1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of ...everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs).
2. The results showed that 100 μM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (K
i
) were calculated to be 2.3, 0.07 and 4.4 μM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively.
3. In vitro-in vivo extrapolation (IVIVE) showed that I/K
i
value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.
Background and Aim
Regulatory T cells (Treg) play a vital role in immunosuppressive crosstalk; however, Tregs from different locations lead to different clinical outcomes. Our aim was, therefore, to ...compare the prevalences and suppressive phenotypes of Tregs in the peripheral blood, peritumor, and intratumor of patients with hepatocellular carcinoma (HCC).
Methods
The frequencies and phenotypes of CD4+CD25+CD127low/−CD49d− Tregs in the periphery, peritumor, and intratumor of 78 HCC patients and 12 healthy controls were evaluated by flow cytometry. Treg‐cell suppressive activity was determined using an in vitro CD154 expression assay. Tregs from tumor and paired peritumor were then hybridized using an Agilent whole genome oligo microarray, and selected genes were validated by real‐time polymerase chain reaction. Functional analysis of the microarray data was performed using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses.
Results
Intratumoral Tregs exhibited higher frequencies and more suppressive phenotypic functions than those in peritumor and periphery, whereas there was no difference between the latter two. Functional analysis showed that complement cascades, p53, and glycosylphosphatidylinositol‐anchor biosynthesis pathways were significantly upregulated in intratumoral Tregs; the salivary secretion pathway was significantly downregulated in intratumoral Tregs, and immune cells and tumor‐immuno‐related Gene Ontology terms were significantly affected.
Conclusions
Tregs in different locations exhibited different functional statuses. A higher prevalence and more suppressive phenotype suggested a critical role for intratumoral Tregs in the formation of multicellular immunosuppressive networks. HCC immunotherapy may be improved, therefore, by specific locational Tregs elimination or suppression.
T-cell reduction is an important characteristic of coronavirus disease 2019 (COVID-19), and its immunopathology is a subject of debate. It may be due to the direct effect of the virus on T-cell ...exhaustion or indirectly due to T cells redistributing to the lungs. HIV/AIDS naturally served as a T-cell exhaustion disease model for recognizing how the immune system works in the course of COVID-19. In this study, we collected the clinical charts, T-lymphocyte analysis, and chest CT of HIV patients with laboratory-confirmed COVID-19 infection who were admitted to Jin Yin-tan Hospital (Wuhan, China). The median age of the 21 patients was 47 years interquartile range (IQR) = 40-50 years and the median CD4 T-cell count was 183 cells/μl (IQR = 96-289 cells/μl). Eleven HIV patients were in the non-AIDS stage and 10 were in the AIDS stage. Nine patients received antiretroviral treatment (ART) and 12 patients did not receive any treatment. Compared to the reported mortality rate (nearly 4%-10%) and severity rate (up to 20%-40%) among COVID-19 patients in hospital, a benign duration with 0% severity and mortality rates was shown by 21 HIV/AIDS patients. The severity rates of COVID-19 were comparable between non-AIDS (median CD4 = 287 cells/μl) and AIDS (median CD4 = 97 cells/μl) patients, despite some of the AIDS patients having baseline lung injury stimulated by HIV: 7 patients (33%) were mild (five in the non-AIDS group and two in the AIDS group) and 14 patients (67%) were moderate (six in the non-AIDS group and eight in the AIDS group). More importantly, we found that a reduction in T-cell number positively correlates with the serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP), which is contrary to the reported findings on the immune response of COVID-19 patients (lower CD4 T-cell counts with higher levels of IL-6 and CRP). In HIV/AIDS, a compromised immune system with lower CD4 T-cell counts might waive the clinical symptoms and inflammatory responses, which suggests lymphocyte redistribution as an immunopathology leading to lymphopenia in COVID-19.
Objective:
The objective of the study was to investigate the relationship of amino acid metabolism with hypertriglyceridemia in diabetic patients under statins free of prior cardiovascular diseases.
...Methods:
Two independent cross-sectional hospital based cohorts, i.e., Liaoning Medical University First Affiliated Hospital (LMUFAH,
n
= 146) and the Second Affiliated Hospital of Dalian Medical University (SAHDMU,
n
= 294) were included in the current analysis. Hypertriglyceridemia was defined as triglyceride ≥1.7 mmol/L, and well-controlled LDL-C was defined as <2.6 mmol/L. The adjusted ORs (95% CI) of circulating metabolic measures for hypertriglyceridemia were assessed using logistic regression. Pooled results of metabolites with the same direction of association in both cohorts were combined using inverse variance-weighted fixed-effect meta-analysis. Difference of identified metabolites in patients with and without hypertriglyceridemia were also obtained in the context of LDL-C.
Results:
Patients, 86 and 106, were with hypertriglyceridemia in LMUFAH and SAHDMU, respectively. We observed that elevated alanine, asparagine, leucine, and valine were consistently associated with increased hypertriglyceridemia in both cohorts. In fixed-effect pooled analysis, the OR (95% CI) per SD increase was 1.71 (1.32–2.20) for alanine, 1.62 (1.20–2.19) for asparagine, 1.64 (1.22–2.20) for leucine, and 1.62 (1.22–2.13) for valine (all
P
values ranged from 0.0018 to <0.0001); adjusting for C-peptide attenuated effect sizes of Ala, Leu, and Val for hypertriglyceridemia. The difference were robust in groups with well- or bad-controlled LDL-C.
Conclusion:
Among 23 amino acids, alanine, asparagine, leucine, and valine were positively associated with increased residual risk of hypertriglyceridemia in diabetic patients with statin treatment.
A deformed dielectric microcavity is used as an experimental platform for the analysis of the statistics of chaotic resonances, in the perspective of testing fractal Weyl laws at optical frequencies. ...In order to surmount the difficulties that arise from reading strongly overlapping spectra, we exploit the mixed nature of the phase space at hand, and only count the high-Q whispering-gallery modes (WGMs) directly. That enables us to draw statistical information on the more lossy chaotic resonances, coupled to the high-Q regular modes via dynamical tunneling. Three different models classical, Random-Matrix-Theory (RMT) based, semiclassical to interpret the experimental data are discussed. On the basis of least-squares analysis, theoretical estimates of Ehrenfest time, and independent measurements, we find that a semiclassically modified RMT-based expression best describes the experiment in all its realizations, particularly when the resonator is coupled to visible light, while RMT alone still works quite well in the infrared. In this work we reexamine and substantially extend the results of a short paper published earlier L. Wang et al., Phys. Rev. E 93, 040201(R) (2016)2470-004510.1103/PhysRevE.93.040201.
Sr2MgMo1−xVxO6−d (x=0–0.2) materials with double perovskite structure were synthesized by sol–gel method, and studied for the possibility of being the anode of solid oxide fuel cells (SOFCs) with ...biogas as the direct fuel. The sample of Sr2MgMo0.95V0.05O6−d synthesized in 5%H2/Ar showed a conductivity higher than the samples with x>0.05, but close to the sample without V. Besides, it showed better catalytic activity, stability, and H2S tolerance (up to 1% of H2S in the feed gas) for biogas combustion than the sample without V. This sample is promising for the anode of SOFCs using biogas fuel.
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To investigate the correlation between clinical indexes and pathological classifications in 202 patients with lupus nephritis (LN).
A total of 202 LN cases were retrospectively analyzed. All these ...patients met the four diagnostic criteria for systemic lupus erythematosus (SLE) of the American College of Rheumatology revised in 1997. The pathological diagnostic criteria of LN were in accordance with the pathological LN classification revised by the International Society of Nephrology and the Society of Kidney Pathology in 2003. The patients were scored according to the improved SLE Disease Activity Index 2000 (SLEDAI-2K), and their basic data, clinical data, laboratory data, and pathological data were collected.
Among the 202 patients, the ratio of male to female was 1:5.73, and type IV was the most common pathological LN classification. There were differences in the urine analysis, hypertension incidence, blood cell analysis, blood lipids, renal function, plasma albumin, immunological indexes, renal pathological score among the different pathological types (
< 0.05). In the early finding of renal function damage of the patients, cystatin C sensitivity was significantly higher than that of serum creatinine and blood urea nitrogen. Multiple linear regression analysis show that there are strong correlations between AI and SLEDAI, 24hU-Pr, serum C3, serum ALB, BUN, creatinine, UA and PLT (
< 0.001); and there are correlations between AI and serum IgM, IgA, C4, TC and LDL-C (
< 0.05).
There is a clear correlation between pathological classifications and clinical indexes of LN.
Shen-PJ-2018-40, Study on Clinical and Molecular Mechanism of SLE.
The removal of C
H
and C
H
from C
H
streams is of great significance for feedstock purification to produce polyethylene and other commodity chemicals but the simultaneous adsorption of C
H
and C
H
...over C
H
from a ternary mixture has never been realized. Herein, a robust metal-organic framework, TJT-100, was designed and synthesized, which demonstrates remarkably selective adsorption of C
H
and C
H
over C
H
. Breakthrough experiments show that TJT-100 can be used as an adsorbent for high-performance purification of C
H
from a ternary mixture of C
H
/C
H
/C
H
(0.5:99:0.5) to afford a C
H
purity greater than 99.997 %, beyond that required for ethylene polymerization. Computational studies reveal that the uncoordinated carboxylate oxygen atoms and coordinated water molecules pointing towards the pore can trap C
H
and C
H
through the formation of multiple C-H⋅⋅⋅O electrostatic interactions, while the corresponding C
H
-framework interaction is unfavorable.
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