Mixing and Thermal Transport Behavior in a Pin or Non-Pin Extruder Equipped with a Field Synergy Elongation Screw.

The ductile forming process of a polymer in a standard screw extruder and pin-barrel extruder, equipped with or without a field synergy elongation screw, was investigated by the finite element method. In order to assess the mixing and heat transfer capabilities of screws, characteristic parameters such as the mixing efficiency, segregation scale, and temperature distribution of different structures were analyzed and compared. The results indicated that the flow pattern of the polymer melt in the extruder was significantly influenced by the screw structure and was improved by the newly designed field synergy screw configuration, which brought a desirable elongational flow to enhance the radial convection. This was attributed to the unique radial wedge-shaped repeated convergence region of the field synergy elongation screw, increasing the synergistic effect between the velocity field, velocity gradient field, and temperature gradient field and thus improving the heat transfer and mixing efficiency. After adding barrel pins, the flow was forced to split, resulting in a more significant stretching effect on the melt. The field synergy effect in the pin mixed region was strengthened, which further increased the heat and mass transfer efficiency of the screw. However, increasing barrel pins could also lead to undesired temperature fluctuation and flow resistance, which have a negative impact on the melt uniformity. This study offers an important reference for optimizing screw structure to obtain strong mixing and heat transfer performances.

An Innovative SbIII-WVI-Cotemplated Antimonotungstate with Potential in Sensing Paroxetine Electrochemically.

Advances in polyoxometalate (POM) self-assembly chemistry are always accompanied by new developments in molecular blocks. The exploration and discovery of uncommon building blocks offer great possibilities for generating unprecedented POM clusters. An intriguing SbIII-WVI-cotemplated antimonotungstate [H2N(CH3)2]11Na[SbW9O33]Er2(H2O)2Sb2[SbWVIW15O57]·22H2O (1) was synthesized, which comprises a classical trivacant Keggin [SbW9O33]9- ({SbW9}) fragment and an unclassical lacunary Dawson-like [SbWVIW15O57]15- ({SbWVIW15}) subunit. Notably, the Dawson-like {SbWVIW15} subunit is the first example of a [SbO3]3- and [WVIO6]6- mixed-heteroatom-directing POM segment. Hexacoordinated [WVIO6]6- can not only serve as the heteroatom function but its additional oxygen sites can also link to lanthanide, main-group metal, and transition-metal centers to form the innovative structure. {SbWVIW15} and {SbW9} subunits are joined by the heterometallic [Er2(H2O)2Sb2O17]22- cluster to give rise to an asymmetric sandwich-type architecture. To further realize its potential application in electrochemical sensing, a conductive 1@rGO composite was obtained by the electrochemical deposition of 1 with graphene oxide (GO). Using a 1@rGO-modified glassy carbon electrode as the working electrode, an electrochemical biosensor for detecting the antidepressant drug paroxetine (PRX) was successfully constructed. This work can provide a viable strategy for synthesizing mixed-heteroatom-directing POMs and demonstrates the application of POM-based materials for the electrochemical detection of drug molecules.

TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2.

Objective: Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Materials and Methods: Mice were fed with 0.12% TMAO for 16 weeks. Then, mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in ischemic stroke, microglia of MCAO/R mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Results: TMAO promoted the release of inflammatory cytokines in the brain of MCAO/R mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating ischemic stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3. TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. Conclusion: Our results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. These findings explained the molecular mechanism of TMAO aggravating ischemic stroke in detail and provided molecular mechanism for clinical treatment.

Acid-sensing ion channel 1: potential therapeutic target for tumor.

Acidic extracellular pH is a major characteristic of tumor tissue, studies suggest that the local pH value of malignant tumor tissues is between 6.0 and 6.9. Acid-sensing ion channel 1 (ASIC1) is proton-gated cation channel activated by low extracellular pH, recently an increasing number of studies have suggested that ASIC1 is involved in different kinds of tumors, which plays an important role in the occurrence and development of tumors. Therefore, this review will summarize studies involved in ASIC1 on tumors and discuss the effect and mechanism of ASIC1 in numerous related tumors, which will provide new perspectives for tumor therapeutic targets.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

The Role of ASIC1a in Inflammatory Immune Diseases: A Potential Therapeutic Target.

It is acknowledged that chronic inflammation is associated with a rise in extracellular proton concentrations. The acid-sensing ion channel 1a (ASIC1a) belongs to the extracellular H+-activated cation channel family. Recently, many studies have been conducted on ASIC1a and inflammatory immune diseases. Here, in this review, we will focus on the role of ASIC1a in several inflammatory immune diseases so as to provide new perspectives for clinical treatment.

Advances in Pathogenesis, Progression, Potential Targets and Targeted Therapeutic Strategies in SARS-CoV-2-Induced COVID-19.

As the new year of 2020 approaches, an acute respiratory disease quietly caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19) was reported in Wuhan, China. Subsequently, COVID-19 broke out on a global scale and formed a global public health emergency. To date, the destruction that has lasted for more than two years has not stopped and has caused the virus to continuously evolve new mutant strains. SARS-CoV-2 infection has been shown to cause multiple complications and lead to severe disability and death, which has dealt a heavy blow to global development, not only in the medical field but also in social security, economic development, global cooperation and communication. To date, studies on the epidemiology, pathogenic mechanism and pathological characteristics of SARS-CoV-2-induced COVID-19, as well as target confirmation, drug screening, and clinical intervention have achieved remarkable effects. With the continuous efforts of the WHO, governments of various countries, and scientific research and medical personnel, the public's awareness of COVID-19 is gradually deepening, a variety of prevention methods and detection methods have been implemented, and multiple vaccines and drugs have been developed and urgently marketed. However, these do not appear to have completely stopped the pandemic and ravages of this virus. Meanwhile, research on SARS-CoV-2-induced COVID-19 has also seen some twists and controversies, such as potential drugs and the role of vaccines. In view of the fact that research on SARS-CoV-2 and COVID-19 has been extensive and in depth, this review will systematically update the current understanding of the epidemiology, transmission mechanism, pathological features, potential targets, promising drugs and ongoing clinical trials, which will provide important references and new directions for SARS-CoV-2 and COVID-19 research.

Efficacy and safety of intermittent versus continuous dose apatinib plus docetaxel as second-line therapy in patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma: a randomized controlled study.

Background: Previous studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Methods: Advanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: In total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72-6.03) months vs. 3.98 (95% CI: 1.06-6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31-12.70) months vs. 9.40 (95% CI: 5.20-13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups. Conclusions: Intermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Trial Registration: ClinicalTrials.gov NCT03334591.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.

Effect of CX3CL1/CX3CR1 gene polymorphisms on the clinical efficacy of carboplatin therapy in Han patients with ovarian cancer.

Gene polymorphisms have a close relationship with the clinical effects of carboplatin for ovarian cancer. Here, we investigated the relationship between CX3CL1 and CX3CR1 genotypes and the clinical efficacy of carboplatin in ovarian cancer, thereby clarifying the unidentified genetic factors that influence the efficacy of carboplatin in ovarian cancer. Based on the above purposes, we used Sequenom Mass ARRAY technology to detect CX3CL1 and CX3CR1 gene polymorphisms in 127 patients with carboplatin-treated ovarian cancer. We performed various statistical analyses to evaluate the effects of CX3CL1 and CX3CR1 genetic variants, demographic data, and clinical characteristics on the effect of carboplatin therapy. The results show that the CX3CL1 genotypes rs223815 (G>C) and rs682082 (G>A) will significantly affect the clinical efficacy of carboplatin for ovarian cancer (p < 0.05), while the other six genotypes and all CX3CR1 genotypes have no significant effect (p > 0.05). In addition, only one population factor, age, had a significant effect on the clinical efficacy of carboplatin-treated ovarian cancer (p < 0.05). Based on the above research results, we concluded that the clinical efficacy of carboplatin in ovarian cancer patients was significantly correlated with age and CX3CL1 polymorphism factors; however, more in-depth effects and mechanisms need to be explored by large-scale, multicenter studies.

Establishment of predicting equation for individual sufentanil dosage postoperatively based on gene polymorphisms.

BACKGROUND: Postoperative analgesia is widely used for patients undergoing major surgeries. Individual differences in genetic polymorphisms may be obstructive factors for accurately anesthetics using. However, the equation for predicting sufentanil dosage postoperatively based on genetic design has been established yet. Our aim was to establish sufentanil dosage postoperatively prediction equation based on patients' genetic polymorphisms. METHODS: One hundred forty patients with total gastrectomy and radical resection of pulmonary carcinoma were included. To establish sufentanil dosage postoperatively for patients with gastric cancer, we collected patients' basic information and CYP3A4*1G, COMTVal158Met, OPRM1A118G, and ABCB1C3435T gene sequencing results. To verify this equation, we put patients' with lung cancer surgeries information into it. RESULTS: The sufentanil dosage prediction equation postoperatively was y = 4.104 - 0.222 × (gender) + 0.021 × (OPRM1A118G) + 0.249 × (ABCB1C3435T). Patients' with lung cancer surgeries information were substituted into it. The results showed no significant differences between predicted and actual sufentanil dosage (p > 0.05). CONCLUSION: We established the prediction equation for individual sufentanil dosage postoperatively based on gene polymorphisms. The results showed this prediction equation was valid, which might be used for different types of surgeries. We established an equation for individual dosage of sufentanil for postoperative analgesia based on gene polymorphisms. The results show that the prediction equation is valid, the information might be used for different types of postoperative analgesia, and the painful patients will have great potential safe and personalized pain control after analgesic therapy. It might also have potential as a clinical tool.

ASIC1a promotes acidic microenvironment-induced HCC cells migration and invasion by inducing autophagy.

Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer with high incidence and metastatic rate. Recent studies have shown that the high metastasis of HCC is closely related to the acidic microenvironment of HCC cells. Acid-sensing ion Channel 1a (ASIC1a) plays an important role in HCC development, which can mediate tumor cell migration and invasion. However, the underlying mechanism of how ASIC1a promotes HCC cell migration and invasion in acidic microenvironments remains unclear, while autophagy may act as a mechanism for tumor cells to adapt to acidic microenvironment. Therefore, this study aims to investigate whether ASIC1a mediates autophagy and its effects on the migration and invasion of HCC cells. Interestingly, our study has shown that ASIC1a and autophagy were increased in HepG2 cells in acidic microenvironment, and both of them can promote HCC cells migration and invasion. Moreover, inhibition of ASIC1a with PcTx1 or ASIC1a ShRNA reduced the autophagy flux. Collectively, ASIC1a can promote acidic microenvironment-induced HepG2 cells migration and invasion by inducing autophagy, which may be correlated with Ca2+ influx.

Efficacy and safety of domestic and imported gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It was approved by the U.S. Food and Drug Administration (FDA) for clinical use in 2003. However, gefitinib has only come to China in recent years. Previous studies have not compared the efficacy and safety of domestic and imported gefitinib. Therefore, we conducted this study. METHODS: This study included 227 patients with advanced non-small cell lung cancer (NSCLC) who received gefitinib treatment in four medical institutions: The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Fudan University Shanghai Cancer Center, Shandong Provincial Institute of Cancer Prevention and Jiangsu Cancer Hospital, from January 2017 to July 2018. The patients were divided into a Yiruike group (55 patients treated with domestic gefitinib, Yiruike) and an Iressa group (172 patients treated with imported gefitinib, Iressa). Because gefitinib resistance usually occurs within 8-10 months of gefitinib administration, the patients were followed up for one year to observe their conditions and compare the occurrence of adverse reactions between the two groups. RESULTS: The two groups had no significant difference in baseline data. The median progression-free survival (PFS) of Yiruike group and that of Iressa group were 10.270±2.036 and 12.970±1.634 months, respectively. The mean PFS of Yiruike group and that of Iressa group were 12.598±1.083 and 15.958±0.987 months, respectively. The one-year disease control rate (DCR) of Yiruike group and that of Iressa group were 61.8% and 59.3%, respectively. The differences were all insignificant (P>0.05). The incidence of adverse reactions in these two groups were not significantly different. CONCLUSIONS: Yiruike was slightly superior to Iressa in terms of DCR. However, comparisons of bioequivalence and DCR were not sufficient for evaluating a drug. Other comparisons require long-term follow-up studies with a large sample size.

Liver metabolomic characterization of Sophora flavescens alcohol extract-induced hepatotoxicity in rats through UPLC/LTQ-Orbitrap mass spectrometry.

This study aimed to observe the influence of Sophora flavescens alcohol extract (SFAE) on hepatic metabolic profiling in rats to explore the possible mechanism of hepatotoxicity induced by S. flavescens.Male Sprague-Dawley rats were randomly divided into three groups (n = 6 in each group) and administered with SFAE at different doses of 0, 1.25 and 2.5 g/kg for two weeks. Ultra-performance liquid chromatography-high resolution mass spectrometry was utilized to detect the change in the metabolites in rat liver. Principal component analysis and orthogonal partial least squares discriminant analysis were adapted to perform multivariate statistical analysis between groups and to screen the potential biomarkers. Related metabolic pathway analysis was also conducted.Results indicated that hepatic metabolites in the three groups were separated on day 14, and 25 major differential metabolites were identified. Six bile acids, four carnitines, four lysophosphatidylcholines and glutathione were closely related to hepatotoxicity. Liver metabolomic results showed that rats orally exposed to SFAE exhibited a disturbance of the metabolism of bile acids, fatty acids, glycerophospholipids and amino acids.This study provided new insights into the possible mechanism of hepatotoxicity induced by SFAE in rats.

ASIC1a promotes high glucose and PDGF-induced hepatic stellate cell activation by inducing autophagy through CaMKKß/ERK signaling pathway.

It is well known that the diabetes mellitus complicates liver fibrosis with high morbidity, and Acid-sensing ion Channel 1a (ASIC1a) plays an important role in the development of diabetes and liver fibrosis. However, the underlying mechanism about how diabetes influences the progression of liver fibrosis remains unclear. This study was to investigate the relationship between autophagy and ASIC1a in the process of liver fibrosis under hyperglycemia. Interestingly, our study showed that the autophagy was elevated in the livers from diabetes combined with liver fibrosis double model in vivo and also in rat hepatic stellate cell line HSC-T6 after stimulation with high glucose and platelet-derived growth factor (PDGF) in vitro, and this response could be attenuated by treatment with ASIC1a nonspecific inhibitor Amiloride or specific ShRNA for ASIC1a. Furthermore, inhibition of autophagy treated with 3-MA significantly attenuated HSC-T6 activation and proliferation. Mechanistically, CaMKKß/ERK pathway was activated in HSC-T6 after stimulation with high glucose and PDGF, and could be suppressed by Amiloride. Collectively, we concluded that autophagy induced by ASIC1a contributes to HSC-T6 activation, which ing pathway.