B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell ...engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
The fourth KSTAR campaign in 2011 concentrated on active edge-localized mode (ELM) control by various methods such as non-axisymmetric magnetic perturbations, supersonic molecular beam injection ...(SMBI), vertical jogs of the plasma column and edge electron heating. The segmented in-vessel control coil (IVCC) system is capable of applying n 2 perturbed field with different phasing among top, middle and bottom coils. Application of an n = 1 perturbed field showed a desirable ELM suppression result. Fast vertical jogs of the plasma column achieved ELM pace-making and ELMs locked to 50 Hz vertical jogs were observed with a high probability of phase locking. A newly installed SMBI system was used for ELM control and the state of mitigated ELMs was sustained by the optimized repetitive SMBI pulse for a few tens of ELM periods. A change in ELM behaviour was seen due to edge electron heating although the effect of ECH launch needs supplementary analyses. The ECEI images of suppressed/mitigated ELM states showed apparent differences when compared with natural ELMy states. Further analyses are ongoing to explain the observed ELM control results.
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Atopic dermatitis (AD) commonly occurs in children and can progress into severe phenotypes or atopic march, causing significant impairment in quality of life. It is important to find ...early biomarkers of future onset of AD before any clinical manifestations.
We sought to find early predictors of future onset of AD in skin stratum corneum (SC).
Skin tape strips were collected from the forearm of newborns (n = 111) with and without family history of atopic diseases at the age of 2 months before any signs of clinical AD. Children were clinically monitored until they reached age 2 years to ensure the presence or absence of AD. Skin tape strips were subjected to lipidomic analyses by the liquid chromatography electrospray ionization tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay.
Overall, 22 of 74 (29.7%) and 5 of 37 (13.5%) infants developed AD in the risk group and the control group, respectively. In the SC of future AD children, protein-bound ceramides were decreased (P < .001), whereas unsaturated sphingomyelin species (P < .0001) and “short-chain” nonhydroxy fatty acid sphingosine and alpha-hydroxy fatty acid sphingosine ceramides were elevated (P < .01 and .05, respectively) as compared with healthy children. Thymic stromal lymphopoietin and IL-13 levels were increased in the SC of future AD subjects (by 74.5% and 78.3%, P = .0022 and P < .0001, respectively). Multivariable logistic regression analysis revealed strong AD predicting power of the combination of family history, type 2 cytokines, and dysregulated lipids, with an odds ratio reaching 54.0 (95% CI, 9.2-317.5).
Noninvasive skin tape strip analysis at age 2 months can identify asymptomatic children at risk of future AD development with a high probability.
The embryoid body test (EBT) is a developmental toxicity test method that measures the size of embryoid bodies (EBs) and the viability of mouse embryonic stem cells (mESCs) and fibroblasts (3T3 ...cells). The previous pre-validation study confirmed the high accuracy (above 80%) of EBT using 26 coded test chemicals. This second-phase validation study assessed the inter-laboratory reproducibility (5 chemicals in common) and predictive capacity (10 chemicals in each laboratory) test using the coded test chemicals at three laboratories. For the prediction model, the accuracy is increased when more data is accumulated. Therefore, we updated the prediction model and analyzed the results of the second year with the newly created-prediction model. Statistical analysis of the inter-laboratory reproducibility test results indicated that accuracy, sensitivity, and specificity were 87%, 78%, and 100%, respectively. The results of the statistical analysis of the predictive capacity test showed an accuracy of 80%, sensitivity of 78%, and specificity of 81%. In conclusion, the EBT can accurately classify various embryotoxicants within a short period and with relatively little effort. Therefore, EBT can be used as a good way to test developmental toxicity.
The identification of blood biomarkers to diagnose acute exacerbation of chronic obstructive pulmonary disease (AECOPD) will have clinical utility. Here, we used a proteomics-based approach to ...identify biomarkers capable of identifying AECOPD.
This prospective, single-center pilot study enrolled 12 patients who came to Asan Medical Center (South Korea) via the outpatient clinic or emergency department with symptoms of AECOPD and were follow-up in the outpatient clinic during convalescence between 2015 and 2017. Paired blood samples collected from each patient during the treatment naïve AECOPD and convalescence stages were analyzed. A sequential window acquisition of all theoretical fragmentation spectra-mass spectrometry (SWATH-MS)-based proteome analysis was performed and a subset of the data were verified by ELISA.
The SWATH-MS analysis identified 226 plasma proteins across all samples examined. The median coefficient of variation for triplicate technical replicates of each sample was 1.13 ± 1.38%, indicating high precision of the technique. Fold-change and paired
-test analyses revealed that 14 proteins were present at higher levels in the AECOPD samples than in the convalescence samples. A gene ontology analysis revealed that these proteins are involved in the acute-phase response. A total of 15 proteins were present at higher levels during the recovery (convalescence) stage than during the acute exacerbation phase, and gene ontology analysis revealed that these proteins are related to lipid metabolism and transport. Verification of the SWATH-MS data was performed using ELISAs for three proteins that were up-regulated in AECOPD, namely, LBP, ORM2, and SERPINA3. Among them, SERPINA3 (p = 0.005) was up-regulated significantly in AECOPD compared with the convalescence state.
Potential plasma biomarkers of AECOPD were discovered using the SWATH-MS proteomics method, and functional molecular associations were investigated. SERPINA3 could be a promising diagnostic biomarker for the early identification and tracking of AECOPD.
Typical ELMy H- mode discharges have been obtained in the KSTAR tokamak with the combined auxiliary heating of neutral beam injection (NBI) and electron cyclotron resonant heating (ECRH). The minimum ...external heating power required for the L-H transition is about 0.9 MW for a line-averaged density of ~2.0 x 10 super(19) m super(-3). There is a clear indication of the increase in the L-H threshold power with decreasing density for densities lower than ~2 x 10 super(19) m super(-3). The L-H transitions typically occurred shortly after the beginning of plasma current flattop (I sub(p) = 0.6 MA) period and after the fast shaping to a highly elongated double-null divertor configuration. The maximum heating power available was marginal for the L-H transition, which is also implied by the relatively slow transition time (> 10 ms) and the synchronization of the transition with large sawtooth crashes. The initial analysis of thermal energy confinement time (tau sub(E) indicates that tau sub(E)is higher than the prediction of multi-machine scaling laws by 10-20%. A clear increase in electron and ion temperature in the pedestal is observed in the H-mode phase but the core temperature does not change significantly. On the other hand, the toroidal rotation velocity increased over the whole radial range in the H-mode phase. The measured ELM frequency was around 10-30 Hz for the large ELM bursts and 50-100 Hz for the smaller ones. In addition, very small and high frequency (200-300 Hz) ELMs appeared between large ELM spikes when the ECRH is added to the NBI-heated H-mode plasmas. The drop of total stored energy during a large ELM is up to 5% in most cases.
Aims/hypothesis This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant ...has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians. Methods The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region. Results Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes odds ratio (OR) 1.256, 95% CI 1.08-1.46, p = 0.003. Inclusion of data from three previously published Asian studies (type 2 diabetes n = 3,283, controls n = 2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18-1.51, p = 0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence. Conclusions/interpretation The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians.
We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add‐ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were ...randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28‐week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was −0.74% for the lobeglitazone group and −0.74% for the pioglitazone group, with a mean difference of 0.01% 95% confidence interval (CI) of difference, −0.16 to 0.18. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add‐on to metformin in terms of their efficacy and safety.
Dipolarization of the magnetic field at the near‐Earth tail is usually associated with the local reduction of pV5/3 compared to that of the background, where p is the plasma pressure and V is the ...volume of the unit magnetic flux tube. This can be interpreted as a bubble, which can propagate earthward by the interchange process. How deep such a bubble can penetrate earthward, and what is the critical factor are critical questions that need to be answered. In this paper, we examine these issues by comparing near‐tail observations by inner probes of THEMIS with geosynchronous magnetic observations by GOES. We identified a number of bubble events associated with near‐tail dipolarization, which we call “tail bubble,” and checked geosynchronous disturbances. We find a statistical trend that geosynchronous disturbance is more likely to occur when associated with (or when hit by) an earthward moving tail bubble with a more‐depleted pV5/3. We estimated the background pV5/3 profile statistically and used it to determine expected equilibrium (or stop) positions for earthward moving bubbles where the bubble's pV5/3 is equal to that of the background. Statistically, we find that the equilibrium position is more inward for tail bubbles with a lower pV5/3, for which the probability of causing geosynchronous disturbance is higher. For example, the probability of a tail bubble being associated with geosynchronous disturbance is 75% if the bubble's equilibrium position is <8 RE. However, for all the events studied here, the bubble equilibrium positions are still outside the geosynchronous altitude. Although this result may be subject to change due to the uncertainty in estimating pV5/3 and the limited number of the events identified near geosynchronous altitude, we suggest that an overshooting of the penetrating bubbles beyond equilibrium positions is a possible explanation.
Key Points
Compared tail bubble THEMIS with geosynchronous disturbance GOES
Estimated pV5/3 for the background and tail bubbles
Tail bubbles with lower pV5/3 more likely associated with geosynch disturbance
Chinese cabbage (Brassica rapa L. ssp. pekinensis), an important vegetable crop, can succumb to diseases such as bacterial soft rot, resulting in significant loss of crop productivity and quality. ...Pectobacterium carotovorum ssp. carotovorum (Pcc) causes soft rot disease in various plants, including Chinese cabbage. To overcome crop loss caused by bacterial soft rot, a gene from Chinese cabbage was isolated and characterised in this study. We isolated the BrWRKY12 gene from Chinese cabbage, which is a group II member of the WRKY transcription factor superfamily. The 645-bp coding sequence of BrWRKY12 translates to a protein with a molecular mass of approximately 24.4 kDa, and BrWRKY12 was exclusively localised in the nucleus. Transcripts of BrWRKY12 were induced by Pcc infection in Brassica. Heterologous expression of BrWRKY12 resulted in reduced susceptibility to Pcc but not to Pseudomonas syringae pv. tomato in Arabidopsis. Defence-associated genes, such as AtPDF1.2 and AtPGIP2, were constitutively expressed in transgenic lines overexpressing BrWRKY12. The expression of AtWKRY12, which is the closest orthologue of BrWRKY12, was down-regulated by Pcc in Arabidopsis. However, the Atwrky12-2 mutants did not show any difference in response to Pcc, pointing to a difference in function of WRKY12 in Brassica and Arabidopsis. Furthermore, BrWRKY12 in Chinese cabbage also exhibited enhanced resistance to bacterial soft rot and increased the expression of defence-associated genes. In summary, BrWRKY12 confers enhanced resistance to Pcc through transcriptional activation of defence-related genes.
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