Objective
Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the ...relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment.
Methods
N‐MOmentum was a prospective, multicenter, double‐blind, placebo‐controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single‐molecule arrays (SIMOA) in 1,260 serial and attack‐related samples from 215 N‐MOmentum participants (92% aquaporin 4‐immunoglobulin G‐seropositive) and in control samples (from healthy donors and patients with relapsing–remitting multiple sclerosis).
Results
At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio 95% confidence interval, 3.09 1.6–6.1, p = 0.001). Median (interquartile range IQR) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9–449.7 pg/ml; attack: 2,160.1, IQR = 302.7–9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline FC, minor attacks: 1.06, IQR = 0.9–7.4; major attacks: 34.32, IQR = 8.7–107.5, p = 0.023). This attack‐related increase in sGFAP occurred primarily in placebo‐treated participants (FC: 20.2, IQR = 4.4–98.3, p = 0.001) and was not observed in inebilizumab‐treated participants (FC: 1.1, IQR = 0.8–24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.
Interpretation
Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895–910
Background and Objective
Inebilizumab is a humanized, affinity-optimized, afucosylated immunoglobulin (Ig)-G1κ monoclonal antibody that binds to CD19, resulting in effective depletion of peripheral B ...cells. It is being developed to treat various autoimmune diseases, including neuromyelitis optica spectrum disorders (NMOSD), systemic sclerosis (SSc), and relapsing multiple sclerosis (MS).
Methods
Pharmacokinetic data from a pivotal study in adult subjects with NMOSD and two early-stage studies in subjects with SSc or relapsing MS were pooled and simultaneously analyzed using a population approach.
Results
Upon intravenous administration, the pharmacokinetics of inebilizumab were adequately described by a two-compartment model with parallel first-order and time-dependent nonlinear elimination pathways. An asymptotic nonlinear elimination suggests that inebilizumab undergoes receptor (CD19)-mediated clearance. The estimated systemic clearance (CL) of the first-order elimination pathway (0.188 L/day) and the volume of distribution (
V
d
) (5.52 L) were typical for therapeutic immunoglobulins. The elimination half-life was approximately 18 days. The maximum velocity (
V
max
) of the nonlinear elimination pathway decreased with time, presumably due to the depletion of B cells upon inebilizumab administration. As for other therapeutic monoclonal antibodies, the CL and
V
d
of inebilizumab increased with body weight.
Conclusions
The presence of antidrug antibodies, status of hepatic or renal function, and use of small-molecule drugs commonly used by subjects with NMOSD had no clinically relevant impact on the pharmacokinetics of inebilizumab. The nonlinear elimination pathway at the 300 mg therapeutic dose level is not considered clinically relevant.
The decomposition mechanism of hot liquid nitromethane at various compressions was studied using reactive force field (ReaxFF) molecular dynamics simulations. A competition between two different ...initial thermal decomposition schemes is observed, depending on compression. At low densities, unimolecular C–N bond cleavage is the dominant route, producing CH3 and NO2 fragments. As density and pressure rise approaching the Chapman–Jouget detonation conditions (∼30% compression, >2500 K) the dominant mechanism switches to the formation of the CH3NO fragment via H-transfer and/or N–O bond rupture. The change in the decomposition mechanism of hot liquid NM leads to a different kinetic and energetic behavior, as well as products distribution. The calculated density dependence of the enthalpy change correlates with the change in initial decomposition reaction mechanism. It can be used as a convenient and useful global parameter for the detection of reaction dynamics. Atomic averaged local diffusion coefficients are shown to be sensitive to the reactions dynamics, and can be used to distinguish between time periods where chemical reactions occur and diffusion-dominated, nonreactive time periods.
Abstract
ZMYM2 is a transcriptional repressor whose role in development is largely unexplored. We found that Zmym2−/− mice show embryonic lethality by E10.5. Molecular characterization of Zmym2−/− ...embryos revealed two distinct defects. First, they fail to undergo DNA methylation and silencing of germline gene promoters, resulting in widespread upregulation of germline genes. Second, they fail to methylate and silence the evolutionarily youngest and most active LINE element subclasses in mice. Zmym2−/− embryos show ubiquitous overexpression of LINE-1 protein as well as aberrant expression of transposon-gene fusion transcripts. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, mediating repression of germline genes and transposons respectively. In the absence of ZMYM2, hypermethylation of histone 3 lysine 4 occurs at target sites, creating a chromatin landscape unfavourable for establishment of DNA methylation. ZMYM2−/− human embryonic stem cells also show aberrant upregulation and demethylation of young LINE elements, indicating a conserved role in repression of active transposons. ZMYM2 is thus an important new factor in DNA methylation patterning in early embryonic development.
Graphical Abstract
Graphical Abstract
Aims
Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody‐mediated, B cell‐driven disease. Inebilizumab is a humanized, affinity‐optimized, afucosylated IgG1 κ monoclonal antibody that ...binds to the B‐cell specific surface antigen CD19, resulting in rapid, profound and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modelling of B‐cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome.
Methods
A haematopoietic transit model was developed to describe the joint effects of reducing influx from pro‐B cells and accelerating CD20+ B‐cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated.
Results
At the 300‐mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD‐related in‐patient hospitalizations) and PK exposure. Subjects with low, medium and high PK exposure had a similar hazard ratio of NMOSD attack vs. placebo group.
Conclusion
The pharmacodynamic modelling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.
Background and Objectives
This feasibility study describes the effects of Nano‐pulse stimulation™ (NPS™) technology using the CellFX™ System on acne vulgaris of the back with the objectives of ...demonstrating safety and effectiveness. The CellFX System applies nanosecond pulses of electrical energy to induce highly localized regulated cell death (RCD) in the cellular structures of the targeted zone with no thermal effect on the tissue and negligible effects on surrounding non‐cellular components.
Study Design/Materials and Methods
Seventeen subjects were enrolled at two sites with thirteen subjects completing treatment. Three 7 X 7 cm regions containing at least five bacne lesions each were identified, one region treated with the CellFX across three treatment sessions, the second region treated as a sham using microneedle tip placement without delivering energy, and the third as an untreated control.
Results
CellFX‐treated areas showed an average reduction of acne lesions of 82% by 90 days post‐last procedure. Acne improvement was observed in 100% of CellFX‐treated regions compared to 39% improvement in Sham regions and 31% improvement in the control regions. The most common skin effects were erythema and hyperpigmentation observed in 23% and 92% of the subjects, respectively, at the last timepoint. No serious adverse events were reported.
Conclusions
CellFX is a safe and effective procedure for clearing back acne.
Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated ...in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance β-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb).
Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and β-cell proliferation and β-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections.
EP3 blockade increased β-cell mass in db/db mice through enhanced β-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased.
The current study suggests that EP3 blockade promotes β-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.
•Systemic blockade of EP3 in vivo in db/db mice increase beta-cell proliferation and mass.•EP3 blockade has no effect on alpha-cell proliferation.•EP3 blockade restores islet architecture and beta-cell identity genes in db/db mice.•Beta cell GLP-1 receptor expression is increased by EP3 blockade.•EP3 blockade activates the Nrf2 anti-oxidant pathway.
As next generation sequence technology has advanced, there have been parallel advances in genome-scale analysis programs for determining evolutionary relationships as proxies for epidemiological ...relationship in public health. Most new programs skip traditional steps of ortholog determination and multi-gene alignment, instead identifying variants across a set of genomes, then summarizing results in a matrix of single-nucleotide polymorphisms or alleles for standard phylogenetic analysis. However, public health authorities need to document the performance of these methods with appropriate and comprehensive datasets so they can be validated for specific purposes, e.g., outbreak surveillance. Here we propose a set of benchmark datasets to be used for comparison and validation of phylogenomic pipelines.
We identified four well-documented foodborne pathogen events in which the epidemiology was concordant with routine phylogenomic analyses (reference-based SNP and wgMLST approaches). These are ideal benchmark datasets, as the trees, WGS data, and epidemiological data for each are all in agreement. We have placed these sequence data, sample metadata, and "known" phylogenetic trees in publicly-accessible databases and developed a standard descriptive spreadsheet format describing each dataset. To facilitate easy downloading of these benchmarks, we developed an automated script that uses the standard descriptive spreadsheet format.
Our "outbreak" benchmark datasets represent the four major foodborne bacterial pathogens (
,
,
, and
) and one simulated dataset where the "known tree" can be accurately called the "true tree". The downloading script and associated table files are available on GitHub: https://github.com/WGS-standards-and-analysis/datasets.
These five benchmark datasets will help standardize comparison of current and future phylogenomic pipelines, and facilitate important cross-institutional collaborations. Our work is part of a global effort to provide collaborative infrastructure for sequence data and analytic tools-we welcome additional benchmark datasets in our recommended format, and, if relevant, we will add these on our GitHub site. Together, these datasets, dataset format, and the underlying GitHub infrastructure present a recommended path for worldwide standardization of phylogenomic pipelines.
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