To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations ...in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.
On the basis of the crystal chemistry and electronic structure of γ-Na
x
CoO
2, we explored many cobalt-based oxide systems and encountered the compound “Ca
3Co
4O
9”. Through the detailed structure ...analyses, the cobalt oxide has been revealed to be a misfit-layered compound, which consists of two interpenetrating monoclinic subsystems. The first subsystem CoO
2 has a CdI
2-type triangular lattice while the second subsystem Ca
2CoO
3 is built up from an ordered three-layered NaCl-type (RS) block. The structure formula can be expressed as Ca
2CoO
3
p
CoO
2, where
p stands for the
b-axis ratio,
b
CoO
2
/
b
RS∼0.62. A typical polycrystalline sample of the compound exhibits reasonable thermoelectric (TE) performance with thermopower
S=130 μV K
−1, resistivity=15 mΩ cm and thermal conductivity
κ=1 W m
−1 K
−1 at 300 K. The resulting figure-of-merit
Z (
S
2/
ρκ)=1.1×10
−4 K
−1 is comparable to that of polycrystalline samples of the γ-phase, indicating that the present misfit cobalt oxide is a potential candidate for a thermoelectric material.
Lactic acid (LA) and glycolic acid (GA), which are low-molecular-weight hydroxyacids, were identified in the particle and gas phases within the marine atmospheric boundary layer over the western ...subarctic North Pacific. A major portion of LA (81%) and GA (57%) was present in the particulate phase, which is consistent with the presence of a hydroxyl group in these molecules leading to the low volatility of the compounds. The average concentration (±SD) of LA in more biologically influenced marine aerosols (33 ± 58 ng m−3) was substantially higher than that in less biologically influenced aerosols (11 ± 12 ng m−3). Over the oceanic region of phytoplankton blooms, the concentration of aerosol LA was comparable to that of oxalic acid, which was the most abundant diacid during the study period. A positive correlation was found between the LA concentrations in more biologically influenced aerosols and chlorophyll a in seawater (r2 = 0.56), suggesting an important production of aerosol LA possibly associated with microbial (e.g., lactobacillus) activity in seawater and/or aerosols. Our finding provides a new insight into the poorly quantified microbial sources of marine organic aerosols (OAs) because such low-molecular-weight hydroxyacids are key intermediates for OA formation.
To improve the thermoelectric (TE) properties of melt-grown higher manganese silicides MnSi
γ
, dissipation of MnSi precipitates that deteriorate the electrical conductivity is required. We have ...investigated the effects of light cobalt (Co) substitution on TE properties and MnSi precipitates of MnSi
γ
. A 4% substitution of Mn with Co is an effective approach to eliminate MnSi precipitates from melt-grown MnSi
γ
, which is confirmed by powder x-ray diffraction and energy-dispersive spectroscopy measurements. Furthermore, this light Co substitution leads to increase of the hole carrier concentration, resulting in a great increase in the electrical conductivity from 24 × 10
3
S/m to 54 × 10
3
S/m at 700 K. The resulting power factor exhibits 1.9 × 10
−3
W/mK
2
around 700 K. Moreover, the lattice thermal conductivity is greatly decreased by partial Co substitution compared with that of Co-free MnSi
γ
. Consequently, the dimensionless figure-of-merit
zT
of (Mn
1−
x
Co
x
)Si
γ
samples increases from 0.27 for
x
= 0 to 0.50 for
x
= 0.04 in the vicinity of 800 K.
Autoimmune forms of encephalitis have been associated with autoantibodies against synaptic cell surface antigens such as NMDA- and AMPA-type glutamate receptors, GABAB receptor, and LGI1. However, it ...remains unclear how many synaptic autoantigens are yet to be defined. Using immunoproteomics, we identified autoantibodies against the GABAA receptor in human sera from two patients diagnosed with encephalitis who presented with cognitive impairment and multifocal brain MRI abnormalities. Both patients had antibodies directed against the extracellular epitope of the beta 3 subunit of the GABAA receptor. The beta 3-subunit-containing GABAA receptor was a major target of the patients' serum antibodies in rat hippocampal neurons because the serum reactivity to the neuronal surface was greatly decreased by 80% when the beta 3 subunit was knocked down. Our developed multiplex ELISA testing showed that both patients had similar levels of GABAA receptor antibodies, one patient also had a low level of LGI1 antibodies, and the other also had CASPR2 antibodies. Application of the patients' serum at the time of symptom presentation of encephalitis to rat hippocampal neuron cultures specifically decreased both synaptic and surface GABAA receptors. Furthermore, treatment of neurons with the patients' serum selectively reduced miniature IPSC amplitude and frequency without affecting miniature EPSCs. These results strongly suggest that the patients' GABAA receptor antibodies play a central role in the patients' symptoms. Therefore, this study establishes anti-GABAA receptor encephalitis and expands the pathogenic roles of GABAA receptor autoantibodies.
Objective
To evaluate the breed‐characteristic features of cervical intervertebral disc disease (C‐IVDD) and associated vertebral instability in small‐breed dogs and to present the concept of ...intervertebral disc degeneration and associated instability stage, method of diagnosis, treatment and outcomes.
Animals
In total, 307 client‐owned dogs with C‐IVDD treated with spinal cord decompression with or without vertebral stabilization (2000–2021).
Methods
Information on age, sex, affected sites, stabilized sites, diagnostic methods for vertebral instability and outcomes were retrieved. The patient's age, affected sites (cranial vs caudal discs), and frequency of vertebral stabilization were compared in six CD and five NCD breed. Multivariable analyses of the chondrodystrophic (CD) vs non‐CD (NCD) groups, and vertebral stabilization (dogs stabilized vs dogs not stabilized) were performed.
Results
In total, 222 (72.3%) and 77 (25.1%) were CD and NCD breeds, respectively. Vertebral instabilities were diagnosed based on the survey radiographs with computed tomography/magnetic resonance imaging (n = 2), dynamic myelography (n = 29), intraoperative spinal manipulation (n = 11) or second surgery in dogs with persistent postoperative paraspinal pain (n = 3). Of these dogs, 295 (96.1%) recovered (median follow‐up: 8.5 range, 1–119 months). Significant differences in age, affected sites and frequency of stabilization were noted among the breeds. Older age and frequent vertebral stabilization were the associated factors for the NCD breed dogs. Male dogs, caudal discs affected (C5–T1) and the NCD breed dogs were risk factors for the dogs with vertebral stabilization.
Conclusion
Vertebral stabilization is indicated for small‐breed dogs with cervical disc‐associated vertebral instability.
Background:
Tofacitinib (TOFA) and baricitinib (BARI) have been widely used in many regions for treatment of rheumatoid arthritis (RA). The selection of JAK inhibitor for RA treatment based on ...patient type remains a major concern.
Objectives:
The differences of efficacy between each Janus kinase (JAK) inhibitors have not been clarified in the patients with RA in clinical practice. Here, we compared the efficacy between TOFA and BARI in clinical practice.
Methods:
A retrospective observational study. The efficacy of TOFA (n=156) in patients with RA was compared with BARI (n=138). Selection bias was reduced to a minimum using propensity score-based inverse probability of treatment weighting (IPTW). We analyzed the trajectories of changes in disease activity in patients receiving TOFA or BARI using growth mixture modeling (GMM). Multivariable logistic regression analysis was performed to identify factors contributing to belonging to treatment-resistance group defined by GMM. The observation period of the study was 24 weeks.
Results:
No significant difference was observed in patient characteristics between the TOFA and BARI groups in after adjustment by propensity score-based IPTW. The retention rates over 24 weeks did not differ between the TOFA and BARI groups. No difference was observed in the incidence of adverse events in the TOFA and BARI groups. Clinical disease activity index (CDAI) at week 24 after the introduction of JAK inhibitors was 8.0 ± 8.9 and 6.2 ± 7.2 in the TOFA and BARI group, respectively. The rates of CDAI-remission at week 24 in the TOFA and BARI groups were 43/153 (28.3%) and 57/141 (40.4%), respectively. Compared to the TOFA group, the BARI group showed a significantly lower CDAI (⊿CDAI=-1.9, 95% confidence interval: -3.7 to -0.3, p=0.02) and a significantly higher rate of CDAI-remission (odds ratio: 1.7, 95% CI: 1.1–2.7, p=0.04) at week 24. Similarly, at week 24, SDAI was significantly lower in the BARI group (TOFA vs. BARI = 10.1 ± 9.9 vs. 7.3 ± 7.5, ⊿SDAI=-2.2, 95% CI: -4.2 to -0.2, p=0.04), and the rates of SDAI-remission (OR: 1.6, 95% CI: 1.0–2.6, p=0.04).
The patients were divided into two groups: patients with MDA to HDA at baseline (Group 1) and patients with HDA at baseline than Group 1 (Groups 2 and 3) based on the analysis of the trajectories of CDAI using GMM, In Groups 1 and 2, disease activity was improved immediately after the introduction of JAK inhibitors. In Group 3, disease activity was partially improved, and LDA was not achieved at week 24 after the introduction of JAK inhibitors. The patients in Group 3 were resistant to treatment (Group 3: treatment-resistance group).
When multivariable logistic regression analysis was performed for all patients receiving JAK inhibitors, the factors contributing to belonging to treatment-resistance group were: high baseline HAQ-DI score (OR: 1.76, 95% CI: 1.09–2.84, p=0.02) and high number of biological disease-modifying anti-rheumatic drugs (bDMARDs) used before JAK inhibitors (OR: 1.51, 95% CI: 1.16–1.95, p=0.002) and TOFA use (OR: 2.13, 95% CI: 1.05–4.30, p=0.03).
Next, multivariable logistic regression analysis was separately performed for each treatment group. The patients receiving more bDMARDs before the JAK inhibitor were more likely to belong to treatment-resistance group in the TOFA group (OR: 1.76, 95% CI: 1.24–4.06). Among patients with RA who received TOFA, those who had received ≥4 bDMARDs before the introduction of TOFA were more likely to be classified into the treatment-resistant group.
In the BARI group, multivariable logistic regression analysis did not identify any factors associated with belonging to treatment-resistance group.
Conclusion:
TOFA may be partially effective in patients resistant to many bDMARDs. Consequently, efficacy may differ between TOFA and BARI. Because TOFA was less effective in RA patients resistant to ≥4 bDMARDs, the present study suggests that BARI may be more appropriate for RA patients resistant to many bDMARDs.
Disclosure of Interests:
Yusuke Miyazaki Speakers bureau: Eli Lilly, Shingo Nakayamada Speakers bureau: Bristol-Myers, UCB, Astellas, Abbvie, Eisai, Pfizer, Takeda, Kazuhisa Nakano Speakers bureau: Bristol-Myers, Sanofi, AbbVie, Eisai, Eli Lilly, Chugai, Pfizer, Takeda, and Mitsubishi-Tanabe, Satoshi Kubo Speakers bureau: Bristol-Myers, Yoshino Inoue: None declared, Yoshihisa Fujino: None declared, Yoshiya Tanaka Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, and Santen
Concentrations of elemental carbon (EC), carbon monoxide (CO), and carbon dioxide (CO2) were measured in Beijing between 2005 and 2006. EC was measured every hour with a semicontinuous thermal ...optical analyzer. The observed concentrations were rather uniform over a distance of about 50 km from the observation site. The annual average concentrations of EC and CO were 6.9 μgC m−3 and 1120 parts per billion by volume, respectively. The concentrations of these species increased with decreasing near‐surface wind speed (WS). The slopes of the CO‐CO2, EC‐CO2, and EC‐CO correlations are used to estimate major EC and CO sources. In the weak wind regime (WS ≤ 2.0 m s−1), the median EC, ΔEC/ΔCO2, and ΔEC/ΔCO (except for winter) increased in the late evening and remained high until early morning. The traffic of heavy duty diesel trucks during nighttime was about 20 times higher than that during daytime. These results indicate a dominant contribution of exhaust from diesel vehicles to the nighttime EC. In winter, the nighttime CO and ΔCO/ΔCO2 ratio were largely higher than those in the other seasons. The most likely cause is the increase in the CO emissions from the exhaust of gasoline vehicles at low temperature. The ΔEC/ΔCO2 ratio in winter was lower than that in fall, indicating no significant additional EC emissions. The diurnal variations of EC, CO, CO2, and ΔEC/ΔCO were similar between weekdays and weekends. The slopes of the CO‐CO2‐EC correlations are compared with the CO‐CO2‐EC ratios derived from a published emission inventory in the Beijing area.
Measurements of black carbon (BC) and organic carbon (OC) were conducted in Bangkok during 2007–2008. Annual trends of BC and OC show strong seasonality with lower and higher concentrations during ...wet and dry seasons, respectively. Flow of cleaner air, wet removal, and negligible biomass burning resulted in the lowest concentrations of aerosols in the wet season. In addition to anthropogenic sources, long‐range transport and biomass burning caused higher concentrations in the dry and hot seasons, respectively. Despite extensive biomass burning in the hot season, moderate levels of aerosols were due to the mixing with air masses from the Pacific Ocean. Diurnal distributions exhibit peaks during rush hour marked by minima in the OC/BC ratio and stagnant wind flow. The lowest concentrations in the afternoon hours could be due to deeper planetary boundary layer and reduced traffic. Overall, the concentrations of both BC and OC decrease with the increase in wind speed. The weekend effects, due to reduced emission during weekends, in the concentrations of both BC and OC were significant. Therefore, stricter abatement in vehicular emissions could substantially reduce pollution. A slope of ΔBC/ΔCO of 9.8 ngm−3 ppbv−1 for the wet season represents the emission ratio from vehicular sources. The highest of ΔOC/ΔBC (3 μg μg−1) in the hot season was due to the predominant influence of biomass burning and significant formation of secondary OC. The levels of BC and OC in Bangkok fall within the ranges of their concentrations measured in the major cities of East Asia.
Key Points
Characteristics of short‐term and seasonal variations of BC and OC in Bangkok
Traffic and biomass burning emissions of aerosols in a megacity of SEA
Roles of transport and factors in variations of aerosols in different seasons
PDF
