39 research outputs found
Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization
Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei
GMP-compliant radiosynthesis of [F]GP1, a novel PET tracer for the detection of thrombi
Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific F-labeled small-molecule radiotracer that binds with high affinity to GPIIb/IIIa receptors of activated platelets. An improved, robust and fully automated radiosynthesis of [F]GP1 has been developed. [F]GP1 has been synthesized with decay corrected radiochemical yields of 38 6%, with a radiochemical concentration up to 1900 MBq/mL, molar activities of 952–9428 GBq/mol and a radio-chemical purity >98%. After determination of the optimal reaction conditions, in particular for HPLC separation, adaption of the reaction conditions to PET center requirements, validation of the manufacturing process and the quality control methods, the synthesis of [F]GP1 was successfully implemented to GMP standards and was available for clinical application. We describe the GMP-compliant synthesis of the novel radiotracer [F]GP1. Moreover, we provide some proof-of-concept examples for clinical application in the cardiovascular field. PET/CT with the novel small-molecular radiotracer [18F]GP1 may serve as a novel highly sensitive tool for visualizing active platelet aggregation at the molecular level
The combined human genotype of truncating and mutations is associated with severe and early onset of dilated cardiomyopathy
A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them and . Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in (tv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 () are also known to be associated with severe cardiomyopathies. is one of the major splicing targets. Most of the pathogenic mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant . Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic and mutations. We show that the splicing of target genes is affected in the mutation carrier. Furthermore, we reveal haploinsufficiency presumably caused by the frameshift mutation in
High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous -gene mutation
Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the and genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous -missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age
Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCNlow Neuroblastoma
An Insight into Suspension Plasma Spray: Injection of the Suspension and Its Interaction with the Plasma Flow
Ric-3 chaperone-mediated stable cell-surface expression of the neuronal α7 nicotinic acetylcholine receptor in mammalian cells
Aim: Studies of the α7-type neuronal nicotinic acetylcholine receptor (AChR), one of the receptor forms involved in many physiologically relevant processes in the central nervous system, have been hampered by the inability of this homomeric protein to assemble in most heterologous expression systems. In a recent study, it was shown that the chaperone Ric-3 is necessary for the maturation and functional expression of α7-type AChRs 1. The current work aims at obtaining and characterizing a cell line with high functional expression of the human α7 AChR. Methods: Ric-3 cDNA was incorporated into SHE-P1-hα7 cells expressing the α7-type AChR. Functional studies were undertaken using single-channel patch-clamp recordings. Equilibrium and kinetic [ 125 I;[alpha;-bungarotoxin binding assays, as well as fluorescence microscopy using fluorescent α-bungarotoxin, anti-α7 antibody, and GFP-α7 were performed on the new clone. Results: The human α7-type AChR was stably expressed in a new cell line, which we coined SHE-P1-hα7-Ric-3, by co-expression of the chaperone Ric-3. Cell-surface AChRs exhibited [ 125 I;[alpha;BTX saturable binding with an apparent K D of about 55 nmol/L. Fluorescence microscopy revealed dispersed and micro-clustered AChR aggregates at the surface of SHE-P1-hα7-Ric-3 cells. Larger micron-sized clusters were observed in the absence of receptor-clustering proteins or upon aggregation with anti-α7 antibodies. In contrast, chaperone-less SHE-P1-hα7 cells expressed only intracellular α7 AChRs and failed to produce detectable single-channel currents. Conclusion: The production of a stable and functional cell line of neuroepithelial lineage with robust cell-surface expression of neuronal α7-type AChR, as reported here, constitutes an important advance in the study of homomeric receptors in mammalian cells.Fil: Valles, Ana Sofia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca. Universidad Nacional del Sur. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca; Argentina. Unesco; ArgentinaFil: Roccamo, Ana Maria. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca. Universidad Nacional del Sur. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca; Argentina. Unesco; ArgentinaFil: Barrantes, Francisco Jose. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca. Universidad Nacional del Sur. Instituto de Investigaciones BioquĂmicas de BahĂa Blanca; Argentina. Unesco; Argentin