BACKGROUND
To ensure that immunoglobulin (Ig) products have adequate functional antibody, the US Food and Drug Administration (FDA) requires that Ig lots contain minimum levels of measles ...neutralizing antibody; the current minimum is 0.48 x US Reference Ig 176.
STUDY DESIGN AND METHODS
In the first part of the study, measles antibody titers were measured in donor plasma samples collected in 2007, 2011, and 2017. In the second part, trough or steady‐state serum levels of measles neutralizing antibody were measured in two studies of patients with primary immunodeficiency (PID) who were treated with intravenous (Study 1; N = 46) or subcutaneous (Study 2; N = 18) Ig replacement therapy, meeting previous requirements for lot potency (≥0.6 x US Reference Ig 176). Serum measles neutralizing antibody titers were then estimated for conditions in which the potency of the Ig replacement product was 0.48 or 0.30 x US Reference Ig 176.
RESULTS
Measles antibody titers in donated plasma samples declined in donors born after 1963. In the two studies of patients with PID who were treated with intravenous or subcutaneous Ig replacement therapy, all patients exhibited trough (intravenous Ig) or steady‐state (subcutaneous Ig) measles neutralizing antibody titers above 0.12 IU/mL, which has been shown to protect against clinical measles in the general population. Estimates suggest that all patients except one would have continued to meet this standard if the Ig lot potency had been 0.48 or 0.30 x US Reference Ig 176.
CONCLUSION
These studies provide supporting evidence that the lot release specification can be safely lowered from 0.48 to 0.30 x US Reference Ig 176, which will accommodate declining measles neutralizing antibody levels in donor plasma.
Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade ...controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%–20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
Pathogenic germline
DICER1
variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense
DICER1
variants in the ...RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline
DICER1
pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with
DICER1
variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in
ARID1B
was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic
DICER1
variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.
We reconstruct recent work on macrosocial stress (Chou, Parmar, & Galinsky,
2016
) as if it were an instance of a research strategy that tests point-alternative hypotheses within a full-fledged ...research program. Because this strategy is free of various deficits that beset dominant strategies (e.g., meta-analysis, Bayes factor analysis), our article demonstrates one way in which the confidence crisis may be overcome.
Thimet oligopeptidase (THOP) is a cytosolic metallopeptidase known to regulate the fate of post-proteasomal peptides, protein turnover and peptide selection in the antigen presentation machinery ...(APM) system. Oxidative stress influences THOP expression and regulates its proteolytic activity, generating variable cytosolic peptide levels, possibly affecting the immune evasion of tumor cells. In the present work, we examined the association between THOP expression/activity and stress oxidative resistance in human leukemia cells using the K562 cell line, a chronic myeloid leukemia (CML), and the multidrug-resistant (MDR) Lucena 1 (K562-derived MDR cell line) as model. The Lucena 1 phenotype was validated under vincristine treatment and the relative THOP1 mRNA levels and protein expression compared to K562 cell line. Our data demonstrated increased THOP1 gene and protein levels in K562 cells in contrast to the oxidative-resistant Lucena 1, even after H2O2 treatment, suggesting an oxidative stress dependence in THOP regulation. Further, it was observed higher basal levels of reactive oxygen species (ROS) in K562 compared to Lucena 1 cell line using DHE fluorescent probe. Since THOP activity is dependent on its oligomeric state, we also compared its proteolytic activity under reducing agent treatment, which demonstrated that its function modulation with respect to changes in redox state. Finally, the mRNA expression and FACS analyses demonstrated a reduced expression of MHC I only in K562 cell line. In conclusion, our results highlight THOP redox modulation, which could influence antigen presentation in multidrug resistant leukemia cells.
•High THOP levels were detected in K562 human leukemia cell line.•Multidrug (MDR) Lucena 1 cells is an important redox model to study THOP expression.•Reactive oxygen species increase THOP expression in non-MDR K562 leukemia cell line.•THOP expression in MDR leukemia cells is unaffected by hydrogen peroxide treatment.•ROS treatment affected differently MHC I and THOP expression in non-MDR K562 cells.
OBJECTIVE:Unlike safety data of baroreflex activation therapy device (Rheos), only few data of the currently used second device (Barostim neo) are available and little is reported about common side ...effects.
METHODS:We prospectively analyzed patients with resistant hypertension treated with Barostim neo. A standardized interview regarding side effects of the therapy was performed in routine follow-up visits after device implantation in 42 patients to determine adverse events staged into three degrees.
RESULTS:Within 6 months of baroreflex activation therapy, the office mean arterial blood pressure decreased from 169 ± 27 to 148 ± 29 mmHg systolic (P < 0.001), respectively, to 145 ± 24 mmHg after 1 year (P < 0.001), whereas the number of prescribed antihypertensive classes decreased from 6.6 ± 1.5 to 5.6 ± 1.8 (P < 0.001). Adverse events were combination of the following field depending on the severity (I° mildlocal discomfort, clinical observation only, no intervention indicated; II° moderatemedically significant such as occurrence of hypertensive crisis, syncope, arrhythmias; III° severelife-threatening events or urgent medical intervention indicated). Adverse events I° were present in almost all patients (97.6%), and occurred mainly within first 6 months after device activation. Device-related events were most frequently and could be resolved by optimization of device parameters. Most procedure-related adverse events were directly related to the incision or anesthetic procedure. Adverse events II° occurred in 28.6% patients treated with Barostim neo, whereas patients’ elevated individual risks might be potential triggers. Because of individual diversity of blood pressure response and the occurrence of adverse events, no standardization of parameters of implantable pulse generator could be found. By adapting the pulse generator settings individually, most of adverse events I° resolved without sequel.
CONCLUSION:Though there are common side effects, Barostim neo significantly lowers blood pressure in resistant hypertension and provides an adequate safety profile. Regular patient visits are necessary to register side effects.
Summary
Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 ...allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. Here we examined the two‐hit concept in leukaemic cells of 25 patients with JMML and NF‐1. Ten patients with JMML/NF‐1 exhibited a NF1 loss‐of‐function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound‐heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF‐1 and no variation in the JMML‐associated driver genes PTPN11, KRAS, NRAS or CBL (JMML‐5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound‐heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF‐1.
Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. We examined the two‐hit concept in leukaemic cells of 25 patients with JMML and clinical diagnosis of NF‐1 and confirmed biallelic NF1 inactivation in all cases but one. Among 16 JMML patients without clinical signs of NF‐1 and no variation in other JMML‐associated driver genes, eight patients exhibited NF1‐inactivating variants (six biallelic, two monoallelic). The data show that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that NF1 genetic analysis should be included in the diagnostic workup of JMML even in the absence of clinical evidence of NF‐1.
The Irish language has recently experienced a remarkable revival in Northern Ireland that has coincided with the violent conflict unfolding throughout the second half of the twentieth century. While ...being widely attributed, both within and outside the language scene, to the crucial agency of Irish Republicans, this article argues that the revival should rather be seen as based on agency that has been distributed across various sets of actors and been beyond the control of any one of them. Focussing on Catholic West Belfast that has been at the heart of the revival, four distinct types of agency are shown to have co-produced this language revival in path-dependent and often unintended ways. Following local parlance, these types of agency are metaphorically identified with the roles of "prophet", "godfather", "rebel", and "prostitute".
Cities invest large sums of money in ‘flagship projects’, with the aim of not only developing the city as such, but also changing the perceptions of the city brand towards a desired image. The city ...of Hamburg, Germany, is currently investing €575 million in order to build a new symphony hall (Elbphilharmonie), €400 million to develop the ‘International Architectural Fair’ and it is also considering candidature again for the ‘Olympic Games’ in 2024/2028. As assessing the image effects of such projects is rather difficult, this article introduces an improved version of the Brand Concept Map approach, which was originally developed for product brands. An experimental design was used to first measure the Hamburg brand as such and then the changes in the brand perceptions after priming the participants (
N
=209) for one of the three different flagship projects. The findings reveal several important structural differences for the brand image dimensions of the city contingent upon the type of flagship project. Hence, this study shows (i) that different flagship projects have different image effects for the city brand and (ii) provides a novel method for measuring perceived place brand image effects of both ongoing and future flagship projects.
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