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SARS-CoV-2 vaccines have contributed to the control of COVID-19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS-CoV-2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein-based pseudoviruses derived from wild type (WT) SARS-CoV-2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two-dose mRNA-1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA-1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA-1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA-based vaccine and the use of an mRNA-based vaccine 2 months after Ad26.COV2.S vaccination.

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs. However, the current SLE-related biomarkers still lack sufficient sensitivity, specificity and predictive power for clinical application. Thus, it is significant to explore new immune-related biomarkers for SLE diagnosis and development.MethodsWe obtained seven SLE gene expression profile microarrays (GSE121239/11907/81622/65391/100163/45291/49454) from the GEO database. First, differentially expressed genes (DEGs) were screened using GEO2R, and SLE biomarkers were screened by performing WGCNA, Random Forest, SVM-REF, correlation with SLEDAI and differential gene analysis. Receiver operating characteristic curves (ROCs) and AUC values were used to determine the clinical value. The expression level of the biomarker was verified by RT‒qPCR. Subsequently, functional enrichment analysis was utilized to identify biomarker-associated pathways. ssGSEA, CIBERSORT, xCell and ImmuCellAI algorithms were applied to calculate the sample immune cell infiltration abundance. Single-cell data were analyzed for gene expression specificity in immune cells. Finally, the transcriptional regulatory network of the biomarker was constructed, and the corresponding therapeutic drugs were predicted.ResultsMultiple algorithms were screened together for a unique marker gene, MX2, and expression analysis of multiple datasets revealed that MX2 was highly expressed in SLE compared to the normal group (all P < 0.05), with the same trend validated by RT‒qPCR (P = 0.026). Functional enrichment analysis identified the main pathway of MX2 promotion in SLE as the NOD-like receptor signaling pathway (NES=2.492, P < 0.001, etc.). Immuno-infiltration analysis showed that MX2 was closely associated with neutrophils, and single-cell and transcriptomic data revealed that MX2 was specifically expressed in neutrophils. The NOD-like receptor signaling pathway was also remarkably correlated with neutrophils (r >0.3, P < 0.001, etc.). Most of the MX2-related interacting proteins were associated with SLE, and potential transcription factors of MX2 and its related genes were also significantly associated with the immune response.ConclusionOur study found that MX2 can serve as an immune-related biomarker for predicting the diagnosis and disease activity of SLE. It activates the NOD-like receptor signaling pathway and promotes neutrophil infiltration to aggravate SLE.

Background Coronavirus disease 2019 (COVID-19) patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear. Methods We performed multicolor staining for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases. Results Lung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like, and endothelial cells. More than 90% of infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, natural killer (NK) cells, B cells, and T cells. Most but not all infected cells were angiotensin-converting enzyme 2 (ACE2) positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high levels of inflammatory cells including macrophages, monocytes, neutrophils, and NK cells, and low levels of B cells but abundant T cells consisting of mainly T helper cells, few cytotoxic T cells, and no regulatory T cells. Robust interleukin-6 expression was present in most cells, with or without infection. Conclusions In fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation, and compromised immune responses.

Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.

The aim was to explore the associations of plasma D-dimers (D-D), homocysteine (HCY), and procalcitonin (PCT) levels with multiple trauma.A total of 116 patients were divided into two groups with severe and mild diseases. After 6 months of follow-up, the group with severe disease was divided into survivor and non-survivor groups. The correlations of APACHE II score and simplified acute physiology score II (SAPS II) with D-D, HCY, and PCT levels were subjected to Spearman's analysis. The influencing factors for prognosis were studied using logistic regression analysis, and the values of these levels for prognostic evaluation were explored by plotting receiver operating characteristic curves.After treatment, the group with severe disease had higher levels of D-D, HCY, PCT, APACHE II score, and SAPS II than those of the group with mild disease (p0.05). The non-survivor group had significantly higher levels than those of the survivor group (p0.05). The levels of 116 patients with multiple trauma had positive correlations with APACHE II score and SAPS II (p0.001). The levels were independent risk factors affecting prognosis. Their combination had high diagnostic value for prognostic evaluation.The combination of plasma D-D, HCY, and PCT levels seems to be a useful index for the early evaluation of severity and prognostic evaluation of patients with multiple trauma.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase family of proteins that activate other proteins in cells. Functionally, PCSK9 binds to the receptor of low-density lipoprotein particles (LDL) to regulate cholesterol metabolism and lipoprotein homeostasis in human body. PCSK9 inhibition is a novel pharmacological strategy to control hypercholesterolemia and cardiovascular diseases. Recently accumulating evidence realizes that PCSK9 possesses other roles in cells, such as regulation of tissue inflammatory response, intratumoral immune cell infiltration, and tumor progression. This review discussed the advancement of PCSK9 research on its role and underlying mechanisms in tumor development and progression. For example, PCSK9 inhibition could attenuate progression of breast cancer, glioma, colon tumor, hepatocellular cancer, prostate cancer, and lung adenocarcinoma and promote apoptosis of glioma, prostate cancer, and hepatocellular cancer cells. PCSK9 deficiency could reduce liver metastasis of B16F1 melanoma cells by lowering the circulating cholesterol levels. PCSK9 gene knockdown substantially attenuated mouse tumor growth in vivo by activation of cytotoxic T cells, although PCSK9 knockdown had no effect on morphology and growth rate of different mouse cancer cell lines in vitro. PCSK9 inhibition thus can be used to control human cancers. Future preclinical and clinical studies are warranted to define anti-tumor activity of PCSK9 inhibition.

ImportanceDelayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown.ObjectiveTo investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant.Design, setting, and participantsThis single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population.InterventionsPatients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 μg/kg/h intraoperatively and 0.1 μg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine.Main outcomes and measuresThe primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30.ResultsOf the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit.Conclusions and relevanceThis randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1900025493.

The expression of G2 and S phase-expressed-1 (GTSE1) was upregulated in human cancer. However, its expression and roles in lung cancer have not been identified yet. In our study, we reported that GTSE1 expression was statistically higher in lung tissues than in the adjacent noncancerous tissues which might be a consequence of hypomethylation of the GTSE1 promoter. The upregulated expression of GTSE1 mRNA predicted the poorer survival of the lung patients. Ectopic expression of GTSE1 in lung cancer cells significantly increased while knockdown of GTSE1 decreased cell proliferation, cell migration, and cell invasion in H460 and A549 cells. Furthermore, knockdown of GTSE1 regulated the cell cycle and promoted cell apoptosis in H460 and A549 cells. Finally, we presented that GTSE1 was able to activate AKT/mTOR signaling in H460 and A549 cells. In conclusion, these results indicated that the overexpressed GTSE1 was involved in the progress of lung cancer by promoting proliferation migration and invasion and inhibiting apoptosis of lung cancer cells via activating AKT/mTOR signaling.

Background: The anticancer activity of silibinin (SB) has been demonstrated in various cancer cell types. However, its low solubility and poor bioavailability limit its clinical potential in biomedical applications. Microbubbles in combination with ultrasound are promising vehicles for local drug delivery. Objective: The present study determined the antitumour effects and molecular mechanism of silibinin-loaded microbubbles (SBMBs) in combination with ultrasound on ovarian cancer in vitro. Methods: SBMBs were prepared using mechanical vibration. The viability of A2780 cells was determined using the MTT assay. Flow cytometry was performed to detect cell apoptosis and the cell cycle. The expression of Receptor Tyrosine Kinase (RTK)-associated downstream proteins was detected using multiplex assays and Western blots. Results: The present study designed and synthesized SBMBs. SBMBs in combination with ultrasound decreased A2780 cell viability in a dose- and time-dependent manner. The half maximal inhibitory concentration (IC50) showed that the cytotoxicity of the SBMBs was approximately 1.5 times greater than that of the SB in A2780 cells. SBMBs in combination with ultrasound resulted in significantly higher apoptosis efficiency compared to the SB group, and the SBMB population of cells was arrested in the G1/G0 phase. Further experiments demonstrated that SBMBs decreased the expression of signal transducer and activator of transcription 3 (STAT3), Ak strain transforming (AKT), and extracellular signal-regulated kinase (Erk) and had a greater effect than SB in A2780 cells. Inhibitors of AKT, Erk and STAT3 promoted the cytotoxicity of SBMBs. Conclusion: SBMBs in combination with ultrasound may enhance the cytotoxicity efficiency of SB via the promotion of apoptosis and cell cycle arrest in ovarian cancer cells and the inactivation of the STAT3, AKT and Erk signalling pathways.

The spread of COVID-19 is not evenly distributed. Neighborhood environments may structure risks and resources that produce COVID-19 disparities. Neighborhood built environments that allow greater flow of people into an area or impede social distancing practices may increase residents&rsquo, risk for contracting the virus. We leveraged Google Street View (GSV) images and computer vision to detect built environment features (presence of a crosswalk, non-single family home, single-lane roads, dilapidated building and visible wires). We utilized Poisson regression models to determine associations of built environment characteristics with COVID-19 cases. Indicators of mixed land use (non-single family home), walkability (sidewalks), and physical disorder (dilapidated buildings and visible wires) were connected with higher COVID-19 cases. Indicators of lower urban development (single lane roads and green streets) were connected with fewer COVID-19 cases. Percent black and percent with less than a high school education were associated with more COVID-19 cases. Our findings suggest that built environment characteristics can help characterize community-level COVID-19 risk. Sociodemographic disparities also highlight differential COVID-19 risk across groups of people. Computer vision and big data image sources make national studies of built environment effects on COVID-19 risk possible, to inform local area decision-making.

Stress urinary incontinence (SUI) is more common in women than in men, and sex differences in anatomic structure and physiology have been suggested as causes; however, the underlying cellular and molecular mechanisms remain unclear. The spontaneous tone (STT) of the urethra has been shown to have a fundamental effect on preventing the occurrence of SUI. Here, we investigated whether the urethral STT exhibited sex differences. First, we isolated urethral smooth muscle (USM) and detected STT in female mice and women. No STT was found in male mice or men. Furthermore, caffeine induced increased contractility and intracellular Ca2+ concentration in urethrae from female mice compared with male mice. EACT [an N-aroylaminothiazole, anoctamin-1 (ANO1) activator] elicited increased intracellular Ca2+ concentration and stronger currents in female mice than in male mice. Moreover, ANO1 expression in single USM cells from women and female mice was almost twofold higher than that found in cells from men and male mice. In summary, ANO1 in USM contributes to sex differences in urethral spontaneous tone. This finding may provide new guidance for the treatment of SUI in women and men.

Myocardial ischemia/reperfusion (I/R) injury leads to high mortality and morbidity due to the incomplete understanding of the underlying mechanism and the consequent lack of effective therapy. The present study revealed and validated key candidate genes in relation to inflammation and apoptosis pathways underlying myocardial I/R injury. Cathepsin S was identified as the top hub protein based on the protein-protein interaction analysis, and, thus, its role during myocardial I/R injury was further investigated. Myocardial I/R in mice resulted in significantly increased levels of myocardial injury biomarkers (cardiac troponin I, lactic dehydrogenase, and creatinine kinase-MB) and inflammatory cytokines (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor-α), elevated apoptosis rate, and upregulated protein expression of cleaved caspase-8, cleaved caspase-3, and cleaved poly ADP-ribose polymerase. These abovementioned changes were blocked by two different selective cathepsin S inhibitors, LY3000328 or MIV-247. Moreover, Kaplan-Meier survival plot showed that cathepsin S inhibition improved 21-day survival rate following myocardial I/R injury. This study demonstrated that the inhibition of cathepsin S alleviated myocardial I/R-induced injury by suppressing inflammation and apoptosis, which may be used in clinical applications of cardioprotection.

Objective. To study the expression, biological function, and mechanism of FKBP4 in non-small-cell lung cancer (NSCLC). Methods. First of all, the expression of FKBP4 in NSCLC tissues and cell lines was detected by qRT-PCR; then, the effects of FKBP4 on proliferation, apoptosis, migration, and invasion of NSCLC were studied by CCK-8 assays, flow cytometry assays, wound-healing assays, and Transwell assays. After that, tumor xenografts were used to explore the effect of FKBP4 on NSCLC tumor growth in vivo, and the phosphorylation of Akt and mTOR was measured by western blot. Results. FKBP4 was highly expressed in NSCLC tissues and cells, and its expression was closely related to NSCLC tumor size, lymph node metastasis, and patient prognosis. In vitro, FKBP4 can promote NSCLC cell proliferation, migration, and invasion and inhibit NSCLC cell apoptosis. In vivo, FKBP4 can promote NSCLC tumor growth. Furthermore, FKBP4 can promote Akt and mTOR phosphorylation and activate the Akt/mTOR signaling pathway and an mTOR inhibitor can neutralize the functions of FKBP4 in NSCLC cells. Conclusion. FKBP4 serves as an oncogene to promote malignant processes in NSCLC, and it has the potential to be used as a biological marker and therapeutic target for NSCLC.

Objective: The aim of this systematic review and meta-analysis was to investigate whether or not the use of haloperidol could reduce the incidence of delirium in adult patients. Subjects and Methods: PubMed, Embase, the Cochrane Library, Elsevier, Wiley, and Ovid were searched for randomized controlled trials and prospective interventional cohort studies that compared haloperidol with placebo for delirium prophylaxis or with second generation antipsychotics for delirium treatment. The primary end point was the incidence and severity of delirium. After reviewing 272 relevant articles, 10 studies with 1,861 patients were finally included (haloperidol vs. placebo in 8 studies [n = 1,734], and haloperidol vs. second-generation antipsychotics in 2 studies [n = 127]). Revman 5.3 was used for the data analysis. Results: Compared with placebo, a high dose of prophylactic haloperidol (≥5 mg/day) may help reduce the incidence of delirium in surgical patients (risk ratio 0.50, 95% CI 0.32, 0.79). There were no differences in the duration of delirium, QTc interval prolongation, extrapyramidal symptoms, intensive care unit stay, hospital stay, or mortality between the haloperidol and placebo groups. For delirium treatment, haloperidol exhibited similar effects as the second-generation antipsychotics. Conclusions: In this study, the limited available data revealed that prophylaxis haloperidol at a dose of ≥5 mg/day might help reduce delirium in adult surgical patients. Further outcome studies with larger sample sizes are required to confirm these findings.

BackgroundNeighbourhood quality has been connected with an array of health issues, but neighbourhood research has been limited by the lack of methods to characterise large geographical areas. This study uses innovative computer vision methods and a new big data source of street view images to automatically characterise neighbourhood built environments.MethodsA total of 430 000 images were obtained using Google’s Street View Image API for Salt Lake City, Chicago and Charleston. Convolutional neural networks were used to create indicators of street greenness, crosswalks and building type. We implemented log Poisson regression models to estimate associations between built environment features and individual prevalence of obesity and diabetes in Salt Lake City, controlling for individual-level and zip code-level predisposing characteristics.ResultsComputer vision models had an accuracy of 86%–93% compared with manual annotations. Charleston had the highest percentage of green streets (79%), while Chicago had the highest percentage of crosswalks (23%) and commercial buildings/apartments (59%). Built environment characteristics were categorised into tertiles, with the highest tertile serving as the referent group. Individuals living in zip codes with the most green streets, crosswalks and commercial buildings/apartments had relative obesity prevalences that were 25%–28% lower and relative diabetes prevalences that were 12%–18% lower than individuals living in zip codes with the least abundance of these neighbourhood features.ConclusionNeighbourhood conditions may influence chronic disease outcomes. Google Street View images represent an underused data resource for the construction of built environment features.

Objectives Refugees resettled in the US may be at risk for cardiovascular disease (CVD). However, little is known about CVD-related issues among Karen refugees who have migrated to the US from the Thai-Myanmar border. The purpose of this study was to examine CVD-related health beliefs and lifestyle issues among Karen refugees resettled in the US. Methods Karen refugees resettled in the US from the Thai-Myanmar border (n=195) participated in a survey study on health beliefs related to CVD, salt intake, physical activity (PA), and smoking in the fall of 2016. Results A high-salt diet, physical inactivity, and smoking were major lifestyle problems. Participants who adhered to a low-salt diet considered themselves to be susceptible to CVD. Most participants did not engage in regular PA. Regular PA was associated with less perceived susceptibility to CVD and greater perceived benefits of a healthy lifestyle for decreasing the likelihood of CVD. Conclusions Each refugee population may require individualized strategies to promote PA and a healthy diet. Future studies should develop health education programs that are specifically designed for Karen refugees and evaluate such programs. In addition to health education programs on healthy lifestyle choices, tobacco cessation programs seem to be necessary for Karen refugees. At the same time, it is important to foster strategies to increase the utilization of preventive care among this population by promoting free or reduced-fee resources in the community to further promote their health.

Cardiac fibrosis is considered the initial change of diabetic cardiomyopathy (DCM). We have shown that curcumin alleviates collagen deposition in DCM, but the mechanism remains unknown. In this study we sought to investigate the effects of curcumin on cardiac fibrosis in vivo and in vitro and to elucidate the underlying mechanisms. Experimental diabetes was induced in rats by injection of low-dose streptozotocin (STZ) combined with high energy diet. The rats were orally treated with curcumin (300 mg·kg−1·d−1) for 16 weeks. Curcumin administration significantly suppressed the deposition of type I and type III collagens in the heart tissues of diabetic rats, accompanied by markedly reduced TGF-β1 production, suppressed TβR II levels and Smad2/3 phosphorylation, and increased Smad7 expression. Similar effects were observed in human cardiac fibroblasts exposed to high glucose (HG, 30 mmol/L) or exogenous TGF-β1 (5 ng/mL). Furthermore, TGF-β1 or HG treatment significantly increased the phosphorylation levels of AMPK and p38 MAPK in the fibroblasts. Application of curcumin (25 μmol/L) inhibited TGF-β1- or HG-induced AMPK/p38 MAPK activation and suppressed collagen synthesis in the fibroblasts. These effects were similar to those of the AMPK inhibitor compound C (10 μmol/L) but opposite to the effects of the AMPK activator metformin (2 mmol/L) in the fibroblasts. Our results demonstrate that curcumin suppresses diabetes-associated collagen synthesis in rat myocardium not only by inhibiting TGF-β1 production and canonical Smad signaling but also by blocking the non-canonical AMPK/p38 MAPK pathway.

Patients with malignant pleural effusions (MPEs) have limited life expectancy. This study aims to investigate the feasibility of intrapleural perfusion with hyperthermic chemotherapy (IPHC) under video-assisted thoracoscopic surgery on MPE patients.MPE patients were enrolled in the study and treated with IPHC. The treatment response was classified as complete response (CR, no re-accumulation of pleural fluid for 4 weeks), partial response (PR, re-accumulation above the post-IPHC level but below the pre-IPHC level for four weeks), no response (NR; re-accumulation or above the pre-IPHC level). The change of Karnofsky performance score (KPS) and tumour markers were also recorded. Follow-up was done every two weeks during first month and monthly thereafter until death.Eighty patients included 46 males and 34 females were included in the study. The total response rate was 100%, with 71.3% of CR and 28.7% of PR. The KPS scores were significantly elevated and the level of tumour markers in pleural effusion were dramatically decreased after IPHC. The median survival was 16.8 months ranged from 2.1 to 67.4 months. One-year and two-year survival rates were 82.5% and 23.8%, respectively. There were no serious clinical compilations during IPHC treatment.IPHC is a safety, effective and promising approach for MPE patients. It provides well survival benefit and minor toxicities.

Viral infection induces translocation of the nucleolar protein GLTSCR2 from the nucleus to the cytoplasm, resulting in attenuation of the type I interferon IFN-β. Addressing the role of GLTSCR2 in viral replication, we detect that knocking down GLTSCR2 by shRNAs results in significant suppression of viral replication in mammalian and chicken cells. Injection of chicken embryo with the GLTSCR2-specific shRNA-1370 simultaneously or 24 h prior to infection with Newcastle disease virus (NDV) substantially reduces viral replication in chicken embryo fibroblasts. Injection of shRNA-1370 into chicken embryo also reduces the replication of avian influenza virus (AIV). In contrast, GLTSCR2-derived protein G4-T, forming α-helical dimers, increases replication of seven various DNA and RNA viruses in cells. Our studies reveal that alteration of the function of cellular GLTSCR2 plays a role in supporting viral replication. GLTSCR2 should be seriously considered as a therapeutic target for developing broad spectrum antiviral agents to effectively control viral infection., Highlights • G4-T, a protein that mimics GLTSCR2, folds in an α-helical dimer structure. • G4-T suppresses type I IFN antiviral response. • G4-T promotes efficient proliferation of DNA and RNA viruses belonging to 7 families. • GLTSCR2-specific shRNA reduces the infection of viruses in mammalian and chicken cells. • Injection of GLTSCR2-specific shRNA into chicken embryo reduces the replication of NDV and AIV.

Clinical studies have shown that fenretinide (4-HPR) is an attractive chemopreventive agent for cancer treatment. However, to date, few studies have demonstrated the mechanism of the preventive effect of 4-HPR. In our current study, we revealed that 4-HPR could significantly suppress IL-4/IL-13 induced M2-like polarization of macrophages, which was demonstrated by the reduced expression of M2 surface markers, the down-regulation of M2 marker genes, and the inhibition of M2-like macrophages promoted angiogenesis. Mechanistically, our study suggested that the inhibition of the phosphorylation of STAT6, rather than the generation of oxidative stress, is involved in the 4-HPR-driven inhibition of M2 polarization. More intriguingly, by utilizing adenomatous polyposis coli (APCmin/+) transgenic mice, we demonstrated that the tumorigenesis was dramatically decreased by 4-HPR treatment accompanied with fewer M2-like macrophages in the tumor tissues, thereby profoundly blocking tumor angiogenesis. These findings, for the first time, reveal the involvement of M2 polarization inhibition in 4-HPR-mediated chemoprevention, which provides a new point of insight and indicates the potential mechanism underlying the chemopreventive effect of 4-HPR.

Using a model of oncogenic virus KSHV-driven cellular transformation of primary cells, we have performed a genome-wide CRISPR-Cas9 screening to identify vulnerable genes of cancer cells. This screening is unique in that this virus-induced oncogenesis model does not depend on any cellular genetic alterations and has matched primary and KSHV-transformed cells, which are not available for similar screenings in other types of cancer. We have identified genes that are both growth promoting and growth suppressive in primary and transformed cells, some of which could represent novel proto-oncogenes and tumor suppressors. In particular, we have demonstrated that the exportin XPO1 is a critical factor for the survival of transformed cells. Using a XPO1 inhibitor (KPT-8602) and siRNA-mediated knockdown, we have confirmed the essential role of XPO1 in cell proliferation and in growth transformation of KSHV-transformed cells, as well as of gastric and liver cancer cells. XPO1 inhibition induces cell cycle arrest by activating p53, but the mechanisms of p53 activation differed among different types of cancer cells. p53 activation is dependent on the formation of PML nuclear bodies in gastric and liver cancer cells. Mechanistically, XPO1 inhibition induces relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. These results illustrate that XPO1 is a vulnerable target of cancer cells and reveal a novel mechanism for blocking cancer cell proliferation by XPO1 inhibition as well as a novel PML- and p62-mediated mechanism of p53 activation in some types of cancer cells., The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, among which the cancer-vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) screening in a unique model of matched primary and oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV)-transformed cells and identified genes that were growth promoting and growth suppressive for both types of cells, among which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by small interfering RNA (siRNA) knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells and in cell lines of other cancers, including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation, but the mechanisms of p53 activation differed among the different types of cancer cells. p53 activation depended on the formation of promyelocytic leukemia (PML) nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken the data together, we have identified novel growth-promoting and growth-suppressive genes of primary and cancer cells and have demonstrated that XPO1 is a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML- and p62-dependent mechanism of p53 activation in some types of cancer cells.

Viruses are obligate intracellular parasites that exploit host cell machineries for replication. In this review, we focus on the current understanding of host cell nuclear proteins whose translocation from the nucleus to cytoplasm is induced and utilized by viruses to support viral replication and infection. Utilization of nuclear proteins for viral replication and infection involves disruption of nuclear import, enhancement of nuclear export, removal of nuclear localization signal (NLS) from nuclear proteins and alteration of nuclear pore complexes (NPCs) to cooperatively support viral replication. Understanding of nucleo-cytoplasmic transport system, and associated mechanisms, utilized by viruses will advance therapeutic development of strategies to produce optimal antiviral agents effective in control of viral diseases.

Mei Yuan,1,2,* Xiao-Wen Meng,1,* Jiao Ma,1,* Hong Liu,3 Shao-Yong Song,1 Qing-Cai Chen,1 Hua-Yue Liu,1 Juan Zhang,1 Nan Song,1 Fu-Hai Ji,1 Ke Peng11Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 2Department of Anesthesiology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, People’s Republic of China; 3Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, CA 95817, USACorrespondence: Fu-Hai Ji; Ke PengDepartment of Anesthesiology, First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel +86 5 126 778 0055; +86 5 126 778 0159Email jifuhaisuda@163.com;pengke0422@163.com*These authors contributed equally to this workPurpose: Intracellular calcium ([Ca2+,]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca2+, signaling.Methods: H9c2 cardiomyocytes were subjected to OGD for 12h, followed by 3h of reoxygenation. DEX was administered 1h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca2+,]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed.Results: Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca2+,]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX.Conclusion: This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca2+,]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.Keywords: dexmedetomidine, H9c2 cardiomyocytes, oxygen-glucose deprivation/reoxygenation, apoptosis, intracellular calcium overload, FKBP12.6/RyR2

Ethnopharmacological relevance Toxicodendron vernicifluum (Stokes) F.A. Barkley (syn. Rhus verniciflua or vernicifera Stokes, Anacardiaceae) (RVS), the lacquer tree, also known as sumac, has been used in China, Japan and South Korea for thousands of years as a highly durable coating material and a traditional herbal medicine, which contains medicinal ingredients with anti-tumor, anti-inflammatory, antiviral, and anti-rheumatic activities. Aim of this review This review intends to provide a comprehensive and critical appraisal of RVS, including its phytochemical data, botanical and pharmacological literature that support its therapeutic potential in treatment on human diseases, with emphasis on the isolation of natural occurring compounds and detailed pharmacological investigations. Materials and methods Specific information of RVS was collected by using the key words “Toxicodendron vernicifluum”, “Rhus verniciflua Stokes”, “Rhus vernicifera Stokes” and “Lacquer tree” through published scientific materials (including PubMed, ScienceDirect, Wiley, ACS, CNKI, Scifinder, Springer, Web of Science, Google Scholar, and Baidu Scholar) and other literature sources. Results The major phytoconstituents, 175 of which are presented in this review, including flavonoids, urushiols, terpenes, phenolic acids and other types of compounds, of which flavonoids and urushiols are main components. The extracts and isolates purified from RVS showed a wide range of in vitro and in vivo pharmacological effects, such as anti-cancer, anti-oxidation, anti-inflammatory, antimicrobial, tyrosinase inhibition and so on. Conclusion The modern pharmacological research of RVS mainly focus on the pharmacological effects of crude extract or active constituents, of which the flavonoids are widely studied. However, there are few reports on the relationship between pharmacological effects and their structures. And at present, there is still a lack of researches that are of both effective and in-depth. Meanwhile, there is little research on quality control. Apart from the wood and lacquer, other botanical parts also need to be explored further. In addition to phenolic compounds, the study on other types of components in T. vernicifluum would start more sparks for the discovery of new bioactive principles.

Currently, there is no available biomarker for lung cancer diagnosis. Here we recruited 844 lung cancer patients and 620 healthy participants from six hospitals. A total of four serum proteins was identified and subsequently assessed in the training and validation cohorts. The concentrations of four serum proteins were found to be significantly higher in lung cancer patients compared with healthy participants. The area under the curve (AUC) for the 4-biomarker were 0.86 in the training cohort, and 0.87 in the validation cohort. The classification improved to a corrected AUC of 0.90 and 0.89 respectively following addition of sex, age and smoking status. Similar results were observed for early-stage lung cancer. Remarkably, in a blinded test with a suspicious pulmonary nodule, the adjusted prediction model correctly discriminated the patients with 86.96% sensitivity and 98.25% specificity. These results demonstrated the 4-biomarker panel improved lung cancer prediction beyond that of known risk factors. Moreover, the biomarkers were valuable in differentiating benign nodules which will remain indolent from those that are likely to progress and therefore might serve as an adjuvant diagnosis tool for LDCT scanning., Highlights • A multicentric, case–control study was conducted to identify serum proteins for diagnosing lung cancer. • A 4-marker panel improved lung cancer prediction beyond that of known risk factors. • The biomarkers can detect lung cancer especially stage I–II from healthy controls or benign nodule patients. Currently, low dose chest computed tomography (LDCT) leads to a high false-positive result. Here we identified a panel of four serum proteins, which provides the potential for accurate diagnosis of lung cancer in a multicentric study. More importantly, the biomarkers allowed accurate detection of lung cancer cases especially stage I-II cases from normal and benign nodule subjects. These results suggest that the 4-protein panel might be a useful biomarker for diagnosing lung cancer patients and help discriminate early stage patients, which may serve as an adjuvant diagnosis tool for LDCT scanning in the future.

Tumors require a blood supply for survival, growth, and metastasis. It is widely accepted that the development of the tumor microcirculation compartment need the production of new blood vessels (angiogenesis). Vasculogenic mimicry (VM) is an alternative type of blood supplement independent of endothelial vessels which refers to the formation of tumor cell-lined vessels and is associated with tumor invasion, metastasis and poor cancer patient prognosis. Although a variety of proteins and microenvironmental factors are known to contribute to VM, the mechanisms underlying its formation remain unclear. The induction of VM seems to be related to hypoxia, which may promote the plastic, transendothelial phenotype of tumor cells capable of VM. Here, with regard to the above aspects, we review the advanced research on VM including molecular mechanisms and its clinical significance; and explore the development of VM-related strategies which are being utilized for anticancer treatment.

Background Vivax malaria is an important public health problem in the Greater Mekong Subregion (GMS), including the China-Myanmar border. Previous studies have found that Plasmodium vivax has decreased sensitivity to antimalarial drugs in some areas of the GMS, but the sensitivity of P. vivax to antimalarial drugs is unclear in the China-Myanmar border. Here, we investigate the drug sensitivity profile and genetic variations for two drug resistance related genes in P. vivax isolates to provide baseline information for future drug studies in the China-Myanmar border. Methodology/Principal findings A total of 64 P. vivax clinical isolates collected from the China-Myanmar border area were assessed for ex vivo susceptibility to eight antimalarial drugs by the schizont maturation assay. The medians of IC50 (half-maximum inhibitory concentrations) for chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate, artemether, dihydroartemisinin were 84.2 nM, 34.9 nM, 4.0 nM, 22.3 nM, 41.4 nM, 2.8 nM, 2.1 nM and 2.0 nM, respectively. Twelve P. vivax clinical isolates were found over the cut-off IC50 value (220 nM) for chloroquine resistance. In addition, sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvcrt-o (P. vivax chloroquine resistance transporter-o), and difference in pvmdr1 copy number were studied. Sequencing of the pvmdr1 gene in 52 samples identified 12 amino acid substitutions, among which two (G698S and T958M) were fixed, M908L were present in 98.1% of the isolates, while Y976F and F1076L were present in 3.8% and 78.8% of the isolates, respectively. Amplification of the pvmdr1 gene was only detected in 4.8% of the samples. Sequencing of the pvcrt-o in 59 parasite isolates identified a single lysine insertion at position 10 in 32.2% of the isolates. The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin. Conclusions Our findings depict a drug sensitivity profile and genetic variations of the P. vivax isolates from the China-Myanmar border area, and suggest possible emergence of chloroquine resistant P. vivax isolates in the region, which demands further efforts for resistance monitoring and mechanism studies., Author summary Vivax malaria is an important parasitic disease in the Greater Mekong Subregion (GMS). Plasmodium vivax, which is less sensitive to chloroquine, has been reported in the region. However, as part of the GMS, the drug sensitivity of P. vivax is unclear in the China-Myanmar border area. In view of the important role of antimalarial drugs in malaria elimination strategies, we investigate the drug sensitivity profile and genetic variations of the P. vivax isolates from the China-Myanmar border. We obtained baseline data of ex vivo sensitivities to eight antimalarial drugs and found that chloroquine-resistant P. vivax was possibly emerging this area. Studies of genetic polymorphisms in two candidate genes of drug resistance (pvmdr1 and pvcrt-o) of the P. vivax isolates from this area and found association between the M908L substitution in pvmdr1 with reduced sensitivities to and chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin. It is worth noting that the M908L substitution was almost fixed in our samples, which limits the robustness of the conclusion. Our finding suggests that more rigorous in vivo and ex vivo studies are needed to monitor the efficacy of the frontline drugs and discover drug resistance mechanisms.

To identify differentially expressed genes in sepsis and potential key role of reactive oxygen species (ROS) genes associated with sepsis. Gene expression dataset was available from GSE46599. Firstly, we screened the differentially expressed genes between sepsis and healthy samples. Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools were utilized to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses at the functional level. Differentially expressed genes mediating ROS levels were validated in the next investigation and analysis. We identified 1094 genes expressed differentially between normal and sepsis samples, including 655 upregulated genes and 439 downregulated genes. At the functional level, GO and KEGG pathway enrichment analysis showed that those differentially expressed genes were majorly associated with the immune response and metabolic process in sepsis. Further analysis revealed that neutrophil cytosolic factor 1(NCF1), a critical gene in the ROS system, upregulated in THP-1 cell and monocytes under lipopolysaccharides stimulation. Moreover, we identified the upregulation of NCF1 in a sepsis model. We screened the differentially expressed genes from the global level and identified NCF1 might be a critical target gene in sepsis.

ObjectivesDexmedetomidine (DEX) is a selective α2-adrenoceptor agonist that has anti-inflammatory and cardioprotective effects in myocardial ischemia/reperfusion (I/R) injury. The present study aimed to investigate the underlying mechanism by which DEX protects against myocardial I/R.MethodsSprague Dawley rats were subjected to either sham operation or myocardial I/R, which was induced by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Rats were treated with either DEX or saline prior to surgery. We measured heart infarct size, serum cardiac Troponin I (cTnI), cardiac High mobility group box-1 (HMGB1) expression, myocardial apoptosis and cytokine production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Besides, we evaluated the heart function at 4 weeks post-reperfusion by echocardiography. Unilateral vagotomy or inhibition of the α7 nicotinic acetylcholine receptor (α7nAChR) with methyllycaconitine (MLA) was applied to investigate whether DEX-induced cardioprotection is mediated via the cholinergic anti-inflammatory pathway. Cardiac-selective overexpression of HMGB1 was administered to further confirm if HMGB1 is a key anti-inflammatory target during DEX-induced cardioprotection.ResultsDEX pretreatment significantly attenuated I/R-induced cardiac damage, as evidenced by decreases in short-term injury indicators including myocardial infarct size, cTnI release, myocardial apoptosis, cardiac HMGB1 expression, IL-6 and TNF-α production, as well as improvement on long-term cardiac function at 4 weeks post-reperfusion. These effects were partially reversed by either unilateral vagotomy or methyllycaconitine treatment. Besides, cardiac HMGB1-overexpression nearly abolished DEX-induced cardioprotection.ConclusionsDEX pretreatment protects against myocardial I/R by inhibiting cardiac HMGB1 production and activating the cholinergic anti-inflammatory pathway.

To complement traditional antivirals, natural compounds that act via host targets and present high barriers to resistance are of increasing interest. In the work reported here, we detected that homoharringtonine (HHT) presents effective antiviral activity. HHT completely inhibited infections of vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and porcine epidemic diarrhea virus (PEDV) at concentrations of 50, 100, and 500 nM in cell cultures, respectively. Treatment with HHT at doses of 0.05 or 0.2 mg/kg significantly reduced viral load and relieved severe symptoms in PEDV- or NDV-infected animals. HHT treatment, however, moderately inhibited avian influenza virus (AIV) infection, suggesting its potent antiviral action is restricted to a number of classes of RNA viruses. In this study, we also observed that HHT actively inhibited herpes simplex virus type 1 (HSV-1) replication with a 50% inhibitory concentration (IC50) of 139 nM, the treatment with HHT at 1000 nM led to reductions of three orders of magnitude. Moreover, HHT antagonized the phosphorylation level of endogenous and exogenous eukaryotic initiation factor 4E (p-eIF4E), which might regulate the selective translation of specific messenger RNA (mRNA). HHT provides a starting point for further progress toward the clinical development of broad-spectrum antivirals.

Background Limited evidences were reported about the risk of pre-pregnancy hair dye use or irregular menstruation with abnormal birth weight during pregnancy, and their joint effects were also unknown. The aim of our study was to explore whether the pre-pregnancy exposure of hair dye and irregular menstruation were associated with the risk of abnormal birth weight. Methods We conducted a nested case-control study from a prospective cohort of 6203 pregnant women. Low birth weight study included 315 mother-infant pairs (105 LBW cases and 210 matched controls), and macrosomia study included 381 mother-infant pairs (127 macrosomia cases and 254 matched controls). Meanwhile, lifestyle information including hair dying custom and menstrual history were collected by face-to-face questionnaires and birth outcomes were extracted from the medical records. The logistic regressions models were used to analyze the join effect of irregular menstruation and hair dye use. Results Pre-pregnancy hair dye use was associated with increased risk of LBW (adjusted OR = 1.71, 95% CI: 1.01–2.92, P = 0.048). Irregular menstruation had high risk of LBW (adjusted OR = 2.79, 95% CI: 1.53–5.09, P = 0.001) and macrosomia (adjusted OR = 1.93, 95% CI: 1.09–3.44, P = 0.023). Additionally, in the LBW study, women who used hair dye with pre-pregnancy BMI

Background Primary palmar hyperhidrosis (PPH) is featured by aberrantly perspiration of the hands, which may bring a lot of inconvenience to patient's daily life and work. The purpose of this study is to summarize the clinical effect of needlescopic video-assisted thoracic bilateral T4 sympathicotomy for the treatment of PPH. Patients and Methods Between January 2009 and March 2014, 200 patients received needlescopic video-assisted thoracic bilateral T4 sympathicotomy. We, respectively, took two 5-mm incisions in the third intercostal space on the anterior axillary line and in the fifth intercostal space on the middle axillary line. After collapsing left lung, needlescopic exploration was the first step to determine the targeted sympathetic chain through the third intercostal space. Electric coagulation hook was inserted from another port to cut T4 sympathetic chain and the bypassing nerve fibers for 2 to 3 cm along the surface of the fourth rib. Right thoracic cavity was also administered the same procedure. The palmar temperature was recorded before and after sympathicotomy. The symptom improvement, operative complications, patients' recovery, and satisfaction were evaluated. Finding One hundred and ninety-seven patients uneventfully received two 5-mm port bilateral sympathicotomy, and another 3 patients with extensive pleural adhesions completed the surgery through enlarging the third intercostal incision to 2 cm without conversion to open surgery. All operative procedures were completed in 15 to 35 minutes. The hospital stay was 2 to 4 days. The palmar temperature increased by 2.0 ± 0.5°C, and hyperhidrosis immediately disappeared in both hands after surgery. The efficacy rate was 100%. The postoperative complications such as hemorrhage, hemopneumothorax, bradycardia, or Horner's syndrome had no occurrence. During 6 to 60 months follow-up, mild compensatory sweating of buttock, back, and thigh occurred in 30 patients (15%) at 2 to 5 days after surgery and gradually disappeared at postoperative 15 to 30 days or longer time. All patients were greatly satisfied with the effect with better confidence and quality of life. Until now, no recurrent palmar hyperhidrosis happened. Conclusion Needlescopic video-assisted thoracic bilateral T4 sympathicotomy could reach an excellent and immediate result of treating PPH. It is a safe, convenient, and minimally invasive method appropriate for wide clinical use.

NOP53 is a tumor suppressor protein located in the nucleolus and is translocated to the cytoplasm during infection by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1), as shown in our previous study. Cytoplasmic NOP53 interacts with the retinoic acid-inducible gene I (RIG-I) to remove its K63-linked ubiquitination, leading to attenuation of type I interferon IFN-β. In the present study, we found no obvious translocation of NOP53 in infection by a mutant virus lacking ICP4 (HSV-1/d120, replication inadequate). Blocking cytoplasmic translocation of NOP53 by the deletion of its nuclear export sequence (NES) abrogated its ability to support viral replication. These results demonstrated that NOP53 redistribution is related to viral replication. It is interesting that treatment with poly (I:C) or RIG-I-N (a constitutively-active variant) directly induced NOP53 cytoplasmic translocation. To better assess the function of cytoplasmic NOP53 in viral replication, the NOP53-derived protein N3-T, which contains a human immunodeficiency virus (HIV)-derived cell-penetrating Tat peptide at the C-terminal region of N3 (residues 330–432), was constructed and expressed. The recombinant N3-T protein formed trimers, attenuated the expression of IFN-β and IFN-stimulated genes, as well as decreased the phosphorylation level of interferon regulatory factor 3 (IRF3). Furthermore, N3-T promoted the efficient replication of enveloped and non-enveloped DNA and RNA viruses belonging to 5 families. Our findings expand the understanding of the mechanism by which viruses utilize the nucleolar protein NOP53 for optimal viral replication.

M2 polarization of macrophages is essential for their function in immunologic tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophage-mediated promotion of tumorigenesis, tumor growth in vivo, and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis.

To ensure efficient virus replication, herpes simplex virus type 1 (HSV-1) encodes several viral proteins to counter host defense response upon infection. Among these proteins, the multifunctional viral protein γ34.5 crucially interferes with or disrupts several antiviral pathways at multiple levels. The current study shows that γ34.5 utilizes nucleolar protein NOP53 to facilitate the dephosphorylation of eukaryotic initiation factor eIF2α for efficient viral translation. Our study shows that: (1) ectopic expression of NOP53 greatly increases the intracellular and extracellular viral yields of HSV-1 (wild strain F) in type I interferon-deficient Vero cells, and more subtly promotes viral replication of γ34.5 deletion mutant virus HSV-1/Δγ34.5. (2) NOP53 is migrated from nuclei in HSV-1/F infected cells, but is redistributed incompletely after infection by either HSV-1/Δγ34.5 or ICP4 deletion mutant virus HSV-1/d120 (replication inadequate). Ectopic expression of γ34.5, consequently, induces cytoplasmic translocation of NOP53 in response to HSV-1/Δγ34.5 infection. (3) Increase of NOP53, in two forms of transient transfection and in vitro expression, attenuates the phosphorylation level of eIF2α in HSV-1/F infected cells, but fails to affect eIF2α phosphorylation induced by HSV-1/Δγ34.5 infection. (4) Knockdown of NOP53, which impairs the specific interaction between γ34.5 and protein phosphatase PP1α, disrupts the ability of γ34.5 to maintain HSV-1 virulence. (5) NOP53 knockdown also significantly reduces tissue damage and decreases viral yield in livers of HSV-1 infected mice. Our findings expand the understanding of the underlying mechanism by which viral protein γ34.5 induces NOP53 redistribution; cytoplasmic NOP53 facilitates γ34.5 recruitment of PP1α to dephosphorylate eIF2α, for optimal viral replication. This paper also demonstrates that blocking the specific interaction between γ34.5 and PP1α would be a useful approach for the development of antiviral agents.

It is still a challenge to optimize postoperative pain management. The effects of adding dexmedetomidine (DEX) to opioid-based postoperative intravenous patient-controlled analgesia (PCA) are not fully understood.The aim of this study is to assess the efficacy and safety of opioid-DEX combinations for postoperative PCA, and a trial sequential analysis (TSA) is utilized to evaluate the robustness of the current evidence.A systematic review and meta-analysis.Randomized controlled trials that compared opioid-DEX combinations with opioid-only for PCA in adult surgical patients.MEDLINE, EMBASE, and CENTRAL databases were searched for relevant articles. The main outcomes analyzed were postoperative pain intensity, opioid requirement, and opioid-related adverse events. The random-effects model was used to estimate mean differences (MDs) or relative risks (RRs) with 95% confidence intervals (CIs). A TSA was performed to test whether the evidence was reliable and significant. The quality of evidence for the main outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.Eighteen studies involving 1,284 patients were included. The meta-analysis indicated that opioid-DEX combinations were associated with lower postoperative pain intensity (at rest: MD [24 hours] = -0.48, 95% CI [-0.75, -0.21], P = 0.0005), lower morphine-equivalent requirement (MD [0 - 24 hours] = -12.16 mg [-16.12, -8.21], P0.00001), and lower adverse events (nausea: RR = 0.66 [0.52, 0.83]; vomiting: RR = 0.65 [0.49, 0.87]; and pruritus: RR = 0.57 [0.40, 0.81]). For the above results, the TSA revealed that the cumulative Z-curve exceeded both the traditional boundary and the trial sequential monitoring boundary for benefit. DEX had no effect on the incidence of hypotension or bradycardia, which was also confirmed by the TSA. The GRADE level of evidence was high for postoperative nausea, moderate for pain intensity at rest at 24 hours postoperatively, morphine-equivalent requirement during 0 - 24 hours postoperatively, and postoperative vomiting, pruritus, and bradycardia, and low for postoperative hypotension.The risk of introducing potentially significant heterogeneity exists, and this study did not evaluate the effects of DEX combined with opioids on long-term outcomes including chronic pain and patients' satisfaction after hospital discharge.Postoperative PCA strategies with opioid-DEX combinations decreased postoperative pain, opioid requirement, and opioid-related adverse events. DEX is a useful adjuvant to opioid-based PCA.Dexmedetomidine, pain, postoperative analgesia, opioid, patient-controlled.

The aim of this meta-analysis is to evaluate the analgesic effects of intra-articular dexmedetomidine (DEX) in arthroscopic knee surgery. A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) comparing intra-articular DEX versus control for postoperative analgesia in knee arthroscopy. Trial sequential analysis (TSA) was applied to determine the reliability of the evidence. Twelve RCTs including 594 patients met the eligibility criteria. DEX treatment significantly improved postoperative pain outcomes, with weighted mean differences (95% confidence interval) between the DEX and control groups of −1.57 (−1.94 to −1.20, P

Purpose We examined openly shared substance-related tweets to estimate prevalent sentiment around substance use and identify popular substance use activities. Additionally, we investigated associations between substance-related tweets and business characteristics and demographics at the zip code level. Methods A total of 79,848,992 tweets were collected from 48 states in the continental United States from April 2015-March 2016 through the Twitter API, of which 688,757 were identified as being related to substance use. We implemented a machine learning algorithm (maximum entropy text classifier) to estimate sentiment score for each tweet. Zip code level summaries of substance use tweets were created and merged with the 2013 Zip Code Business Patterns and 2010 US Census Data. Results Quality control analyses with a random subset of tweets yielded excellent agreement rates between computer generated and manually generated labels: 97%, 88%, 86%, 75% for underage engagement in substance use, alcohol, drug, and smoking tweets, respectively. Overall, 34.1% of all substance-related tweets were classified as happy. Alcohol was the most frequently tweeted substance, followed by marijuana. Regression results suggested more convenience stores in a zip code were associated with higher percentages of tweets about alcohol. Larger zip code population size and higher percentages of African Americans and Hispanics were associated with fewer tweets about substance use and underage engagement. Zip code economic disadvantage was associated with fewer alcohol tweets but more drug tweets. Conclusions The patterns in substance use mentions on Twitter differ by zip code economic and demographic characteristics. Online discussions have great potential to glorify and normalize risky behaviors. Health promotion and underage substance prevention efforts may include interactive social media campaigns to counter the social modeling of risky behaviors.

Hypoxia is a common phenomenon occurring in the majority of human tumors and has been proved to play an important role in tumor progression. However, it remains unclear that whether the action of hypoxia on macrophages is a main driving force of hypoxia-mediated aggressive tumor behaviors. In the present study, we observe that high density of M2 macrophages is associated with metastasis in adenocarcinoma Non-Small Cell Lung Cancer (NSCLC) patients. By applying the in vivo hypoxia model, the results suggest that intermittent hypoxia significantly promotes the metastasis of Lewis lung carcinoma (LLC), accompanied with more CD209+ macrophages infiltrated in primary tumor tissue. More intriguingly, by skewing macrophages polarization away from the M1- to a tumor-promoting M2-like phenotype, hypoxia and IL-6 cooperate to enhance the LLC metastasis both in vitro and in vivo. In addition, we also demonstrate that skewing of macrophage M2 polarization by hypoxia relies substantially on activation of ERK signaling. Collectively, these observations unveil a novel tumor hypoxia concept involving the macrophage phenotype shift and provide direct evidence for lung cancer intervention through modulating the phenotype of macrophages.

Glioma tumor suppressor candidate region gene 2 protein (GLTSCR2) is a nucleolar protein. In the investigation of the role of GLTSCR2 that played in the cellular innate immune response to viral infection, we found GLTSCR2 supported viral replication of rhabdovirus, paramyxovirus, and coronavirus in cells. Viral infection induced translocation of GLTSCR2 from nucleus to cytoplasm that enabled GLTSCR2 to attenuate type I interferon IFN-β and support viral replication. Cytoplasmic GLTSCR2 was able to interact with retinoic acid-inducible gene I (RIG-I) and the ubiquitin-specific protease 15 (USP15), and the triple interaction induced USP15 activity to remove K63-linked ubiquitination of RIG-I, leading to attenuation of RIG-I and IFN-β. Blocking cytoplasmic translocation of GLTSCR2, by deletion of its nuclear export sequence (NES), abrogated its ability to attenuate IFN-β and support viral replication. GLTSCR2-mediated attenuation of RIG-I and IFN-β led to alleviation of host cell innate immune response to viral infection. Our findings suggested that GLTSCR2 contributed to efficient viral replication, and GLTSCR2 should be considered as a potential target for therapeutic control of viral infection.

Objectives Contextual factors can influence health through exposures to health-promoting and risk-inducing factors. The aim of this study was to (1) build, from geotagged Twitter and Yelp data, a national food environment database and (2) to test associations between state food environment indicators and health outcomes. Study design This is a cross-sectional study based upon secondary analyses of publicly available data. Methods Using Twitter's Streaming Application Programming Interface (API), we collected and processed 4,041,521 food-related, geotagged tweets between April 2015 and March 2016. Using Yelp's Search API, we collected data on 505,554 unique food-related businesses. In linear regression models, we examined associations between food environment characteristics and state-level health outcomes, controlling for state-level differences in age, percent non-Hispanic white, and median household income. Results A one standard deviation increase in caloric density of food tweets was related to higher all-cause mortality (+46.50 per 100,000), diabetes (+0.75%), obesity (+1.78%), high cholesterol (+1.40%), and fair/poor self-rated health (2.01%). More burger Yelp listings were related to higher prevalence of diabetes (+0.55%), obesity (1.35%), and fair/poor self-rated health (1.12%). More alcohol tweets and Yelp bars and pub listings were related to higher state-level binge drinking and heavy drinking, but lower mortality and lower percent reporting fair/poor self-rated health. Supplemental analyses with county-level social media indicators and county health outcomes resulted in finding similar but slightly attenuated associations compared to those found at the state level. Conclusions Social media can be utilized to create indicators of the food environment that are associated with area-level mortality, health behaviors, and chronic conditions.

To observe wet cupping therapy (WCT) on local blood perfusion and analgesic effects in patients with nerve-root type cervical spondylosis (NT-CS). Fifty-seven NT-CS patients were randomly divided into WCT group and Jiaji acupoint-acupuncture (JA) group according a random number table. WCT group (30 cases) was treated with WCT for 10 min, and JA group (27 cases) was treated with acupuncture for 10 min. The treatment efficacies were evaluated with a Visual Analogue Scale (VAS). Blood perfusion at Dazhui (GV 14) and Jianjing (GB 21) acupoints (affected side) was observed with a laser speckle flowmetry, and its variations before and after treatment in both groups were compared as well. In both groups, the VAS scores significantly decreased after the intervention (P

Vascular endothelial growth factor (VEGF) functions as a regulator of neovascularization in malignant cells. VEGF as a mitogen is thought to alter renal cell carcinoma formation and tumor progression. We investigated the expression of the VEGF gene in order to evaluate its clinical significance in renal cell carcinoma. Tissue samples from 198 patients with renal cell carcinoma were examined with an immunohistochemical stain for the expression of the VEGF gene. The expression rate was compared to 34 normal renal cortical samples obtained from renal surgery from noncancer patients. There were significant differences between normal renal cortex (0%) and cancer tissue (54.5%) in positive staining of VEGF protein (P

Lung cancer is the leading cause of cancer-related deaths for both men and women. Early diagnosis of lung cancer has a 5-year survival rate of 48.8%, however, nearly 35% of stage I patients relapses after surgical resection, thus portending a poor prognosis. Therefore, detecting lung cancer in early stage and further identifying the high-risk patients would allow the opportunity to provide adjuvant therapy and possibly increase survival. There is considerable evidence that the immune system produces an autoantibody response to neoplastic cells. The detection of such autoantibodies has been shown to have diagnostic and prognostic value. Here we took advantage of the high-throughput Luminex technique to multiplex a total of 14 tumor-associated autoantigens to detect the autoantibody from the patients sera. The 14 antigens were expressed by in vitro transcription/translation system with HaloTag at N-terminus. The fusion proteins were then covalently immobilized onto the Luminex microspheres conjugated by the halo-link ligand, thus eliminating the protein purification procedure. Sera samples from cancer patients and healthy controls were interacted with the microsphere-antigen complex to measure the autoantibodies. We have developed a quick multiplex detection system for measuring autoantibody signature from patient sera with minimal cross-reaction. A panel of seven autoantibody biomarkers has generated an AUC>80% in distinguishing the lung cancers from healthy controls. This study is the first report by combining Luminex platform and HaloTag technology to detect humoral immune response in cancer patients. Due to the flexibility of the Luminex technology, this approach can be applied to others conditions such as infectious, neurological, and metabolic diseases. One can envision that this multiplex Luminex system as well as the panel of seven biomarkers could be used to screen the high-risk population with subsequent CT test based on the blood test result.

We aimed to elucidate whether serum VEGFR2 concentration before and after transarterial chemoembolization (TACE) can predict survival in patients with unresectable hepatocellular carcinoma (HCC). Serum VEGFR2 concentrations were serially measured in 169 patients with advanced HCC before and after TACE. We defined a decrease in the serum VEGFR2 level>10% from the pretreatment level as response. Serum VEGFR2 concentrations decreased in 44 (26.0%) patients at week 4. Patients who had a VEGFR2 response at week 4 had a longer median survival than those who did not have a VEGFR2 decrease (19.0 vs. 9.8 months, p

To investigate the abnormal expression of microRNAs (miR-216, miR-222, miR-181) in the serum of patients with hepatocellular carcinoma (HCC) and its clinical significance.Serum miRNAs expression was investigated in 49 patients with HCC and 25 healthy normal controls by using real-time PCR technique, and then correlations between miRNAs expression and the clinicopathological features and prognosis of HCC patients were evaluated.No differences were observed between the HCC patients and healthy controls with respect to the expressions of serum miR-181 and miR-216 (P0.05), while miR-222 was found to be significantly overexpressed in HCC serum samples (6.1 ± 6.6 vs 1.2 ± 0.6, P0.01). According to the median fold change of miR-222 (3-fold) in all HCC serum samples, we divided the 49 patients into two groups:a low expression group (25 patients) and a high expression group (24 patients).High level of miR-222 expression was correlated with cirrhosis (P0.01), tumor number (P = 0.013), portal vein tumor thrombosis (P = 0.002) and TNM stage (P = 0.020), while not correlated with serum alpha-fetoprotein level, tumor size and HbsAg. Kaplan-Meier survival analysis showed that the median overall survival in the high miR-222 expression group was significantly shorter than that in the low expression group (8.7 months vs 16.5 months, P = 0.036). In multivariate Cox analysis, TNM stage and serum miR-222 expression were two independent prognostic factors.Serum miR-222, upregulated in HCC, maybe helpful in prognosis of HCC patients.

To study the relationship of protein intake and energy supply with the physical growth in very/extremely low birth weight infant at their early life.Retrospective survey was performed in Neonatal Intensive Care Unit (NICU) in Peking University First Hospital. Inclusion criteria were preterm infant, birth weight1500 g, hospitalization for longer than 2 weeks, discharge with body weight greater than 1800 g. The infants were divided into two groups according to gestational age (GA). GA32 weeks and ≥ 32 weeks. Physical growth and its relation with the protein intake and energy supply were analyzed. The predictive value of serum blood urea nitrogen (BUN) on protein intake was studied.Ninety-three very/extremely low birth weight infants were involved, 69 in GA32 weeks group and 24 in GA ≥ 32 weeks group.Compared with GA ≥ 32 group, GA32 weeks preterm infants had more weight loss, (9.2 ± 4.4)% vs. (5.0 ± 3.1)%, P = 0.000; slower birth weight recovery (10.6 ± 3.8) d vs. (7.1 ± 2.6) d, P = 0.000; poorer weight gain at 1, 4, 5 weeks of life, (-4.5 ± 9.3) g/ (kg·d) vs. (3.4 ± 6.9) g/ (kg·d), P = 0.000 , (13.5 ± 7.3) g/ (kg·d) vs. (19.2 ± 4.9) g/ (kg·d), P = 0.001, (14.6 ± 5.6) g/ (kg·d) vs. (18.2 ± 4.5) g/ (kg·d), P = 0.031; less energy supply at 1 to 5 weeks (P value was 0.000,0.000,0.025,0.001,0.008 respectively) and less protein intake at 1, 4, 5 weeks of life (P value was 0.009,0.006,0.032). Extrauterine growth retardation (EUGR) was still predominant in our subjects, 47.8% in GA32 weeks group, and 95.8% in GA ≥ 32 weeks group, P = 0.000. The incidence increased greater in GA32 weeks infants, 43.5% vs. 20.8%, P = 0.000.The duration of weight loss and mechanical ventilation correlated negatively with weight gain rate, respectively β = -0.591, P = 0.000 and β = -0.281, P = 0.005; the average energy supply and time taken to reach full enteral feeding were factors improving weight gain, respectively β = 0.202, P = 0.021 and β = 0.354, P = 0.000. After birth, serum BUN declined gradually. Positive relation showed between average protein intake at 3(rd) week and BUN level at the end of 3 weeks, r = 0.420, P = 0.000. Serum BUN 1.44, 1.49 mmol/L at the end of 3(rd) and 4(th) week were cut-off predictors for protein intake less than 3 g/(kg·d) at related period, sensitivity and specificity were 65.3%, 83.3% and 60%, 80% respectively.No enough protein intake and energy supply, poor weight gain are critical problems in the management of very/extremely low birth weight infants. Prevention from NEC, appropriate parenteral/enteral nutrition transforming will benefit their physical growth. Low serum BUN after 3 weeks of life is a valuable predictor of low protein intake.

With retrieval of articles on extraordinary acupoint that were published in domesticin recent five years, one hundred and eight articles of clinical application are screened out and one hundred and twenty-three extraordinary acupoints that are extensively recognized are collected. Of those acupoints, 23 acupoints are included in the latest national standard. Of the rest 100 extraordinary acupoints, 48 acupoints are located on the running courses of fourteen meridians, 4 acupoints are shared with the meridian points and the other 52 acupoints have not been clarified to be located on the running courses of meridians based on the literature data. It is found in the collection of these acupoints that there are many extraordinary acupoints that are extensively used in clinical practice. But the nomenclatures and locations of acupoints have not been unified. Hence, a further standardization on these aspects is anticipated.

This study was designed to investigate the effects of occlusal splints in the treatment of sagittal fractures of the mandibular condyle in children. From January 1995 to December 2011, 37 sagittal fractures of the mandibular condyle in 30 patients aged 4–8 years old were included in this study. All the patients were treated with 1–2 mm occlusal splints in the molar region. The mouths of the patients were kept slightly open by the occlusal splints for 3–6 months, and we reviewed the clinical and radiological remodelling of the affected condyles after treatment. Excellent ( n = 20) and good ( n = 10) clinical outcomes were achieved with full radiological remodelling seen in 19 and partial remodelling in 11. Treatment with occlusal splints is effective in delivering good results and function with minimal morbidity in children with sagittal fractures of the condyle, while permitting ongoing remodelling and growth in the short term.

To explore the prognostic significance of serum vascular endothelial growth factor receptor-2 (VEGFR-2) in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE).A total of 69 HCC patients undergoing TACE from October 2008 to April 2012 were recruited and examined. Their serum level of VEGFR-2 level was measured by enzyme-linked immunosorbent assay (ELISA). The relationship between VEGFR-2 and their clinicopathologic features were observed. Prognostic significance of VEGFR-2 was assessed for their survival.Significant differences existed when the serum level of VEGFR-2 was categorized by tumor number and liver cirrhosis (P = 0.021, P = 0.049). The post-treatment serum level of VEGFR-2 was significant higher than that at pre-treatment (P = 0.045). When the mean pre-treatment serum level of VEGFR-2 (8709 ng/L) was used as a cut-off point, the patients with a low serum level of VEGFR-2 had better overall and progression-free survival than those with a high serum level of VEGF (17 vs. 28 months, P = 0.001 and 10 vs. 15 months P = 0.031 respectively). As revealed by multivariate Cox analysis, the pre-treatment serum level of VEGFR-2 was an independent and significant prognostic factor of survival for HCC patients at post-TACE.The pre-treatment serum level of VEGFR-2 may predict the post-TACE prognosis in HCC patients.