxybenzamine maximum daily dose, preoperative preparation time, intraoperative urine volume, crystalloid and colloidal fluid volumes, allogeneic red blood cell transfusion, plasma and autologous blood transfusion volumes, incidence of prolonged hypotension, postoperative drainage volume, lowest and discharge hemoglobin concentrations, length of stay in intensive care unit and length of postoperative hospitalization. Binary logistic regression analysis indicated increased risk of intraoperative massive blood loss in subjects with tumors proximal to vessels or other organs (odds ratio (OR): 4.227), with tumors ≥ 5 cm (OR: 7.321), or with preoperative preparation time of ≤ 14 days (OR: 17.747).
CONCLUSIONS
Tumors proximal to vessels and other organs or with maximum diameter of ≥ 5 cm (as shown by preoperative radiographic evidence), and preoperative preparation time of ≤ 14 days were independent risk factors of intraoperative massive blood loss in patients treated with adrenalectomy for pheochromocytoma.
PubMed: 29108378
DOI: 10.18632/oncotarget.20396 -
Frontiers in Physiology 2017Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine...
Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine operate analogously to epinephrine and norepinephrine in the vertebrates. Octopamine and tyramine bind to G-protein coupled receptors (GPCRs) leading to changes in second messenger levels and thereby modifying the function in target tissues and insect behavior. In this paper, we report the cDNA sequences of two GPCRs, RhoprOctβ2-R, and RhoprTyr1-R, have been cloned and functionally characterized from . Octopamine and tyramine each activate RhoprOctβ2-R and RhoprTyr1-R in a dose-dependent manner. Octopamine is one order of magnitude more potent than tyramine in activating RhoprOctβ2-R. Tyramine is two orders of magnitude more potent than octopamine in activating RhoprTyr1-R. Phentolamine and gramine significantly antagonize RhoprOctβ2-R, whereas yohimbine and phenoxybenzamine are effective blockers of RhoprTyr1-R. The transcripts of both receptors are enriched in the central nervous system (CNS) and are expressed throughout the adult female reproductive system. It has been shown in other insects that Octβ2-R is essential for processes such as ovulation and fertilization. We previously reported that octopamine and tyramine modulate oviducts and bursa contractions in . Our data confirm the importance of octopamine and tyramine signaling in the reproductive system of .
PubMed: 29018364
DOI: 10.3389/fphys.2017.00744 -
Endocrine Connections Nov 2017Preoperative preparation for adrenalectomy for pheochromocytomas and paragangliomas (PPGL) is universally recognized as necessary, while the optimal strategy remains...
PURPOSE
Preoperative preparation for adrenalectomy for pheochromocytomas and paragangliomas (PPGL) is universally recognized as necessary, while the optimal strategy remains controversial. Our aims were to increase intraoperative hemodynamic stability, expedite postoperative recovery, decrease side effects and reduce costs for patients with PPGL undergoing adrenalectomy.
METHODS
We identified 526 patients undergoing open adrenalectomy for PPGL in the West China Hospital of Sichuan University between May, 2007 and December, 2016. 149 patients received preoperative selective α-blockade with phenoxybenzamine, and 377 patients received non-selective α-blockade with prazosin, doxazosin or terazosin. There were no statistical differences between groups regarding preoperative patient and tumor characteristics. Operations were planned once hypertensive patients were well-controlled with blood pressure ≤130/85 mmHg. Intraoperatively, all patients received arterial blood pressure monitoring, and indwelling urinary catheters to record urine output. We recorded intraoperative hemodynamics, status in the postanesthesia or intensive care unit, postoperative recovery and complications.
RESULTS
Patients in the non-selective group showed a more significant decline in postoperative systolic blood pressure than the selective group ( = 0.041). Also, patients in the non-selective group appeared to receive a long-term anti-hypertensive effect, especially for diastolic blood pressure ( = 0.037), which was a novel finding, based on the current literature.
CONCLUSIONS
Our results confirmed that non-selective α-blockade produced a more significant anti-hypertensive effect than selective α-blockade. However, we found no significant difference in intraoperative hemodynamic instability, postoperative recovery and postoperative complications between groups.
PubMed: 28986400
DOI: 10.1530/EC-17-0232 -
International Journal of Surgery... Oct 2017To describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with...
INTRODUCTION
To describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with patients who had phenoxybenzamine (PBZ) pretreatment.
METHODS
Retrospective review of perioperative outcomes for PCC/PGL patients treated with MET and propensity-matched comparison of MET and PBZ (MET + PBZ) with PBZ alone.
RESULTS
MET preparation was given in 63 cases (26 laparoscopic and 37 open, of which 55 also received PBZ). All patients had wide perioperative hemodynamic oscillations. Patients with open procedures required more intravenous fluids and blood transfusions; 35% required postoperative vasopressor infusions for hypotension and 38% developed acute kidney injury. One laparoscopic procedure required postoperative vasopressor infusion, and 12% of patients developed acute kidney injury. Forty-five MET + PBZ patients were propensity-matched with PBZ-only patients. Intraoperatively, MET + PBZ patients had lower minimum systolic and diastolic blood pressures than PBZ-only patients (median systolic, 74 vs 80 mm Hg, P = 0.01; median diastolic, 42 vs 46 mm Hg, P = 0.005) and larger intraoperative blood pressure oscillations (median systolic range, 112 vs 93 mm Hg, P = 0.06; median diastolic range, 58 vs 51 mm Hg, P = 0.02). Postoperative vasopressor infusion use was similar between MET + PBZ and PBZ only (16% vs 11%, P = 0.76). Major outcomes were not different between regimens.
CONCLUSION
Large hemodynamic oscillations were present in our PCC/PGL patients treated with MET + PBZ. These patients had a wider range of intraoperative blood pressure variations than PBZ-only patients. No differences in postoperative comorbid outcomes were found between MET + PBZ and PBZ-only groups.
Topics: Adrenal Gland Neoplasms; Adult; Blood Pressure; Drug Therapy, Combination; Enzyme Inhibitors; Female; Hemodynamics; Humans; Intraoperative Period; Laparoscopy; Male; Middle Aged; Paraganglioma; Phenoxybenzamine; Pheochromocytoma; Postoperative Period; Propensity Score; Retrospective Studies; Treatment Outcome; Vasoconstrictor Agents; alpha-Methyltyrosine
PubMed: 28803996
DOI: 10.1016/j.ijsu.2017.08.026 -
Frontiers in Pediatrics 2017Pheochromocytoma (PCC) and paraganglioma (PGL) are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors.... (Review)
Review
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors. Although a rare cause of secondary hypertension in pediatrics, the presentation of hypertension in these patients is characteristic, and treatment is definitive. The gold standard for diagnosis is measurement of plasma free metanephrines, with imaging studies performed for localization, identification of metastatic lesions and for surgical resection. Preoperative therapy with alpha-blocking agents, beta blockers, and potentially tyrosine hydroxylase inhibitors aid in a safe pre-, intra- and postoperative course. PCC and PGL are inherited in as much as 80% of pediatric cases, and all patients with mutations should be followed closely given the risk of recurrence and malignancy. While the presentation of chromaffin cell tumors has been well described with multiple endocrine neoplasia, NF1, and Von Hippel-Lindau syndromes, the identification of new gene mutations leading to chromaffin cell tumors at a young age is changing the landscape of how clinicians approach such cases. The paraganglioma-pheochromocytoma syndromes (SDHx) comprise familial gene mutations, of which the SDHB gene mutation carries a high rate of malignancy. Since the inheritance rate of such tumors is higher than previously described, genetic screening is recommended in all patients, and lifelong follow-up for recurrent tumors is a must. A multidisciplinary team approach allows for optimal health-care delivery in such children. This review serves to provide an overview of pediatric PCC and PGL, including updates on the preferred methods of imaging, guidelines on gene testing as well as management of hypertension in such patients.
PubMed: 28752085
DOI: 10.3389/fped.2017.00155 -
Kardiologia Polska 2017Adrenalectomy with preoperative pharmacological preparation is strongly recommended in patients diagnosed with pheochromocytoma, in order to prevent perioperative... (Comparative Study)
Comparative Study
BACKGROUND
Adrenalectomy with preoperative pharmacological preparation is strongly recommended in patients diagnosed with pheochromocytoma, in order to prevent perioperative complications.
AIM
To compare phenoxybenzamine (PhB) and doxazosin (DOX) in terms of perioperative haemodynamic status in patients with pheochromocytoma, who have been prepared for adrenalectomy.
METHODS
Retrospective analysis of 44 patients with pheochromocytoma (aged 16-80 years, 29 females) who underwent adrenalectomy. Patients were divided into two groups: 35 patients on DOX and nine patients on PhB.
RESULTS
Mean time of preparation for surgery was 38.8 days in the DOX group and 18.3 days in the PhB group (p = 0.04). No statistically significant differences between the DOX and PhB groups in intraoperative blood pressure (BP) fluctuations were found: < 170/100 mm Hg (34% vs. 44%, respectively, p = 0.42), ≥ 200/110 mm Hg (40% vs. 22%, respectively, p = 0.28). Mean greatest intraoperative systolic BP (195 ± 53 vs. 166 ± 42 mm Hg, p = 0.21) and diastolic BP (98 ± 20 vs. 89 ± 46 mm Hg, p = 0.21), and mean lowest intraoperative systolic BP (87 ± 13 vs. 79 ± 17 mm Hg, p = 0.25) and diastolic BP (49 ± 8 vs. 46 ± 12 mm Hg, p = 0.60) were not different between the DOX and PhB groups, respectively. Sodium nitroprusside was administrated in 30% DOX vs. 11% PhB patients (p = 0.25). Laparoscopic surgery was conducted in 97% DOX vs. 89% PhB patients (p = 0.64). Postoperative BP drop below 90/60 mm Hg was noted in 48% of the DOX vs. 43% of the PhB group (p = 0.56). Negative correlation was found between the length of DOX administration with maximal intraoperative systolic BP (r = -0.45, p = 0.006) and diastolic BP (r = -0.39, p = 0.019).
CONCLUSIONS
There are no clinically relevant differences between patients with pheochromocytoma, who have been prepared for adrenalectomy with DOX or PhB.
Topics: Adrenalectomy; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Disease Management; Doxazosin; Female; Humans; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Postoperative Complications; Prohibitins; Retrospective Studies; Young Adult
PubMed: 28715066
DOI: 10.5603/KP.a2017.0147 -
Frontiers in Pharmacology 2017Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor consists of the...
Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of Akrinor and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings. Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37°C. CGP 20712A and ICI 118,551 were used to elaborate β- and β-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction. Clinically relevant concentrations of Akrinor (4.2-420 mg/l) robustly increased force in human atrial trabeculae (EC 41 ± 3 mg/l). This direct sympathomimetic action was mediated via β-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of Akrinor increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of Akrinor (4.2-168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC 6.18 ± 0.08 to 5.23 ± 0.05 M. Akrinor increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an α-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of Akrinor differs from noradrenaline and norephedrine . We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of Akrinor.
PubMed: 28588484
DOI: 10.3389/fphar.2017.00272 -
British Journal of Pharmacology Aug 2017Mirabegron has been classified as a β -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the...
BACKGROUND AND PURPOSE
Mirabegron has been classified as a β -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers.
EXPERIMENTAL APPROACH
Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37°C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), β (L-748,337), β (CGP 20712A), β (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine.
KEY RESULTS
Mirabegron significantly increased contractile force in human right atrium (1 μM, 7.6 ± 2.6%, n = 7; 10 μM, 10.2 ± 1.5%, n = 22 compared with (-)-isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 μM) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 μM). In contrast, mirabegron (10 μM) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 μM) also reduced contractile force in the presence of desipramine or phenoxybenzamine.
CONCLUSIONS AND IMPLICATIONS
Mirabegron increases human atrial force through β - but not β -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through β (or β )-adrenoceptors, consistent with lack of β -adrenoceptor function on human atrial contractility.
Topics: 1-Methyl-3-isobutylxanthine; Acetanilides; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aged; Atrial Function; Female; Heart Atria; Humans; Imidazoles; In Vitro Techniques; Male; Middle Aged; Myocardial Contraction; Propanolamines; Receptors, Adrenergic, beta; Thiazoles
PubMed: 28574581
DOI: 10.1111/bph.13897