Role of TRPV4-P2X7 Pathway in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion.

Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable non-selective cation channel that is involved in the development of neuropathic pain. P2X7 receptor (P2X7) belongs to a class of ATP-gated nonselective cation channels that plays an important role in neuropathic pain. Nevertheless, little is known about the interaction between them for neuropathic pain. In this paper, we investigated role of TRPV4-P2X7 pathway in neuropathic pain. We evaluated the effect of TRPV4-P2X7 pathway on neuropathic pain in a chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) model. We analyzed the effect of P2X7 on mechanical and thermal hyperalgesia mediated by TRPV4 in CCD. Furthermore, we assessed the effect of TRPV4 on the expression of P2X7 and the release of IL-1ß and IL-6 in DRG after CCD. We found that intraperitoneal injection of TRPV4 agonist GSK-1016790A led to a significant increase of mechanical and thermal hyperalgesia in CCD, which was partially suppressed by P2X7 blockade with antagonist Brilliant Blue G (BBG). Then, we further noticed that GSK-1016790A injection increased the P2X7 expression of CCD, which was decreased by TRPV4 blockade with antagonist RN-1734 and HC-067047. Furthermore, we also discovered that the expressions of IL-1ß and IL-6 were upregulated by GSK-1016790A injection but reduced by RN-1734 and HC-067047. Our results provide evidence that P2X7 contributes to development of neuropathic pain mediated by TRPV4 in the CCD model, which may be the basis for treatment of neuropathic pain relief.

Do cerebral and somatic tissue oxygen saturation measurements correlate with each other during surgery?

Intraoperative maintenance of optimal tissue oxygenation is critical; however, it is uncertain whether measurements of different tissue beds correlate with each other. Cerebral tissue oxygen saturation (SctO2) measured on the forehead and somatic tissue oxygen saturation (SstO2) measured on limbs, using a tissue near-infrared spectroscopy, were simultaneously recorded every 2 s in patients having spine surgery or robotic hysterectomy. Simple linear regression was used to determine the static correlation between SctO2 and SstO2 using the median values of each min for each patient. The dynamic correlation between SctO2 and SstO2 was assessed by Pearson's correlation coefficient (CC) for each non-overlapping 2-min epoch. In patients having spine surgery (n = 99), SctO2 and SstO2 (mean ± SD) were 69.8 ± 4.9% and 75.5 ± 8.7%, whereas in patients having robotic hysterectomy (n = 106), the corresponding values were 74.9 ± 6.8% and 83.7 ± 6.2%. The static correlation between SctO2 and SstO2 was inconsistent (r ranging from - 0.86 to 0.93 in spine surgery and from - 0.74 to 0.85 in robotic hysterectomy). The proportional durations with CC ≤ - 0.3 (negative correlation), - 0.3 < CC < 0.3 (poor correlation) and CC ≥ 0.3 (positive correlation) were 18.3 ± 9.6%, 52.6 ± 12.1% and 29.0 ± 9.6%, respectively, in patients having spine surgery and 19.6 ± 9.0%, 58.6 ± 13.1% and 21.8 ± 8.0%, respectively, in patients having robotic hysterectomy. There are a large discrepancy and inconsistent correlation between intraoperative SctO2 and SstO2 measurements, suggesting their non-interchangeability.

Target-Controlled Infusion of Propofol in Training Anesthesiology Residents in Colonoscopy Sedation: A Prospective Randomized Crossover Trial.

BACKGROUND: Propofol is widely used in sedation for colonoscopy, but its adverse effects on cardiovascular and respiratory systems are still concerning. The present study investigated whether target controlled infusion (TCI) of propofol could provide a better sedation quality than manually controlled infusion (MCI) in training inexperienced anesthesiology residents. MATERIAL/METHODS: Eighteen training residents were allocated into 2 groups receiving TCI and MCI training in their first month in the endoscopy center, while receiving MCI and TCI training instead in their second month. The last 2 patients at the end of each month were included to analyze the sedation quality of TCI and MCI techniques by comparing satisfaction of endoscopist and patients based on the visual analogue scale (VAS). Heart rate (HR), mean blood pressure (MAP), SpO2, and recovery time were also compared as the secondary outcomes. RESULTS: The demographic data were similarly distributed among the TCI and MCI patients. Endoscopist's satisfaction score in the TCI group was significantly higher than in the MCI group, 81.3±7.2 versus 74.2±9.5 (P=0.003), but the patients' satisfaction score was similar between the 2 groups. More stable hemodynamic status was obtained in the TCI group, manifested as higher lowest MAP and lower highest MAP than in the MCI group. Lowest SpO2 in the TCI group was significantly higher than in the MCI group. Patients in the TCI group recovered earlier than in the MCI group. CONCLUSIONS: TCI is a more effective and safer technique for anesthesiology residents in sedation for colonoscopy.

Target-controlled infusion of remifentanil with or without flurbiprofen axetil in sedation for extracorporeal shock wave lithotripsy of pancreatic stones: a prospective, open-label, randomized controlled trial.

BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) is an effective therapeutic method used to treat patients with pancreatic stones. However, the anesthesia for this procedure has been underappreciated, with minimal reports of these procedures in certain case series with general or epidural anesthesia. METHODS: A cohort of 60 patients who elected to undergo ESWL in order to treat pancreatic stones for the first time were randomly selected and divided into two groups. One group of patients received target controlled infusion (TCI) of remifentanil, while the other group of patients received TCI of remifentanil plus a bolus of flurbiprofen axetil (a cyclooxygenase inhibitor) (Rem group and Rem + Flu group, n = 30 for each group). The Dixon's up-and-down method was used to calculate the half maximum effective concentration (EC50) of remifentanil. Visual analogue scales of pain, Ramsay sedation scale, hemodynamic changes, and adverse events were also recorded. RESULTS: The EC50 of remifentanil was calculated to be 4.0 ng/ml (95 % confidential interval: 3.84 ng/ml, 4.16 ng/ml) and 2.76 ng/ml (95 % confidential interval: 2.63 ng/ml, 2.89 ng/ml) in the Rem group and Rem + Flu group respectively (p < 0.001). Pain score was comparable between the two groups, while the Ramsay sedation scale was higher in the Rem group. Hemodynamic data showed that patients in the Rem group experienced higher mean arterial pressures and higher heart rates across the procedures. Patients in Rem group demonstrated a lower respiratory rate (p < 0.001) and a lower SpO2 (p = 0.001). Less adverse events occurred in Rem + Flu group, including a reduced respiratory depression requiring wake-up as well as reduced postoperative nausea and vomiting. CONCLUSION: Remifentanil plus flurbiprofen axetil provided satisfactory analgesia and sedation for ESWL of pancreatic stones with less adverse events. (Clinicaltrial.gov: NCT01998217 ; registered on November 19, 2013).

C-reactive protein and erythrocyte sedimentation rate changes after arthroscopic anterior cruciate ligament reconstruction: guideline to diagnose and monitor postoperative infection.

PURPOSE: The purposes of our study were to determine normative C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values from a retrospective review of patients with and without infection after anterior cruciate ligament (ACL) reconstruction and to determine CRP and ESR threshold levels that can serve as diagnostic indicators of infection. We also tried to draw a curve of CRP and ESR value changes after treatment of ACL infection to evaluate the response to treatment of the infection. METHODS: A retrospective chart review was performed of arthroscopic ACL reconstruction patients from 2007 to 2008 (noninfection group) and all patients with postoperative intra-articular infection from 1997 to 2010 (infection group). We collected the CRP and ESR values on the third and fifth postoperative days in the noninfection group and before infection treatment and on the first, third, fifth, seventh, 10th, 14th, 21st, 28th, and 35th days after infection treatment in the infection group. Sensitivity, specificity, and Youden's index were calculated for different threshold values of CRP and ESR as predictors of infection. Receiver operator curves were obtained for CRP and ESR on the fifth postoperative day. RESULTS: Of 122 patients, 83 had normal joints and 39 had septic joints. The mean CRP and ESR values in patients with septic joints were 101.9 mg/L and 57.1 mm/h, respectively, which were significantly higher than those in the noninfection group (P < .01). A CRP value of 41 mg/L and ESR value of 32 mm/h were the optimal thresholds to predict an infection, which had the highest Youden's index of all calculated values and had sensitivity values of 94.1% and 91.2%, respectively, and specificity values of 97.6% and 80.5%, respectively. The peak CRP level after infection treatment occurred earlier than the peak ESR level (first day v third day) and returned to normal more quickly (21st day v 28th day). CONCLUSIONS: Both CRP and ESR were helpful in determining the presence of a normal or septic joint. The threshold values of 41 mg/L for CRP and 32 mm/h for ESR had the most optimal sensitivity and specificity. The peak CRP level occurred earlier than the peak ESR level after treatment of postoperative infection and returned to normal more quickly. In this study CRP was more useful than ESR to evaluate the response of infection to treatment. LEVEL OF EVIDENCE: Level IV, diagnostic study.

Ginsenoside Rg1 attenuates concanavalin A-induced hepatitis in mice through inhibition of cytokine secretion and lymphocyte infiltration.

The effect of ginsenoside Rg1 (Rg1) on hepatic damage caused by concanavalin A (Con A) has not been fully elucidated. This study was designed to evaluate the protective effect of Rg1 on Con A-induced hepatitis in mice and explore the potential mechanisms of this effect. C57BL/6 mice were divided randomly into the following four experimental groups: phosphate-buffered saline group, Rg1 group, Con A group, Con A + Rg1 group. Mice received Rg1 (20 mg/kg) 3 h before intravenous administration of Con A (15 mg/kg). Levels of alanine transaminase, aspartate transaminase and cytokine production were measured, the amount of phosphorylated IκBα and p65 were tested, the numbers of CD4(+) and CD8(+) T lymphocytes infiltrated in the blood, spleen and liver were calculated, intercellular adhesion molecule-1 (ICAM-1) and interferon-inducible chemokine-10 (CXCL-10) levels were measured and histological examination of the livers was conducted. Pretreatment with Rg1 markedly reduced the elevated levels of serum aminotransferase, ameliorated liver damage and suppressed proinflammatory cytokines secretion via inhibition NF-κB activity following Con A injection of mice. Furthermore, Rg1 administration reduced ICAM-1 and CXCL-10 mRNA expression in the liver as well as the number of CD4(+) and CD8(+) T lymphocytes infiltrating in the liver. Rg1 reduced the incidence of liver damage through inhibition of the proinflammatory response and suppressed the recruitment of CD4(+) and CD8(+) T lymphocytes to the liver. These data indicate that Rg1 represents a novel agent for the treatment of T lymphocyte-dependent liver injury.

PD-L1 blockade attenuated sepsis-induced liver injury in a mouse cecal ligation and puncture model.

Liver plays a major role in hypermetabolism and produces acute phase proteins during systemic inflammatory response syndrome and it is of vital importance in host defense and bacteria clearance. Our previous studies indicated that programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) are crucial modulators of host immune responses during sepsis. Our current study was designed to investigate the role of PD-L1 in sepsis-induced liver injury by a mouse cecal ligation and puncture (CLP) model. Our results indicated that there was a significant increase of PD-L1 expression in liver after CLP challenge compared to sham-operated controls, in terms of levels of mRNA transcription and immunohistochemistry. Anti-PD-L1 antibody significantly alleviated the morphology of liver injury in CLP mice. Anti-PD-L1 antibody administration decreased ALT and AST release in CLP mice, decreased the levels of tumor necrosis factor (TNF)-α , interleukin (IL)-6, and IL-10 mRNA in liver after sepsis challenge. Thus, anti-PD-L1 antibody might have a therapeutic potential in attenuating liver injury in sepsis.

[The development of quality of life questionnaire of Chinese medicine for postoperative patients with colorectal cancer and item screening].

OBJECTIVE: To develop quality of life questionnaire of Chinese medicine for postoperative patients with colorectal cancer (QLQ-CMPPCC), thus comprehensively and objectively evaluating the clinical efficacy of Chinese medicine and pharmacy in treating postoperative patients with colorectal cancer (CC). METHODS: The theoretical structure model of the questionnaire was addressed in combined with basic theories of Chinese medicine according to the principle of WHO quality of life (QOL). The primary questionnaire was developed using methods of structuralization policy making after we extensively retrieve various universal and specific questionnaires for CC cancer patients at home and abroad. The 205 CC patients were tested by questionnaire. The items were screened using experts grading method, item selection analysis, dispersion trends of standard deviation, t-test, correlation coefficient method, factor analysis,and Cronbach's alpha. RESULTS: The QLQ-CMPPCC was developed containing four domains of physical, psychological, independence, and social functions, involving 20 aspects and 54 items. Of them, non-fistula patients answered 43 items and fistula patients answered 46 items. One item covered the general QOL evaluation. CONCLUSIONS: QLQ-CMPPCC showed Chinese medical features. It comprehensively reflected the connotation of QOL for postoperative CC patients. It could be taken as a tool for evaluating Chinese medical efficacy for postoperative CC patients.

Deep muscle stimulator in the treatment of post-stroke spasticity: A protocol for systematic review and meta-analysis.

BACKGROUND: Spasticity is one of the most common complications and sequelae of stroke, with the main clinical manifestations being increased muscle tension, pain, stiffness, and other disorders. It not only increases the length of hospitalization and medical costs but also affects the quality of daily life and the stress of returning to society, increasing the burden on patients and their families. At present, 2 driver types of deep muscle stimulator (DMS) have been used in the clinical treatment of post-stroke spasticity (PSS) with good clinical results, but there is no evidence of clinical efficacy and safety. Therefore, this study aims to integrate direct and indirect comparative clinical evidence through a systematic review and network meta-analysis (NMA). According to the data, different driver types for DMS with the same body of evidence will be collected, analyzed, and sequenced in a quantitative and comprehensive manner and then screened for the optimal driver type of DMS device for PSS treatment. The study also aims to provide reference value and an evidence-based theoretical basis for the clinical optimization of DMS equipment selection. METHODS: A comprehensive retrieval of China National Knowledge Infrastructure, Chinese scientific journal database, China biological feature database, Wanfang Chinese databases and the Cochrane Library, PubMed, Web of Science, and Embase foreign databases will be conducted. Randomized controlled trials of these 2 driver types of DMS devices combined with conventional rehabilitation training of PSS will be searched and published. The retrieval time is from the establishment of the database to December 20, 2022. The 2 first authors will screen references that meet the inclusion criteria, independently extract data according to predesigned rules, and assess the quality of the included studies and the risk of bias according to the Cochrane 5.1 Handbook criteria. R programming and Aggregate Data Drug Information System software will be used to perform a combined NMA of the data and to evaluate the probability of ranking for all interventions. RESULTS: The NMA and probability ranking will determine the best driver type of DMS device for PSS. CONCLUSION: This study will offer a comprehensive evidence-based approach to DMS therapy and assist doctors, PSS patients, and decision-makers in selecting a more efficient, secure, and cost-effective treatment option.

Exploring the mechanism of Ginkgo biloba L. leaves in the treatment of vascular dementia based on network pharmacology, molecular docking, and molecular dynamics simulation.

BACKGROUND: Ginkgo biloba L. leaves (GBLs) play a substantial role in the treatment of vascular dementia (VD); however, the underlying mechanisms of action are unclear. OBJECTIVE: This study was conducted to investigate the mechanisms of action of GBLs in the treatment of VD through network pharmacology, molecular docking, and molecular dynamics simulations. METHODS: The active ingredients and related targets of GBLs were screened using the traditional Chinese medicine systems pharmacology, Swiss Target Prediction and GeneCards databases, and the VD-related targets were screened using the OMIM, DrugBank, GeneCards, and DisGeNET databases, and the potential targets were identified using a Venn diagram. We used Cytoscape 3.8.0 software and the STRING platform to construct traditional Chinese medicine-active ingredient-potential target and protein-protein interaction networks, respectively. After gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis of potential targets using the DAVID platform, the binding affinity between key active ingredients and targets was analyzed by molecular docking, and finally, the top 3 proteins-ligand pairs with the best binding were simulated by molecular dynamics to verify the molecular docking results. RESULTS: A total of 27 active ingredients of GBLs were screened and 274 potential targets involved in the treatment of VD were identified. Quercetin, luteolin, kaempferol, and ginkgolide B were the core ingredients for treatment, and AKT1, TNF, IL6, VEGFA, IL1B, TP53, CASP3, SRC, EGFR, JUN, and EGFR were the main targets of action. The main biological processes involved apoptosis, inflammatory response, cell migration, lipopolysaccharide response, hypoxia response, and aging. PI3K/Akt appeared to be a key signaling pathway for GBLs in the treatment of VD. Molecular docking displayed strong binding affinity between the active ingredients and the targets. Molecular dynamics simulation results further verified the stability of their interactions. CONCLUSION SUBSECTIONS: This study revealed the potential molecular mechanisms involved in the treatment of VD by GBLs using multi-ingredient, multi-target, and multi-pathway interactions, providing a theoretical basis for the clinical treatment and lead drug development of VD.

Exploring the molecular mechanism of Nux Vomica in treating ischemic stroke using network pharmacology and molecular docking methods.

BACKGROUND: Nux Vomica (NV) has the effects of dredging collaterals, relieving pain, dispersing knots, and detumescence, and has a verified effect in treating ischemic stroke (IS), but its molecular mechanism for treating IS remains unclear. In this study, network pharmacology and molecular docking methods were adopted to explore the pharmacological mechanism of NV in treating IS. METHODS: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the HERB database were searched to screen the active components and targets of NV. IS disease targets were retrieved from the DisGeNET, DrugBank, GeneCards, and Therapeutic Target Database. Venn diagram and intersection targets were obtained from the Venny website. Subsequently, the STRING database was employed to analyze the interrelationship of the intersection targets. Metascape database was used for Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of intersection targets. Furthermore, Cytoscape was employed to plot a drug-component-target network, and other networks, and molecular docking method was adopted to predict the effective components and targets of NV for treating IS. RESULTS: A total of 14 active compounds and 59 targets of NV were screened, of which 35 targets were related to IS. Stigmasterol, brucine, isobrucine, isostrychnine N-oxide (I), (S)-stylopine, icaride A, and (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one were the main active ingredients, and SLC6A4, NR3C1, SLC6A3, HTR3A, CHRNA7, MAOA, PTGS2, ESR1, catalase (CAT), ADRB2, and AR were the core targets. Molecular docking shows that these compounds bind well to the core targets. In addition, the treatment of IS by NV may mainly involve salivary secretion, serotonergic synapse, calcium signaling pathway, cGMP-PKG signaling pathway, and neuroactive ligand-receptor interaction. CONCLUSIONS: This study revealed that NV exerts its therapeutic effect on IS through multi-component, multi-target, and multi-pathway, which provides a basis for clinical treatment of IS.

Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis.

INTRODUCTION: Early diagnosis of sepsis is vital to the clinical course and outcome of septic patients. Recently, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) appears to be a potential marker of infection. The objective of this systematic review and meta-analysis was to evaluate the accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients. METHODS: A systematic literature search of PubMed, Embase and Cochrane Central Register of Controlled Trials was performed using specific search terms (up to 15 October 2012). Studies were included if they assessed the accuracy of plasma sTREM-1 for sepsis diagnosis in adult patients with systemic inflammatory response syndrome (SIRS) and provided sufficient information to construct a 2 X 2 contingency table. RESULTS: Eleven studies with a total of 1,795 patients were included. The pooled sensitivity and specificity was 79% (95% confidence interval (CI), 65 to 89) and 80% (95% CI, 69 to 88), respectively. The positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 4.0 (95% CI, 2.4 to 6.9), 0.26 (95% CI, 0.14 to 0.48), and 16 (95% CI, 5 to 46), respectively. The area under the curve of the summary receiver operator characteristic was 0.87 (95% CI, 0.84 to 0.89). Meta-regression analysis suggested that patient sample size and assay method were the main sources of heterogeneity. Publication bias was suggested by an asymmetrical funnel plot (P = 0.02). CONCLUSIONS: The present meta-analysis showed that plasma sTREM-1 had a moderate diagnostic performance in differentiating sepsis from SIRS. Accordingly, plasma sTREM-1 as a single marker was not sufficient for sepsis diagnosis in systemic inflammatory patients.

Theoretical study on thermal decomposition mechanism of 1-nitroso-2-naphthol.

1-nitroso-2-naphthol has thermal instability of thermal decomposition, spontaneous combustion and even explosion. Its thermal decomposition characteristics were tested by synchronous thermal analyzer (TGA/DSC); The activation energy of the thermal decomposition process was calculated by Kissinger method; The infrared absorption characteristic spectra of the gas products produced in the thermal decomposition process were measured by TGA/DSC-FTIR, and the thermal decomposition reaction process was speculated. The results show that the initial temperature (Tonset) of TGA exothermic decomposition of 1-nitroso-2 naphthol is between 129.01 and 155.69 °C, and the faster the heating rate(ß), the higher the Tonset, but the faster the thermal decomposition rate, the greater the heat release and the worse the thermal stability. The activation energy (E) of the thermal decomposition process is 83.323 kJ/mol calculated by Kissinger method. The dynamic test results of TGA/DSC-FTIR show that the main reaction of 1-nitroso-2 naphthol during heating is intermolecular dehydration to form ether, and the secondary reaction is decomposition into aliphatic nitro compounds, carbonyl compounds and amines. Sodium hydroxide will reduce the thermal stability of 1-nitroso-2 naphthol. After adding sodium hydroxide, the thermal decomposition process of 1-nitroso-2 naphthol has changed. The main reaction is that 1-nitroso-2-naphthol reacts with sodium hydroxide to produce sodium nitrophenol, which is further decomposed into aliphatic nitro compounds. The research results have guiding significance for finding the reasonable conditions and temperature of 1-nitroso-2 naphthol during storage and transportation.

Repetitive transcranial magnetic stimulation in patients with fibromyalgia: A protocol for systematic review and network meta-analysis.

BACKGROUND: Fibromyalgia is a chronic disease characterized by widespread pain. Repetitive transcranial magnetic stimulation (rTMS) effectively relieves pain intensity in patients with fibromyalgia. The frequency and target site of rTMS have significant roles in therapy effectiveness. However, there is disagreement over the best rTMS protocol. Thus, we will conduct a thorough systematic review and network meta-analysis to rank the efficacy of these various rTMS protocols and determine which is most beneficial in lowering pain and enhancing the quality of life. METHODS: Databases PubMed, Web of Science, Embase, and Cochrane Library will be searched for clinical randomized controlled trials of rTMS in fibromyalgia. The retrieval time is from the inception of the database until October 1, 2022. Following the Cochrane Handbook, 2 reviewers will independently review the literature, extract data, and evaluate the risk of bias of included articles. Pain intensity and quality of daily life are outcome indicators. Stata 17.0 and ADDIS 1.16.8 software will be used for pairwise meta-analysis and network analysis to evaluate the effectiveness of rTMS and the ranking probability of all protocols. The recommended grading assessment, development, and evaluation will be used to assess the overall quality of the evidence. RESULTS: The meta-analysis and probability ranking of the network determined the best TMS protocol for fibromyalgia. CONCLUSION: This study will provide systematic support of evidence-based medicine for TMS in fibromyalgia, integrate the results of direct and indirect comparisons of the efficacy of different rTMS protocol, and provide the best one.

m6A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Recent studies have highlighted the biological significance of exosomes and m6A modifications in immunity. Nonetheless, it remains unclear whether the m6A modification gene in exosomes of body fluid has potential roles in the tumor microenvironment (TME). Herein, we identified three different m6A-related exosomal gene modification patterns based on 59 m6A-related exosomal genes, which instructed distinguishing characteristics of TME in colon cancer (CC). We demonstrated that these patterns could predict the stage of tumor inflammation, subtypes, genetic variation, and patient prognosis. Furthermore, we developed a scoring mode-m6A-related exosomal gene score (MREGS)-by detecting the level of m6A modification in exosomes to classify immune phenotypes. Low MREGS, characterized by prominent survival and immune activation, was linked to a better response to anti-PDL1 immunotherapy. In contrast, the higher MREGS group displayed remarkable stromal activation, high activity of innate immunocytes, and a lower survival rate. Hence, this work provides a novel approach for evaluating TME cell infiltration in colon cancer and guiding more effective immunotherapy strategies.

Elucidation of the conformational dynamics and assembly of Argonaute-RNA complexes by distinct yet coordinated actions of the supplementary microRNA.

Argonaute (AGO) proteins, the core of RNA-induced silencing complex, are guided by microRNAs (miRNAs) to recognize target RNA for repression. The miRNA-target RNA recognition forms initially through pairing at the seed region while the additional supplementary pairing can enhance target recognition and compensate for seed mismatch. The extension of miRNA lengths can strengthen the target affinity when pairing both in the seed and supplementary regions. However, the mechanism underlying the effect of the supplementary pairing on the conformational dynamics and the assembly of AGO-RNA complex remains poorly understood. To address this, we performed large-scale molecular dynamics simulations of AGO-RNA complexes with different pairing patterns and miRNA lengths. The results reveal that the additional supplementary pairing can not only strengthen the interaction between miRNA and target RNA, but also induce the increased plasticity of the PAZ domain and enhance the domain connectivity among the PAZ, PIWI, N domains of the AGO protein. The strong community network between these domains tightens the mouth of the supplementary chamber of AGO protein, which prevents the escape of target RNA from the complex and shields it from solvent water attack. Importantly, the inner stronger matching pairs between the miRNA and target RNA can compensate for weaker mismatches at the edge of supplementary region. These findings provide guidance for the design of miRNA mimics and anti-miRNAs for both clinical and experimental use and open the way for further engineering of AGO proteins as a new tool in the field of gene regulation.

Mechanistic Insights into the Protection Effect of Argonaute-RNA Complex on the HCV Genome.

While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5' end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein to protect the 5' end of HCV RNA from exonucleolytic attacks. Experiments showed that the disruption of the stem-loop 1(SL1) structure and the 9th nucleotide (T9) of HCV site 1 RNA could enhance the affinity of the Ago2 protein to the HCV site 1 RNA (target RNA). However, the underlying mechanism of how the conformation and dynamics of the Ago2: miRNA: target RNA complex is affected by the SL1 and T9 remains unclear. To address this, we performed large-scale molecular dynamics simulations on the AGO2-miRNA complex binding with the WT target, T9-abasic target and SL1-disruption target, respectively. The results revealed that the T9 and SL1 structures could induce the departing motion of the PAZ, PIWI and N domains, propping up the mouth of the central groove which accommodates the target RNA, causing the instability of the target RNA and disrupting the Ago2 binding. The coordinated motion among the PAZ, PIWI and N domains were also weakened by the T9 and SL1 structures. Moreover, we proposed a new model wherein the Ago2 protein could adopt a more constraint conformation with the proximity and more correlated motions of the PAZ, N and PIWI domains to protect the target RNA from dissociation. These findings reveal the mechanism of the Ago2-miRNA complex's protective effect on the HCV genome at the atomic level, which will offer guidance for the design of drugs to confront the protection effect and engineering of Ago2 as a gene-regulation tool.

Prognostic Factors in Stage IV Colorectal Cancer Patients With Resection of Liver and/or Pulmonary Metastases: A Population-Based Cohort Study.

Importance: Currently, surgical resection of distant metastatic lesions has become the preferred treatment for select colorectal cancer (CRC) patients with liver metastasis (LM) and/or pulmonary metastasis (PM). Metastasectomy is the most common curative method. However, evidence of the factors affecting the prognosis of CRC patients after resection of LM and/or PM is still insufficient. Objective: To explore the prognostic factors of CRC patients with LM and/or PM who have undergone resection of metastatic tumors and to provide reliable selection factors for surgical treatment in patients affected by LM and/or PM from CRC. Methods: The SEER database was used to identify eligible CRC LM and/or PM patients who underwent resection of the primary tumor and distant metastases from January 1, 2010, to December 31, 2018. The Kaplan-Meier method was used to calculate survival, and comparisons were performed using the log-rank test for univariate analysis. A Cox proportional hazards regression model was used to identify prognostic factors for the multivariate analysis. The outcomes included overall survival (OS) and cancer-specific survival (CSS). Results: A total of 3,003 eligible colorectal cancer patients with LM and/or PM were included in this study. The 3-year and 5-year OS rates were 53% and 33.6%, respectively, and the 3-year and 5-year CSS rates were 54.2% and 35.3%, respectively. In the adjusted multivariate analysis, age < 65 years (OS: p=0.002, CSS: p=0.002) was associated with better long-term outcomes, and primary tumors located on the left side of the colon (OS: p=0.004, CSS: p=0.006) or rectum (OS: p=0.004, CSS: p=0.006), T3 stage (OS: p<0.001, CSS: p<0.001), number of regional lymph nodes examined ≥ 12 (OS: p<0.001, CSS: p=0.001), and CRC LM (OS: p<0.001, CSS: p<0.001) were positive prognostic factors for survival after resection of metastatic tumors. Conclusion: Age < 65 years is associated with better long-term outcomes in colorectal cancer patients with LM and/or PM, analogously to the left sided primary tumor, T3 stage, number of regional lymph nodes examined ≥ 12 and liver metastases.

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity. Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients. Design, Setting, and Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle. Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion. Main Outcomes and Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12. Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] µg/dL vs 6.1 [3.4] µg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population. Conclusions and Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression. Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.

Femoral nerve block versus fascia iliaca block for pain control in knee and hip arthroplasties: A meta-analysis.

BACKGROUND: This meta-analysis aimed to compare the efficiency of fascia iliaca compartment block (FICB) and femoral nerve block (FNB) for pain management in knee and hip surgeries. METHODS: We searched four electronic databases (Pubmed, Embase, Cochrane library database, Web of Science) from inception to January 2019. Only randomized controlled trials (RCTs) were included. Two review authors independently extracted data for each included study. Primary outcomes were visual analogue scale at 12 hours, 24 hours, 48 hours, total morphine consumption, the length of hospital stay and the occurrence of nausea and vomiting. Standardized mean difference (SMD) or risk ratio (RR) and 95% confidence intervals (CIs) were calculated for continuous outcomes and discontinuous outcomes respectively. We used the Cochrane Risk of Bias tool to assess risk of bias. Stata 12.0 was used for meta-analysis. RESULTS: Finally, 7 RCTs involving 508 patients (FICB = 254, FNB = 254) were included in this meta-analysis. Compared with FNB group, FICB has no benefit for visual analogue scale at 12 hours (SMD = 0.02, 95% CI, -0.15 to 0.19; P = .820), 24 hours (SMD = -0.02, 95% CI, -0.22 to 0.18; P = .806), and 48 hours (SMD = -0.02, 95% CI, -0.22 to 0.19; P = .872). No significant differences were found regarding total morphine consumption (SMD = -0.07, 95% CI, -0.29 to 0.15; P = .533). What's more, there was no significant difference between the length of hospital stay and the occurrence of nausea and vomiting (P > .05). CONCLUSION: FICB has equivalent pain control and morphine-sparing efficacy when compared with FNB. More high-quality RCTs are needed to identify the optimal drugs and volume of local infiltration protocols.