102 research outputs found
Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects
Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects
Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination
<p>Abstract</p> <p>Background</p> <p>Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. However, the role of CTGF in gastric cancer remains largely unknown.</p> <p>Results</p> <p>In this study, we showed that CTGF was highly expressed in gastric cancer tissues compared with matched normal gastric tissues. The CTGF expression in tumor tissue was associated with histologic grade, lymph node metastasis and peritoneal dissemination (P < 0.05). Patients with positive CTGF expression had significantly lower cumulative postoperative 5 year survival rate than those with negative CTGF expression (22.9% versus 48.1%, P < 0.001). We demonstrated that knockdown of CTGF expression significantly inhibited cell growth of gastric cancer cells and decreased cyclin D<sub>1 </sub>expression. Moreover, knockdown of CTGF expression also markedly reduced the migration and invasion of gastric cancer cells and decreased the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Animal studies revealed that nude mice injected with the CTGF knockdown stable cell lines featured a smaller number of peritoneal seeding nodules than the control cell lines.</p> <p>Conclusions</p> <p>These data suggest that CTGF plays an important role in cell growth and invasion in human gastric cancer and it appears to be a potential prognostic marker for patients with gastric cancer.</p
A Conserved Cysteine Motif Is Critical for Rice Ceramide Kinase Activity and Function
Ceramide kinase (CERK) is a key regulator of cell survival in dicotyledonous plants and animals. Much less is known about the roles of CERK and ceramides in mediating cellular processes in monocot plants. Here, we report the characterization of a ceramide kinase, OsCERK, from rice (Oryza sativa spp. Japonica cv. Nipponbare) and investigate the effects of ceramides on rice cell viability.OsCERK can complement the Arabidopsis CERK mutant acd5. Recombinant OsCERK has ceramide kinase activity with Michaelis-Menten kinetics and optimal activity at 7.0 pH and 40°C. Mg2+ activates OsCERK in a concentration-dependent manner. Importantly, a CXXXCXXC motif, conserved in all ceramide kinases and important for the activity of the human enzyme, is critical for OsCERK enzyme activity and in planta function. In a rice protoplast system, inhibition of CERK leads to cell death and the ratio of added ceramide and ceramide-1-phosphate, CERK's substrate and product, respectively, influences cell survival. Ceramide-induced rice cell death has apoptotic features and is an active process that requires both de novo protein synthesis and phosphorylation, respectively. Finally, mitochondria membrane potential loss previously associated with ceramide-induced cell death in Arabidopsis was also found in rice, but it occurred with different timing.OsCERK is a bona fide ceramide kinase with a functionally and evolutionarily conserved Cys-rich motif that plays an important role in modulating cell fate in plants. The vital function of the conserved motif in both human and rice CERKs suggests that the biochemical mechanism of CERKs is similar in animals and plants. Furthermore, ceramides induce cell death with similar features in monocot and dicot plants
Does or did the supernova remnant Cassiopeia A operate as a PeVatron?
For decades, supernova remnants (SNRs) have been considered the prime sources
of Galactic Cosmic rays (CRs). But whether SNRs can accelerate CR protons to
PeV energies and thus dominate CR flux up to the knee is currently under
intensive theoretical and phenomenological debate. The direct test of the
ability of SNRs to operate as CR PeVatrons can be provided by ultrahigh-energy
(UHE; ~TeV) -rays. In this context, the historical
SNR Cassiopeia A (Cas A) is considered one of the most promising target for UHE
observations. This paper presents the observation of Cas A and its vicinity by
the LHAASO KM2A detector. The exceptional sensitivity of LHAASO KM2A in the UHE
band, combined with the young age of Cas A, enabled us to derive stringent
model-independent limits on the energy budget of UHE protons and nuclei
accelerated by Cas A at any epoch after the explosion. The results challenge
the prevailing paradigm that Cas A-type SNRs are major suppliers of PeV CRs in
the Milky Way.Comment: 11 pages, 3 figures, Accepted by the APJ
Measurement of ultra-high-energy diffuse gamma-ray emission of the Galactic plane from 10 TeV to 1 PeV with LHAASO-KM2A
The diffuse Galactic -ray emission, mainly produced via interactions
between cosmic rays and the interstellar medium and/or radiation field, is a
very important probe of the distribution, propagation, and interaction of
cosmic rays in the Milky Way. In this work we report the measurements of
diffuse -rays from the Galactic plane between 10 TeV and 1 PeV
energies, with the square kilometer array of the Large High Altitude Air Shower
Observatory (LHAASO). Diffuse emissions from the inner
(, ) and outer
(, ) Galactic plane are detected with
and significance, respectively. The outer Galactic
plane diffuse emission is detected for the first time in the very- to
ultra-high-energy domain (~TeV). The energy spectrum in the inner Galaxy
regions can be described by a power-law function with an index of
, which is different from the curved spectrum as expected from
hadronic interactions between locally measured cosmic rays and the
line-of-sight integrated gas content. Furthermore, the measured flux is higher
by a factor of than the prediction. A similar spectrum with an index of
is found in the outer Galaxy region, and the absolute flux for
TeV is again higher than the prediction for hadronic
cosmic ray interactions. The latitude distributions of the diffuse emission are
consistent with the gas distribution, while the longitude distributions show
clear deviation from the gas distribution. The LHAASO measurements imply that
either additional emission sources exist or cosmic ray intensities have spatial
variations.Comment: 12 pages, 8 figures, 5 tables; accepted for publication in Physical
Review Letters; source mask file provided as ancillary fil
Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease
BACKGROUND:
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.
METHODS:
We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.
RESULTS:
During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.
CONCLUSIONS:
Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)
Structural Safety Analysis of Cantilever External Shading Components of Buildings under Extreme Wind Environment
The high intensity of solar radiation and long sunshine time in the Turpan area lead to the necessity of sunshade construction. Sunshade components can effectively block direct solar radiation and the secondary heating of buildings. Through the analysis of the importance and sensitivity of sunshade components, it was found that the importance of sunshade components accounts for the largest proportion of multi-parameters, and the sensitivity of sunshade components accounts for about 60% of the total. At the same time, the change in sunshade length has an important influence on the proportion of air conditioning energy consumption and space comfort when the sunshade length reached the 0.6 m–0.8 m range. The energy consumption curve of air conditioning no longer decreased and tended to be horizontal, which showed that a sunshade could effectively reduce the energy consumption of air conditioning, while the PMV comfort curve gradually increased and tended to be horizontal, indicating that a sunshade could effectively improve indoor comfort; therefore, a sunshade could reduce direct solar radiation, reduce the energy consumption of air conditioning and improve indoor thermal comfort. In view of the extremely harsh climate characteristics of Turpan, although Turpan needs to carry out shading design, as a typical wind-sensitive component, the structural safety of the visor under the action of an extreme wind environment is the primary focus of designers. The design requires wind loads as control loads. Based on the ANSYS Workbench platform, this study used the fluid–structure coupling technology to calculate and solve for the wind load stress and strain of a horizontal sunshade and a vertical sunshade in a cantilevered external sunshade of different buildings orientations. In this study, by solving for the maximum principal stress and maximum principal elastic strain under 10 working conditions, the results showed that the maximum principal stress of the sun visor under all working conditions was 0.39 MPa, which is much smaller than the tensile strength of C25 concrete. The calculated maximum principal elastic strain of the sun visor was 0.12 × 10−4, which is much smaller than the maximum strain value of concrete. Therefore, the wind load under this research condition had no great influence on the structural safety of the concrete sunshade, which proves the structural feasibility of the building sunshade member in the Turpan area, and provides a reference for the future practical engineering of cantilever members in the Turpan area
Phosphorylation: new star of pathogenesis and treatment in steatotic liver disease
Abstract Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stability, affect localization, transform molecular function, and cooperate with other protein modifications. Among them, adenosine 5’-monophosphate-activated protein kinase (AMPK), serine/threonine kinase (AKT), and nuclear factor kappa-B (NF-kB) are considered the core mechanisms in steatotic liver disease. As to treatment, lifestyle changes, prescription drugs, and herbal ingredients can alleviate symptoms by influencing phosphorylation. It demonstrates the significant role of phosphorylation as a mechanism occurrence and a therapeutic target in steatotic liver disease, which could be a new star for future exploration
Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects
ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects
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