Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National ...Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma.
In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18–60 years with previously untreated, non-keratinising stage III–IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68–70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62–68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30–32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed.
From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9–81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7–80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio HR 0·98, 95% CI 0·69–1·39; log-rank p=0·92), with a difference of 0·5% (95% CI −7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (−6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3–4 adverse events were mucositis (102 41% of 252 in the lobaplatin-based group vs 99 40% of 249 in the cisplatin-based group), leucopenia (39 16% vs 56 23%), and neutropenia (25 10% vs 59 24%). No treatment-related deaths were reported.
Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma.
National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University.
For the Chinese translation of the abstract see Supplementary Materials section.
The effect of kaempferol, a regulator of oestrogen receptors, on atherosclerosis (AS) and the underlying mechanism is elusive.
To explore the effect and mechanism of kaempferol on AS.
In vivo, ...C57BL/6 and apolipoprotein E (APOE)
-/-
mice were randomly categorized into six groups (C57BL/6: control, ovariectomy (OVX), high-fat diet (HFD); APOE
-/-
: OVX-HFD, OVX-HFD + kaempferol (50 mg/kg) and OVX-HFD + kaempferol (100 mg/kg) and administered with kaempferol for 16 weeks, intragastrically. Oil-Red and haematoxylin-eosin (HE) staining were employed to examine the effect of kaempferol. In vitro, human aortic endothelial cells (HAECs) were pre-treated with or without kaempferol (5, 10 or 20 μM), followed by administration with kaempferol and oxidized low-density lipoprotein (ox-LDL) (200 μg/mL). The effect of kaempferol was evaluated using flow cytometry, and TdT-mediated dUTP Nick-End Labelling (TUNEL).
In vivo, kaempferol (50 and 100 mg/kg) normalized the morphology of blood vessels and lipid levels and suppressed inflammation and apoptosis. It also activated the G protein-coupled oestrogen receptor (GPER) and PI3K/AKT/nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. In vitro, ox-LDL (200 μg/mL) reduced the cell viability to 50% (IC
50
). Kaempferol (5, 10 or 20 μM) induced-GPER activation increased cell viability to nearly 10%, 19.8%, 30%, and the decreased cellular reactive oxygen species (ROS) generation (16.7%, 25.6%, 31.1%), respectively, consequently attenuating postmenopausal AS. However, the protective effects of kaempferol were blocked through co-treatment with si-GPER.
The beneficial effects of kaempferol against postmenopausal AS are associated with the PI3K/AKT/Nrf2 pathways, mediated by the activation of GPER.
The presence of reduced aminothiols, including homocysteine (Hcy), cysteine (Cys), cysteinyl-glycine (CG), and glutathione (GSH), is significantly increased in the pathological state. However, there ...have been no reports on the relationship between reduced aminothiols (Hcy, Cys, CG, and GSH) and different genders, ages, and drug combinations in human blood. The accurate quantification of these reduced thiols in biological fluids is important for monitoring some special pathological conditions of humans. However, the published methods typically not only require cumbersome and technically challenging processing procedures to ensure reliable measurements, but are also laborious and time-consuming, which may disturb the initial physiological balance and lead to inaccurate results. We developed a hollow fiber centrifugal ultrafiltration (HFCF-UF) method for sample preparation coupled with a high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method and used it to determine four reduced aminothiols (Hcy, Cys, CG, and GSH) in human blood for the first time. A total of 96 clinical patients were enrolled in our study. The influence of different genders, ages, and drug combinations on the levels of four reduced thiols in human blood was also discussed by SPSS 24.0. The sample preparation was simplified to a single 5 min centrifugation step in a sealed system that did not disturb the physiological environment. The validation parameters for the methodological results were excellent. The procedure was successfully applied to monitoring the concentrations of four reduced aminothiols (Hcy, Cys, CG, and GSH) in 96 clinical blood samples. There were no significant differences in Hcy, Cys, CG, or GSH for the different genders, ages, or combinations with methotrexate or vancomycin (
P
> 0.05). However, there was a significant increase in Hcy concentration in patients treated with valproic acid who were diagnosed with epilepsy (
p
=0.0007). It is advisable to measure reduced Hcy level in patients taking valproic acid. The developed HFCF-UF method was simple and accurate. It can be easily applied in clinical research to evaluate oxidative stress in further study.
Graphical abstract
Atherosclerosis (AS) is an excessive chronic inflammatory hyperplasia caused by the damage of vascular endothelial cell morphology and function. Changes in mitochondrial internal conformation and ...increase of reactive oxygen species (ROS) can lead to energy metabolism disorders in mitochondria, which further affects the occurrence of atherosclerosis by impairing vascular endothelial function. Coenzyme Q10 (CoQ10) is one of the components of mitochondrial respiratory chain, which has the functions of electron transfer, reducing oxidative stress damage, improving mitochondrial function and promoting energy metabolism. The main purpose of this study is to investigate the protective effects of CoQ10 against AS by improving mitochondrial energy metabolism. Both in high fat diet (HFD) fed APOE
−/−
mice and in ox-LDL-treated HAECs, CoQ10 significantly decreased the levels of TG, TC and LDL-C and increased the levels of HDL-C, thus playing a role in regulating lipid homeostasis. Meanwhile, CoQ10 decreased the levels of LDH and MDA and increased the levels of SOD and GSH, thus playing a role in regulating oxidation level. CoQ10 also inhibited the over-release of ROS and increased ATP content to improve mitochondrial function. CoQ10 also decreased the levels of related inflammatory factors (ICAM-1, VCAM-1, IL-6, TNF-α and NLRP3). In order to study the mechanism of the experiment, AMPK and YAP were silenced
in vitro
. The further study suggested AMPK small interfering RNA (siRNA) and YAP small interfering RNA (siRNA) affected the expression of OPA1, a crucial protein regulating the balance of mitochondrial fusion and division and decreased the therapeutic effects of CoQ10. These results indicated that CoQ10 improved mitochondrial function, inhibited ROS production, promoted energy metabolism and attenuated AS by activating AMPK-YAP-OPA1 pathway. This study provides a possible new mechanism for CoQ10 in the treatment of AS and may bring a new hope for the prevention and treatment of AS in the future.
Femoroacetabular impingement (FAI) is a common cause of hip pain and even tearing of the acetabular labrum in young adults and athletes. Either arthroscopic labral debridement (LD) or labral repair ...(LR) technique for FAI patients is needed to choose. We conducted this systematic review and meta-analysis to compare the clinical outcomes of arthroscopic LD versus LR intervention.
The five studies were acquired from PubMed, Medline, Embase, and Cochrane Library. The data were extracted by two of the coauthors independently and were analyzed by RevMan5.3. Mean differences (MDs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration's Risk of Bias Tool and Newcastle-Ottawa Scale were used to assess risk of bias.
Four observational studies and one prospective randomized study were assessed. The methodological quality of the trials indicated a low to moderate risk of bias. The pooled results of Non-Arthritic Hip Score (NAHS), failure rate of surgeries and complications showed that the differences were not statistically significant between the two interventions. The difference of modified Harris Hip Score (mHHS), the Visual Analogue Scale (VAS) score and satisfaction rate was statistically significant between LD and LR intervention, and LR treatment was more effective. Sensitivity analysis proved the stability of the pooled results and there were too less included articles to verify the publication bias.
Hip arthroscopy with either LR or LD is an effective treatment for symptomatic FAI. The difference of mHHS, VAS score, and satisfaction rate was statistically significant between LD and LR intervention, and arthroscopic LR could re-create suction-seal effect, potentially reduce microinstability, which demonstrated a trend toward better clinical efficacy and comparable safety compared with LD. The arthroscopic LR technique is recommended as the optical choice for acetabular labrum tear with FAI.
Purpose
Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple ...CYPs in the metabolism of rivaroxaban to provide new information for medication safety.
Methods
The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions.
Results
Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions.
Conclusion
CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.
2198 aluminum–lithium alloy was friction stir-welded with a KUKA Robot integrated with a compact friction stir-welding head with a rotation speed of 800 rpm at different welding speeds. The real-time ...tool force in the three directions of Fx, Fy and Fz was measured with a load sensor. Mechanical properties and microstructure evolution were investigated systematically. The results showed that Fz force increased from 3.2 kN to 8.5 kN as welding speed increased from 50 mm/min to 500 mm/min. Ultimate tensile strength of 383 MPa, 88% of base metal, was obtained when the welding speed was 100 mm/min. The nugget zone consisted of refined grains with an average size of 4 μm. TEM investigation demonstrates that T1 precipitation predominated in the base metal and disappeared in the nugget zone, as a small amount of δ’ was retained. The W-shape hardness profile in all weldments and higher welding speed lead to a higher hardness value.
The aim of this study was to evaluate the prognostic value of pre-treatment plasma hemostatic parameters in patients with advanced pancreatic cancer.
A total of 320 patients diagnosed with advanced ...pancreatic cancer between January 1, 2011 to December 31, 2015 were enrolled in this retrospective study. The prognostic significance of hemostatic parameters such as prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW) was determined by univariate and multivariate Cox hazard models. Then, Kaplan-Meier methods and log-rank tests were performed to compare the survival of patients in different risk groups.
Univariate and multivariate analyses showed that prolonged PT, high FBG, and high MPV were independent prognostic factors for poor overall survival (PT > 11.3 s, HR = 1.46, 95%CI = 1.10–1.94, p = 0.009; FBG>2.5 g/L, HR = 1.41, 95%CI = 1.08–1.84, p = 0.011; MPV>12.2 fL, HR = 1.52, 95%CI = 1.13–2.04, p = 0.005). Moreover, all the patients were stratified into three groups by a scoring system based on these three hemostatic markers. The median survival time of the three groups was 8.8 months, 6.3 months and 4.3 months (P < 0.001).
PT, FBG and MPV were independent prognostic factors in advanced pancreatic cancer. A novel scoring system based on these hemostatic parameters could be used to predict the survival of patients with advanced pancreatic cancer.
The 2D geometry nature and low dielectric constant in transition-metal dichalcogenides lead to easily formed strongly bound excitons and trions. Here, we studied the photoluminescence of van der ...Waals heterostructures of monolayer MoS2 and graphene at room temperature and observed two photoluminescence peaks that are associated with trion emission. Further study of different heterostructure configurations confirms that these two peaks are intrinsic to MoS2 and originate from a bound state and Fermi level, respectively, of which both accept recoiled electrons from trion recombination. We demonstrate that the recoil effect allows us to electrically control the photon energy of trion emission by adjusting the gate voltage. In addition, significant thermal smearing at room temperature results in capture of recoil electrons by bound states, creating photoemission peak at low doping level whose photon energy is less sensitive to gate voltage tuning. This discovery reveals an unexpected role of bound states for photoemission, where binding of recoil electrons becomes important.
High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents
, whereas only the free drug can reach the ...site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient
of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L
(
= 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (
= 0.023,
= -0.236 for total MTX and
= 0.020,
= -0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.
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