Enhanced antigen-specific CD8 T cells contribute to early protection against FMDV through swine DC vaccination.

Foot-and-mouth disease virus (FMDV) remains a challenge for cloven-hooved animals. The currently licensed FMDV vaccines induce neutralizing antibody (NAb)-mediated protection but show defects in the early protection. Dendritic cell (DC) vaccines have shown great potency in inducing rapid T-cell immunity in humans and mice. Whether DC vaccination could enhance early protection against FMDV has not been elaborately explored in domestic pigs. In this study, we employed DC vaccination as an experimental approach to study the roles of cellular immunity in the early protection against FMDV in pigs. Autologous DCs were differentiated from the periphery blood mononuclear cells of each pig, pulsed with inactivated FMDV (iFMDV-DC) and treated with LPS, and then injected into the original pigs. The cellular immune responses and protective efficacy elicited by the iFMDV-DC were examined by multicolor flow cytometry and tested by FMDV challenge. The results showed that autologous iFMDV-DC immunization induced predominantly FMDV-specific IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells (CTLs), high NAb titers, compared to the inactivated FMDV vaccine, and accelerated the development of memory CD4 and CD8 T cells, which was concomitantly associated with early protection against FMDV virulent strain in pigs. Such early protection was associated with the rapid proliferation of secondary T-cell response after challenge and significantly contributed by secondary CD8 effector memory T cells. These results demonstrated that rapid induction of cellular immunity through DC immunization is important for improving early protection against FMDV. Enhancing cytotoxic CD8+ T cells may facilitate the development of more effective FMDV vaccines.IMPORTANCEAlthough the currently licensed FMDV vaccines provide NAb-mediated protection, they have defects in early immune protection, especially in pigs. In this study, we demonstrated that autologous swine DC immunization augmented the cellular immune response and induced an early protective response against FMDV in pigs. This approach induced predominantly FMDV-specific IFN-γ-producing CD4+ T cells and cytotoxic CD8+ T cells, high NAb titers, and rapid development of memory CD4 and CD8 T cells. Importantly, the early protection conferred by this DC immunization is more associated with secondary CD8+ T response rather than NAbs. Our findings highlighted the importance of enhancing cytotoxic CD8+ T cells in early protection to FMDV in addition to Th1 response and identifying a strategy or adjuvant comparable to the DC vaccine might be a future direction for improving the current FMDV vaccines.

Foot-and-mouth disease virus downregulates vacuolar protein sorting 28 to promote viral replication.

Vacuolar protein sorting 28 (Vps28), a component of the ESCRT-I (endosomal sorting complex required for transport I), plays an important role in the pathogen life cycle. Here, we investigated the reciprocal regulation between Vps28 and the foot-and-mouth disease virus (FMDV). Overexpression of Vps28 decreased FMDV replication. On the contrary, the knockdown of Vps28 increased viral replication. Subsequently, the mechanistic study showed that Vps28 destabilized the replication complex (RC) by associating with 3A rather than 2C protein. In addition, Vps28 targeted FMDV VP0, VP1, and VP3 for degradation to inhibit viral replication. To counteract this, FMDV utilized tactics to restrict Vps28 to promote viral replication. FMDV degraded Vps28 mainly through the ubiquitin-proteasome pathway. Additional data demonstrated that 2B and 3A proteins recruited E3 ubiquitin ligase tripartite motif-containing protein 21 to degrade Vps28 at Lys58 and Lys25, respectively, and FMDV 3Cpro degraded Vps28 through autophagy and its protease activity. Meantime, the 3Cpro-mediated Vps28 degradation principally alleviated the ability to inhibit viral propagation. Intriguingly, we also demonstrated that the N-terminal and C-terminal domains of Vps28 were responsible for the suppression of FMDV replication, which suggested the elaborated counteraction between FMDV and Vps28. Collectively, our results first investigate the role of ESCRTs in host defense against picornavirus and unveil underlying strategies utilized by FMDV to evade degradation machinery for triumphant propagation. IMPORTANCE ESCRT machinery plays positive roles in virus entry, replication, and budding. However, little has been reported on its negative regulation effects during viral infection. Here, we uncovered the novel roles of ESCRT-I subunit Vps28 on FMDV replication. The data indicated that Vps28 destabilized the RC and impaired viral structural proteins VP0, VP1, and VP3 to inhibit viral replication. To counteract this, FMDV hijacked intracellular protein degradation pathways to downregulate Vps28 expression and thus promoted viral replication. Our findings provide insights into how ESCRT regulates pathogen life cycles and elucidate additional information regarding FMDV counteraction of host antiviral activity.

Association between BMI and osteoporotic fractures at different sites in Chinese women: a case-control retrospective study in Changsha.

BACKGROUND: Osteoporotic fractures are a growing problem in an aging society. The association between body mass index (BMI) and osteoporotic fractures varies by fracture site and ethnicity. Limited knowledge exists regarding this association in native Chinese, particularly utilizing local databases as reference sources. OBJECTIVE: To investigate the association between BMI and osteoporotic fractures at different sites in Chinese women. METHODS: Three thousand ninety-eight female patients with radiographic fractures and 3098 age- and sex-matched healthy controls without fractures were included in the study. Both of them underwent assessment using dual-energy X-ray absorptiometry (DXA), with BMD measurements calculated using our own BMD reference database. Participants were classified into underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 24.0 kg/m2), overweight (24 ≤ BMI < 28 kg/m2) and obese (BMI ≥ 28 kg/m2) according to the Chinese BMI classification standard. RESULTS: There were 2296 (74.1%) vertebral fractures, 374 (12.1%) femoral neck fractures, and 428 (13.8%) other types of fractures in the case group. Bone mineral density (BMD) was almost lower in the fracture groups compared to the control groups (p = 0.048 to < 0.001). Compared with normal weight, underweight had a protective effect on total [odds ratio (OR) = 0.61; 95% confidence interval (CI), 0.49 -0.75; P< 0.001], and lumbar fractures (OR = 0.52; 95% CI, 0.41 - 0.67; P < 0.001), while obesity was associated with an increased risk for total (OR = 2.26; 95% CI, 1.85 - 2.76; P < 0.001), lumbar (OR = 2.17; 95% CI, 1.72 - 2.73; P < 0.001), and femoral neck fractures (OR = 4.08; 95% CI, 2.18 - 7.63; P < 0.001). Non-linear associations were observed between BMI and fractures: A J-curve for total, lumbar, and femoral neck fractures, and no statistical change for other types of fractures. Underweight was found to be a risk factor for other types of fracturess after adjusting for BMD (OR = 2.29; 95% CI, 1.09 - 4.80; P < 0.001). Osteoporosis and osteopenia were identified as risk factors for almost all sites of fracture when compared to normal bone mass. CONCLUSIONS: Underweight has a protective effect on total and lumbar spine fractures in Chinese women, while obesity poses a risk factor for total, lumbar, and femoral neck fractures. The effect of BMI on fractures may be mainly mediated by BMD.

Local and systemic effects of IDH mutations on primary glioma patients.

Adult gliomas are divided into isocitrate dehydrogenase (IDH) wild-type and IDH mutant subtypes according to the new 2021 World Health Organization classification system. However, the local and systemic effects of IDH mutations on primary glioma patients are not well illustrated. Retrospective analysis, immune-cell infiltration analysis, meta-analysis, and immunohistochemistry assay were applied in the present study. The results from our cohort showed that IDH mutant gliomas own a lower proliferating rate compared to that in wild-type gliomas. Patients with mutant IDH exhibited a higher frequency of seizures in both our cohort and the cohort from the meta-analysis. Mutations in IDH result in lower levels of intra-tumour but higher levels of circulating CD4+ and CD8+ T lymphocytes. Levels of neutrophils in both intra-tumour and circulating blood were lower in IDH mutant gliomas. Moreover, IDH mutant glioma patients receiving radiotherapy in combination with chemotherapy exhibited better overall survival with respect to radiotherapy alone. Mutations in IDH alters the local and circulating immune microenvironment, and increases the sensitivity of tumour cell to chemotherapy.

Efficacy and Safety of PL-5 (Peceleganan) Spray for Wound Infections: A Phase IIb Randomized Clinical Trial.

OBJECTIVE: To assess the safety and efficacy of antimicrobial peptide PL-5 (Peceleganan) spray in the treatment of wound infections. BACKGROUND: Antimicrobial peptide PL-5 spray is a novel topical antimicrobial agent. METHODS: We conducted a multicenter, open-label, randomized, controlled phase IIb clinical trial to evaluate the efficacy and safety of PL-5 spray, as compared with silver sulfadiazine, in patients with skin wound infections. The primary efficacy outcome was the clinical efficacy rate on the first day after ending the treatment (D8). The secondary efficacy outcome was the clinical efficacy rate on the fifth day posttreatment (D5), the bacteria clearance rate, and the overall efficacy rate at the mentioned 2 time points. The safety outcomes included adverse reactions and pharmacokinetic analysis posttreatment. RESULTS: A total of 220 patients from 27 hospitals in China were randomly assigned to 4 groups. On D8, the efficacy rate was 100.0%, 96.7%, 96.7% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 87.5% for the control group. The efficacy rate among the 4 groups was significantly different ( P <0.05). On D5, the efficacy rate was 100.0%, 93.4%, 98.3% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 82.5% for the control group. The efficacy rate among the 4 groups was significantly different ( P <0.05). The blood concentration of PL-5 was not detectable in pharmacokinetic analysis. No severe adverse event related to the application of PL-5 was reported. CONCLUSIONS: Antimicrobial peptide PL-5 spray is safe and effective for the treatment of skin wound infections. TRIAL REGISTRATION: ChiCTR2000033334.

Self-Healable and Stretchable Ionic-Liquid-Based Thermoelectric Composites with High Ionic Seebeck Coefficient.

The advancement of wearable electronics, particularly self-powered wearable electronic devices, necessitates the development of efficient energy conversion technologies with flexible mechanical properties. Recently, ionic thermoelectric (TE) materials have attracted great attention because of their enormous thermopower, which can operate capacitors or supercapacitors by harvesting low-grade heat. This study presents self-healable, stretchable, and flexible ionic TE composites comprising an ionic liquid (IL), 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIM:OTf); a polymer matrix, poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP); and a fluoro-surfactant (FS). The self-healability of the IL-based composites originates from dynamic ion-dipole interactions between the IL, the PVDF-HFP, and the FS. The composites demonstrate excellent ionic TE properties with an ionic Seebeck coefficient (Si ) of ≈38.3 mV K-1 and an ionic figure of merit of ZTi  = 2.34 at 90% relative humidity, which are higher than the values reported for other IL-based TE materials. The IL-based ionic TE composites developed in this study can maintain excellent ionic TE properties under harsh conditions, including severe strain (75%) and multiple cutting-healing cycles.

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity.

Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals that causes a significant economic burden globally. Vaccination is the most effective FMD control strategy. However, FMD virus (FMDV) particles are prone to dissociate when appropriate physical or chemical conditions are unavailable, such as an incomplete cold chain. Such degraded vaccines result in compromised herd vaccination. Therefore, thermostable FMD particles are needed for use in vaccines. This study generated thermostable FMDV mutants (M3 and M10) by serial passages at high temperature, subsequent amplification, and purification. Both mutants contained an alanine-to-threonine mutation at position 13 in VP1 (A1013T), although M3 contained 3 additional mutations. The selected mutants showed improved stability and immunogenicity in neutralizing antibody titers, compared with the wild-type (wt) virus. The sequencing analysis and cryo-electron microscopy showed that the mutation of alanine to threonine at the 13th amino acid in the VP1 protein (A1013T) is critical for the capsid stability of FMDV. Virus-like particles containing A1013T (VLPA1013T) also showed significantly improved stability to heat treatment. This study demonstrated that Thr at the 13th amino acid of VP1 could stabilize the capsid of FMDV. Our findings will facilitate the development of a stable vaccine against FMDV serotype O. IMPORTANCE Foot-and-mouth disease (FMD) serotype O is one of the global epidemic serotypes and causes significant economic loss. Vaccination plays a key role in the prevention and control of FMD. However, the success of vaccination mainly depends on the quality of the vaccine. Here, the thermostable FMD virus (FMDV) mutants (M3 and M10) were selected through thermal screening at high temperatures with improved stability and immunogenicity compared with the wild-type virus. The results of multisequence alignment and cryo-electron microscopy (cryo-EM) analysis showed that the Thr substitution at the 13th amino acid in the VP1 protein is critical for the capsid stability of FMDV. For thermolabile type O FMDV, this major discovery will aid the development of its thermostable vaccine.

Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner.

Internal ribosome entry site (IRES)-driven translation is a common strategy among positive-sense, single-stranded RNA viruses for bypassing the host cell requirement of a 5' cap structure. In the current study, we identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation of foot-and-mouth disease virus (FMDV) but found that it is not essential for cellular global translation. RPL13 is also a determinant for translation and infection of Seneca Valley virus (SVV) and classical swine fever virus (CSFV), and this suggests that its function may also be conserved in unrelated IRES-containing viruses. We further showed that depletion of DEAD box helicase DDX3 disrupts binding of RPL13 to the FMDV IRES, whereas the reduction in RPL13 expression impairs the ability of DDX3 to promote IRES-driven translation directly. DDX3 cooperates with RPL13 to support the assembly of 80S ribosomes for optimal translation initiation of viral mRNA. Finally, we demonstrated that DDX3 affects the recruitment of the eukaryotic initiation factor eIF3 subunits e and j to the viral IRES. This work provides the first connection between DDX3 and eIF3e/j and recognition of the role of RPL13 in modulating viral IRES-dependent translation. This previously uncharacterized process may be involved in selective mRNA translation.IMPORTANCE Accumulating evidence has unveiled the roles of ribosomal proteins (RPs) belonging to the large 60S subunit in regulating selective translation of specific mRNAs. The translation specificity of the large-subunit RPs in this process is thought provoking, given the role they play canonically in catalyzing peptide bond formation. Here, we have identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation during FMDV infection. Our study supports a model whereby the FMDV IRESs recruit helicase DDX3 recognizing RPL13 to facilitate IRES-driven translation, with the assistance of eIF3e and eIF3j. A better understanding of these specific interactions surrounding IRES-mediated translation initiation could have important implications for the selective translation of viral mRNA and thus for the development of effective prevention of viral infection.

Construction and Verification of a Radiation Pneumonia Prediction Model Based on Multiple Parameters.

OBJECTIVE: Patients with lung cancer are at risk of radiation pneumonia (RP) after receiving radiotherapy. We established a prediction model according to the critical indicators extracted from radiation pneumonia patients. MATERIALS AND METHODS: 74 radiation pneumonia patients were involved in the training set. Firstly, the clinical data, hematological and radiation dose parameters of the 74 patients were screened by Logistics regression univariate analysis according to the level of radiation pneumonia. Next, Stepwise regression analysis was utilized to construct the regression model. Then, the influence of continuous variables on RP was tested by smoothing function. Finally, the model was externally verified by 30 patients in validation set and visualized by R code. RESULTS: In the training set, there was 40 patients suffered≥ level 2 acute radiation pneumonia. Clinical data (diabetes), blood indexes (lymphocyte percentage, basophil percentage, platelet count) and radiation dose (V15 > 40%, V20 > 30%, V35 >18%, V40 > 15%) were related to radiation pneumonia (P < 0.05). Particularly, stepwise regression analysis indicated that the history of diabetes, the basophils percentage, platelet count and V20 could be the best combination used for predicting radiation pneumonia. The column chart was obtained by fitting the regression model with the combined indicator. The receiver operating characteristic (ROC) curve showed that the AUC in the development term was 0.853, the AUC was 0.656 in the validation term. And calibration curves of both groups showed the high stability in efficiently diagnostic. Furthermore, the DCA curve showed that the model had a satisfactory positive net benefit. CONCLUSION: The combination of the basophils percentage, platelet count and V20 is available to build a predictive model of radiation pneumonia for patients with advanced lung cancer.

Bi-functional gold nanocages enhance specific immunological responses of foot-and-mouth disease virus-like particles vaccine as a carrier and adjuvant.

Virus-like particle (VLP) vaccines have become one of the dominant vaccine candidates for foot-and-mouth disease (FMD). To further enhance the immunogenicity of VLP vaccines, gold nanocages (AuNCs) were selected as an adjuvant for the vaccine. Our experiments demonstrated that AuNCs had little biotoxicity in vivo and in vitro and improved the uptake of VLP in BHK-21 and RAW264.7 cell lines. The VLP-AuNCs activated DCs mainly through toll-like receptor 4 (TLR4) and promoted the secretion of IL-6, IL-1ß, and TNF-α. The conjugation of VLP and AuNCs triggered a strong immune response against FMD virus (FMDV) in mice and guinea pigs. The VLP-AuNCs significantly enhanced the proliferation of CD8+ T cells (P < 0.05) and the secretion of cellular immune-related cytokines (IFN-γ, P < 0.05; IL-12p70, P < 0.01) compared with VLP. The present study demonstrated that AuNCs, as a great potential adjuvant for FMDV VLP vaccines, significantly enhance the immune response.

Graphene-based low-threshold and tunable optical bistability in one-dimensional photonic crystal Fano resonance heterostructure at optical communication band.

In this paper, the one-dimensional photonic crystal Fano resonance heterostructure is used to achieve low-threshold and tunable graphene-based optical bistability of the transmitted and reflected light beam at optical communication band. The low-threshold of optical bistability (OB) originates from the local field enhancement owing to the Fano resonance excited by topological edge states mode and Fabry-Perot cavity mode. The study found that it is feasible to continuously adjust the hysteresis behavior and optical bistable thresholds by altering the Fermi energy of the left and right graphene respectively. Furthermore, the OB can also be controlled by changing the number of graphene layers or the angle of incident beam, which makes this structure a feasible object of experimental research at optical communication band in the future.

Enhanced protective immune response of foot-and-mouth disease vaccine through DNA-loaded virus-like particles.

Foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects cloven-hoofed animals. Virus-like particles (VLPs) can induce a robust immune response and deliver DNA and small molecules. In this study, a VLP-harboring pcDNA3.1/P12A3C plasmid was generated, and the protective immune response was characterized. Guinea pigs were injected with VLPs, naked DNA vaccine, DNA-loaded VLPs, or phosphate-buffered saline twice subcutaneously at four-week intervals. Results demonstrated that the VLPs protected the naked DNA from DNase degeneration and delivered the DNA into the cells in vitro. The DNA-loaded VLPs and the VLPs alone induced a similar level of specific antibodies (P > 0.05) except at 49 dpv (P < 0.05). The difference in interferon-γ was consistent with that in specific antibodies. The levels of neutralizing antibodies induced by the DNA-loaded VLPs were significantly higher than those of other samples (P < 0.01). Similarly, the lymphocyte proliferation by using DNA-loaded VLPs was significantly higher than those using other formulas after booster immunization. Vaccination with DNA-loaded VLPs provided higher protection (100%) against viral challenge compared with vaccination with VLPs (75%) and DNA vaccine (25%). This study suggested that VLPs can be used as a delivery carrier for DNA vaccine. In turn, the DNA vaccine can enhance the immune response and prolong the serological duration of the VLP vaccine. This phenomenon contributes in providing complete protection against the FMDV challenge in guinea pigs and can be valuable in exploring novel nonreplicating vaccines and controlling FMD in endemic countries worldwide.

Insight into the Effect of Ligands on the Optical Properties of Germanium Quantum Dots and Their Applications in Persistent Cell Imaging.

Germanium quantum dots (GeQDs) show unique advantages in fluorescence applications due to their large quantum confinement effect and excellent biocompatibility. However, GeQDs are confronted with difficulty in accurately controlling the fluorescence emission. This defect brings challenges to understanding the fluorescence mechanism and limits the potential applications of GeQDs. In this paper, a series of GeQDs with the average diameter of about 2.6 nm modified with different ligands were synthesized by the chemical reduction method. The fluorescence emission of GeQDs can be changed from blue to yellow-green through adjusting the surface ligands. The influence of surface ligands on the fluorescence emission of GeQDs was thoroughly investigated by experimental and theoretical calculations. Furthermore, the synthesized GeQDs exhibit good biocompatibility and photostability and can act as high-performance fluorescence probes for long-term fluorescent bioimaging. This work provides a good and deep understanding of the fluorescence mechanism of GeQDs and will facilitate diverse promising applications of GeQDs in the near future.

Development of a novel SYBR green I-based quantitative RT-PCR assay for Senecavirus A detection in clinical samples of pigs.

Porcine vesicular disease caused by Senecavirus A (SVA) is a newly emerging disease in many countries. Based on clinical signs only, it is very challenging to distinguish SVA infection from other similar diseases, such as foot and mouth disease, swine vesicular disease, and vesicular stomatitis. Therefore, it is crucial to establish a detection assay for the clinical diagnosis of SVA infection. In this study, a pair of specific primers were designed based on the highly conserved L/VP4 gene sequence of SVA. The established SYBR green I-based quantitative reverse transcription polymerase chain reaction (qRT-PCR) method was used to detect SVA nucleic acids in clinical samples. The limit of detection SVA nucleic acids by qRT-PCR was 6.4 × 101 copies/µL, which was significantly more sensitive than that by gel electrophoresis of 6.4 × 103 copes/µL. This assay was specific and had no cross-reaction with other seven swine viruses. Using SYBR green I-based qRT-PCR, the SVA positive rates in experimental animal samples and field samples were 67.60% (96/142) and 80% (24/30) respectively. The results demonstrate that SYBR green I-based qRT-PCR is a rapid and specific method for the clinical diagnosis and epidemiological investigation of related vesicular diseases caused by SVA.

NLRP3 inflammasome activation by Foot-and-mouth disease virus infection mainly induced by viral RNA and non-structural protein 2B.

Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae. Early studies show that some viruses of Picornaviridae, such as EMCV and EV71, induce NLRP3 inflammasome activation. Our current study demonstrates that FMDV induces the secretion of caspase-1 and interleukin 1 beta (IL-1ß), as well as activates the NLRP3 inflammasome in a dose- and time-dependent manner. Meanwhile, NLRP3 inflammasome can suppress FMDV replication during virus infection. Both FMDV RNA and viroporin 2B stimulate NLRP3 inflammasome activation. FMDV RNA triggers NLRP3 inflammasome through p-NF-κB/p65 pathway not dependent on RIG-I inflammasome. FMDV 2B activates NLRP3 inflammasome through elevation of intracellular ion, but not dependent on mitochondrial reactive oxygen species (ROS) and lysosomal cathepsin B. It further demonstrates that 2B viroporin activates NLRP3 inflammasome and induces IL-1ß in mice, which enhances the specific immune response against FMDV as an ideal self-adjuvant for FMD VLPs vaccine in guinea pigs. The results reveal a series of regulations between NLRP3 inflammasome complex and FMDV. Amino acids 140-145 of 2B is essential for forming an ion channel. By mutating the amino acid and changing the hydrophobic properties, the helical transmembrane region of the viroporin 2B is altered, so that the 2B is insufficient to trigger the activation of NLRP3 inflammasome. This study demonstrates the functions of FMDV RNA and 2B viroporin activate NLRP3 inflammasome and provides some useful information for the development of FMD vaccine self-adjuvant, which is also helpful for the establishment of effective prevention strategies by targeting NLRP3 inflammasome.

Efficacy and safety of urate-lowering treatments in patients with hyperuricemia: A comprehensive network meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Hyperuricemia (HUA) and gout are considerable public health problems because of their increasing incidence and interactions with other diseases. We aimed to evaluate the efficacy and safety of urate-lowering therapies (ULTs) for patients. METHODS: A systematic literature review was conducted, and a network meta-analysis was performed on the included studies using the Markov Chain Monte Carlo simulation method and a Bayesian statistical framework. We calculated surface under the cumulative ranking curve (SUCRA) values and performed clustered ranking to combine the efficacy and safety results. RESULTS: Twenty-two randomized controlled studies were identified for the efficacy analysis, and 20 studies were identified for the safety analysis. Compared with the placebo, the ULTs were efficient and safe. Febuxostat 120 mg/d and allopurinol 200 mg/d had the highest SUCRA scores for efficacy and safety, respectively. Clustered ranking results showed that febuxostat 120 mg/d was the best in terms of efficacy and safety, topiroxostat 120/160 mg/d was similar to febuxostat 80 mg/d in terms of efficacy but safer, and allopurinol was not inferior to topiroxostat. WHAT IS NEW AND CONCLUSION: Febuxostat had the best efficacy and safety results among the tested agents, and topiroxostat and allopurinol appeared to have fewer adverse events.

Dependence of artesunate on long noncoding RNA-RP11 to inhibit epithelial-mesenchymal transition of hepatocellular carcinoma.

As a first line medicine for malaria treatment, artesunate (ART) also shows antitumor potential. However, little is known about the effect of ART on the cancer cell epithelial-mesenchymal transition (EMT). In this study, we found that ART inhibited cell growth in SK-HEP1 and SM7721 hepatocellular carcinoma cell lines. A microarray was used to identify differentially expressed protein-coding RNAs (pcRNA) and long noncoding RNAs (lncRNA) between SK-HEP1 cells with and without ART treatment. A differentially expressed lncRNA-RP11, the most related to the EMT of liver cancer cells-RP11 was identified by abioinformatics method Overexpressing and silencing assays were used to verify the role of RP11 in cancer cell EMT. The levels of RP11- and EMT-related genes in liver cancer samples from 75 patients were detected by using qualitative polymerase chain reaction or immunohistochemistry. We identified 1334 pcRNAs and 1670 lncRNA with differential expression induced by ART. ART inhibits EMT, proliferation, migration, invasion, and adhesion of liver cancer cells. RP11 depresses the inhibitory effect of ART on cancer cell EMT. The level of RP11 is associated with cancer cell EMT and metastasis and survival rate of the patient. These data suggest that RP11-linking ART and cancer cell EMT are important for ART-inhibited metastasis of liver cancer.

Artesunate promotes sensitivity to sorafenib in hepatocellular carcinoma.

Enhancing sensitivity of carcinoma to sorafenib (Sor) is critical to overcome the limits of high frequency resistance and moderate efficiency during chemotherapy for advanced hepatocellular carcinoma (HCC). Here, we promote sensitivity of HCC to Sor by combination with Artesunate (Art), a derivative of artemisinin extracted from Chinese medical herb. The positive synergy of Art on inhibiting HCC growth contributes 48% dosage of Sor to reduce tumor cell viability in vitro and tumor size in vivo. Mechanically, in spite of effective suppression of RAF/MEK/ERK pathway, Sor is not able to eliminate chemoresistance of HCC driven by PI3K/AKT/mTOR pathway, while Art inhibits phosphorylation of AKT and mTOR significantly. Furthermore, combination with Art and Sor further improves apoptosis of HCC by dual inhibition of both pathways. Our study reveals a function of Art that induces HCC apoptosis via PI3K/AKT/mTOR pathway inhibition and suggests a potential therapeutic regimen of combination with Art and SOR against advanced HCC.

Hollow mesoporous silica nanoparticles as delivery vehicle of foot-and-mouth disease virus-like particles induce persistent immune responses in guinea pigs.

Foot-and-mouth disease (FMD) is an acute and febrile infectious disease, which can cause great economic losses. Virus-like particles (VLPs) as an advantageous antigen can induce significant specific immune response. To improve immunity of VLPs, especially, make it induce persistent immune response, the hollow mesoporous silica nanoparticles (HMSNs) as a potential nano-adjuvant were synthesized and loaded the FMD virus (FMDV) VLPs. They were injected into guinea pigs and the specific immune response was detected. The results confirmed that HMSNs/VLPs can induce persistent humoral immunity with high-level antibody titer for more than three months. HMSNs also improve the T-lymphocyte proliferation and IFN-γ induced by FMDV VLPs, and provides the ideal protection against FMDV challenge. These consequences indicated that HMSNs were good protein delivery vehicle and potential nano-adjuvant of vaccines.

A Randomized Control Trial of Preoperative Oral Antibiotics as Adjunct Therapy to Systemic Antibiotics for Preventing Surgical Site Infection in Clean Contaminated, Contaminated, and Dirty Type of Colorectal Surgeries.

BACKGROUND: Preoperative bowel preparation with or without oral antibiotics is controversial in terms of postoperative surgical site infections. OBJECTIVE: This study aimed to evaluate the efficacy of oral antibiotics as adjunct therapy to systemic antibiotics with mechanical bowel preparation for preventing surgical site infections in clean contaminated, contaminated, and dirty colorectal procedures. DESIGN: This was a single-center, prospective randomized study. SETTING: This study was conducted at the General Surgery Department at Jinling Hospital, Nanjing University, China, from July 15, 2014 to January 20, 2016. PATIENTS: Patients aged ≥18 years scheduled for abdominal surgery with clean-contaminated, contaminated, and dirty wounds were selected. INTERVENTIONS: Patients were randomly assigned to receive preoperative mechanical bowel preparation or mechanical bowel preparation with oral antibiotics. MAIN OUTCOMES: The primary outcome was the rate of surgical site infections. The secondary outcomes were extra-abdominal complications, duration of postoperative ileus, and readmission rate. RESULTS: Ninety-five patients were allocated to each group. Eight and 26 surgical site infections (8.42% vs 27.3 %, p = 0.004) occurred in the mechanical bowel preparation with oral antibiotics and mechanical bowel preparation groups. Thirteen extra-abdominal complications were reported: 6 in the mechanical bowel preparation with oral antibiotics group and 7 in the mechanical bowel preparation group (6.3% vs 7.3%, p = 0.77). Postoperative ileus duration did not differ between groups (p = 0.23). There were 4 readmissions in the mechanical bowel preparation group and none in the mechanical bowel preparation with oral antibiotics group (p = 0.04). On multivariable analysis, blood loss ≥500 mL (OR, 5.1; 95% CI, 1.27-20.4; p = 0.02), ASA score ≥3 (OR, 3.9; 95% CI, 1.2-12.5; p = 0.01), contaminated types (OR, 3.6; 95% CI, 1.5-8.6; p = 0.01), and administration of preoperative oral antibiotics (OR, 0.20; 95% CI, 0.06-0.60; p = 0.005) independently affected the incidence of surgical site infections. LIMITATIONS: This was a single-center study. CONCLUSION: Preoperative oral antibiotics, as adjunct therapy to systemic antibiotics and mechanical bowel preparation, significantly reduced surgical site infections and minimized the readmission rates in clean contaminated, contaminated, and dirty types of colorectal surgery. See Video Abstract at http://links.lww.com/DCR/A437.