Effect of Agricultural Organic Inputs on Nanoplastics Transport in Saturated Goethite-Coated Porous Media: Particle Size Selectivity and Role of Dissolved Organic Matter.

The transport of nanoplastics (NPs) through porous media is influenced by dissolved organic matter (DOM) released from agricultural organic inputs. Here, cotransport of NPs with three types of DOM (biocharDOM (BCDOM), wheat strawDOM (WSDOM), and swine manureDOM (SMDOM)) was investigated in saturated goethite (GT)-coated sand columns. The results showed that codeposition of 50 nm NPs (50NPs) with DOM occurred due to the formation of a GT-DOM-50NPs complex, while DOM loaded on GT-coated sand and 400 nm NPs (400NPs) aided 400NPs transport due to electrostatic repulsion. According to the quantum chemical calculation, humic acid and cellulose played a significant role in 50NPs retardation. Owing to its high concentration, moderate humification index (HIX), and cellulose content, SMDOM exhibited the highest retardation of 50NPs transport and promoting effect on 400NPs transport. Owing to a high HIX, the effect of BCDOM on the mobility of 400NPs was higher than that of WSDOM. However, high cellulose content in WSDOM caused it to exhibit a 50NPs retardation ability that was similar to that of BCDOM. Our results highlight the particle size selectivity and significant influence of DOM type on the transport of NPs and elucidate their quantum and colloidal chemical-interface mechanisms in a typical agricultural environment.

Association between dental conditions, sliver diamine fluoride application, parental satisfaction, and oral health-related quality of life of preschool children.

OBJECTIVES: To investigate the associations between dental conditions, sliver diamine fluoride (SDF) application, parental satisfaction, and oral health-related quality of life (OHRQoL) of preschool children. MATERIALS AND METHODS: In a clinical trial conducted in Hong Kong, preschool children who had carious lesions into dentine were randomly assigned to receive an application of SDF solution or placebo on their caries lesions 10 weeks before they received restorations. Additionally, a random sample of caries-free children was also recruited. Parents of the study children rated their satisfaction with their child's teeth using a 5-point scale (5 = very satisfied, 1 = very dissatisfied) 10 weeks after SDF or placebo application. Besides, the Chinese version of the Early Childhood Oral Health Impact Scale (C-ECOHIS) was used to assess the children's OHRQoL. RESULTS: There were 127, 133, and 154 children in the SDF, placebo, and caries-free groups, respectively. The parents whose child had 4 or more decayed teeth reported lower satisfaction scores (mean = 2.0 ± 0.7) with their child's dental health status compared with those of parents whose child had fewer (mean = 2.6 ± 0.9) or no (mean = 3.7 ± 0.7) decayed teeth (p < 0.001). These parents also reported higher C-ECOHIS scores. However, there was no significant difference in parental satisfaction and children's OHRQoL between the SDF and placebo groups (p > 0.05). CONCLUSIONS: In this study population, parental satisfaction and children's OHRQoL were associated with children's dental caries status but not with SDF application. CLINICAL RELEVANCE: This study provides valuable information about the factors, including SDF application, that can influence parental satisfaction and OHRQoL of preschool children.

Liposomal paclitaxel versus docetaxel in induction chemotherapy using Taxanes, cisplatin and 5-fluorouracil for locally advanced nasopharyngeal carcinoma.

BACKGROUND: We wished to evaluate the efficacy and safety of liposomal paclitaxel and docetaxel for induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC). METHODS: A total of 1498 patients with newly-diagnosed NPC between 2009 and 2017 treated with IC plus concurrent chemotherapy were included in our observational study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and grade-3-4 toxicities were compared between groups using propensity score matching (PSM). RESULTS: In total, 767 patients were eligible for this study, with 104 (13.6%) and 663 (86.4%) receiving a liposomal paclitaxel-based and docetaxel-based taxanes, cisplatin and 5-fluorouracil (TPF) regimen, respectively. PSM identified 103 patients in the liposomal-paclitaxel group and 287 patients in the docetaxel group. There was no significant difference at 3 years for OS (92.2% vs. 93.9%, P = 0.942), PFS (82.6% vs. 81.7%, P = 0.394), LRFS (94.7% vs. 93.3%, P = 0.981) or DMFS (84.6% vs. 87.4%, P = 0.371) between the two groups after PSM. Significant interactions were not observed between the effect of chemotherapy regimen and sex, age, T stage, N stage, overall stage, or Epstein-Barr virus DNA level in the subgroup multivariate analysis. The prevalence of grade-3-4 leukopenia and neutropenia in the liposomal-paclitaxel group was significantly lower than that of the docetaxel group (P < 0.05 for all). CONCLUSIONS: Compared with docetaxel, liposomal paclitaxel has identical anti-tumor efficacy, but causes fewer and milder adverse reactions in IC for NPC.

Pretreatment quality of life as a predictor of survival for patients with nasopharyngeal carcinoma treated with IMRT.

BACKGROUND: To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. METHODS: We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. RESULTS: Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003, < 0.0001, and 0.031, respectively. In multivariate analysis, pretreatment cognitive functioning of QLQ-C30 was significantly associated with LRFS, with HR of 0.971(95%CI 0.951-0.990), P = 0.004. Among scales of QLQ-H&N35 for multivariate analysis, pretreatment teeth (P = 0.026) and felt ill (P = 0.012) was significantly associated with PFS, with HR of 0.984 (95%CI 0.971-.998) and 1.004 (95%CI 1.001-1.007), respectively. Felt ill of QLQ-H&N35 was significantly associated with DMFS, with HR of 1.004(95%CI 1.000-1.007), P = 0.043. There is no QoL scale significantly associated with OS after multivariate analysis. CONCLUSIONS: In conclusion, our analysis confirms that pretreatment teeth and felt ill was significantly associated with PFS in NPC patients treated with IMRT. In addition, the posttreatment EBV DNA was significantly associated with OS.

Targeted Delivery of a Mannose-Conjugated BODIPY Photosensitizer by Nanomicelles for Photodynamic Breast Cancer Therapy.

The targeted delivery of a photosensitizer (PS) with appropriate carriers represents an attractive means of selectively delivering cargo to target tissues or subcellular compartments for photodynamic therapy (PDT). Herein, a three-arm distyryl BODIPY derivative conjugated with mannose units (denoted by BTM) that can co-assemble with Tween 80 to form nanomicelles (BTM-NMs) for targeted PDT is reported. MDA-MB-231 breast cancer cells recognized and specifically internalized BTM-NMs via mannose-receptor-mediated endocytosis with preferential accumulation in the lysosomes. These NMs could disassemble in cell lysosomes and subsequently induce highly efficient singlet oxygen (1 O2 ) generation upon light irradiation. 1 O2 disrupted the lysosomal membrane and promoted the escape of BTM from the lysosome into the cytoplasm, thereby resulting in the efficient and selective killing of cancer cells through PDT. This study may provide a new strategy for designing targeted PDT systems to fight cancer.

Evaluation of Hemostatic Effects of Carbonized Hair-Loaded Poly(L-Lactic) Acid Nanofabrics.

Carbonized human hair is used to stop bleeding in traditional Chinese medicine. The present study was aimed to prepare a novel nanofiber containing carbonized human hair and evaluate its hemostatic effect. Carbonized human hair-loaded poly(L-lactic) acid nanofiber was prepared by electrospinning. The hemostatic efficacies of dressings composed of either carbonized human hair, carbonized human hair-loaded poly(L-lactic) acid nanofiber, Yunnan White Drug power or poly(L-lactic) acid nanofiber were investigated in several swine arterial and venous bleeding models. Blood loss and bleeding time were measured. In vitro, carbonized human hair, carbonized human hair-loaded nanofiber and Yunnan White Drug Powder significantly shortened the clotting time in comparison with the nanofiber control group. The hemostatic effects of the carbonized human hair-load nanofiber on liver and spleen traumatic wounds were better than those of carbonized human hair and Yunnan White Drug Powder in terms of blood loss and bleeding time. Similar effects were observed in swine femoral artery wound model. In the swine femoral vein wound model, bleeding could not be stopped in the control animals. In the carbonized human hair group, Yunnan White Drug Powder group and carbonized human hair-load nanofiber group, bleeding was stopped in 83.3%, 83.3% and 100% of the animals, respectively. In conclusion, dressing using carbonized human hair-load nanofibers is effective in controlling severe, uncontrolled bleeding. This dressing may offer a cheap alternative to dressings composed of coagulation proteins.

The Inhibition of Escherichia coli Biofilm Formation by Gallium Nitrate-Modified Titanium.

Periprosthetic infections are notoriously difficult to treat due to biofilm formation. Previously, we reported that gallium-EDTA attached to PVC (polyvinyl chloride) surface could prevent bacterial colonization. Herein we examined the effect of this gallium-EDTA complex on Escherichia coli biofilm formation on titanium. It was clearly demonstrated that gallium nitrate significantly inhibited the growth and auto-aggregation of Escherichia coli. Furthermore, titanium with gallium-EDTA coating resisted bacterial colonization as indicated by crystal violet staining. When the chips were immersed in human serum and incubated at 37 °C, they demonstrated significant antimicrobial activity after more than 28 days of incubation. These findings indicate that gallium-EDTA coating of implants can result in a surface that can resist bacterial colonization. This technology holds great promise for the prevention and treatment of periprosthetic infections.

Novel ethylcellulose-coated pellets for controlled release of metoprolol succinate without lag phase: characterization, optimization and in vivo evaluation.

The objective of this study was to develop a novel ethylcellulose (EC)-coated pellet with partial active dose as a pore former for the controlled release of water-soluble metoprolol succinate (MS) without an initial lag phase (slow/non-drug release phase). MS-layered cores with a high drug-loading efficiency (97%, w/w), a smooth surface, and an acceptable level of resistance to abrasion were first obtained by spraying a concentrated drug solution (60% w/w at 70 °C) on non-pareils in the absence of other binders. The presence of the drug in an EC coating solution significantly improved the coating process by reducing pellet stickiness. Central composite design and response surface methodology was employed to optimize and explore the effect of pore former MS level (X1) and EC coating level (X2) on the drug release. The pore former level had a positive effect on the MS release and the coating level had a negative effect. The level of X1 and X2 of the optimization were 17% and 23%, respectively, and the cumulative percent of MS released within 1 h was up to 9.2%. Accordingly, the initial lag phase associated with in vitro drug release from EC-coated pellets was absent when MS drug was used as a pore former, which was further confirmed by in vivo drug release in beagle dogs. Thus, a novel approach for the controlled release of MS from coated pellets without lag phase has been successfully developed, which is valuable for the advancement of sustained-release pellets.

Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening.

Hand, foot, and mouth disease (HFMD) is a common pediatric illness mainly caused by enteroviruses, which are important human pathogens. Currently, there are no available antiviral agents for the therapy of enterovirus infection. In this study, an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed. Using this screening system, we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, exhibits potential inhibitory effects against various enteroviruses that cause HFMD, such as EV-A71, CV-A10, CV-B3 and CV-A16. Further investigations revealed that FAN targets the early stage of the enterovirus life cycle. Through the selection of FAN-resistant EV-A71 viruses, we demonstrated that the VP1 protein could be a potential target of FAN, as two mutations in VP1 (E145G and V258I) resulted in viral resistance to FAN. Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

An impact resistant hydrogel enabled by bicontinuous phase structure and hierarchical energy dissipation.

High performance hydrogels have essential applications in many fields such as tissue engineering and soft robot. Herein, we develop an impact resistant hydrogel composed of bicontinuous structures of polymer-hard phase and polymer-soft phase. This unique bicontinuous phase structure is formed by modulating various hydrogen bonding interactions. During loading, the polymer-hard phase is broken accompanied by the dissociation of hydrogen bonds to dissipate energy, while the polymer-soft phase distributes the load to avoid stress concentration, thus enabling the bicontinuous hydrogel to achieve excellent strength and toughness simultaneously. Furthermore, the fracture of hierarchical energy dissipation structures efficiently reduces impact strength and increases buffer time. Owing to the synergy of the bicontinuous phase structure and hierarchical energy dissipation, the resulting bicontinuous hydrogel remains intact even if it undergoes impact at a strain rate of ∼13 000 s-1. Based on these findings, it is expected that the bicontinuous hydrogel has a potential application in the field of articular cartilage repair.

Mucus-Permeable Sonodynamic Therapy Mediated Amphotericin B-Loaded PEGylated PLGA Nanoparticles Enable Eradication of Candida albicans Biofilm.

Background: Candida albicans (C. albicans) forms pathogenic biofilms, and the dense mucus layer secreted by the epithelium is a major barrier to the traditional antibiotic treatment of mucosa-associated C. albicans infections. Herein, we report a novel anti-biofilm strategy of mucus-permeable sonodynamic therapy (mp-SDT) based on ultrasound (US)-mediated amphotericin B-loaded PEGylated PLGA nanoparticles (AmB-NPs) to overcome mucus barrier and enable the eradication of C. albicans biofilm. Methods: AmB-NPs were fabricated using ultrasonic double emulsion method, and their physicochemical and sonodynamic properties were determined. The mucus and biofilm permeability of US-mediated AmB-NPs were further investigated. Moreover, the anti-biofilm effect of US-mediated AmB-NPs treatment was thoroughly evaluated on mucus barrier abiotic biofilm, epithelium-associated biotic biofilm, and C. albicans-induced rabbit vaginal biofilms model. In addition, the ultrastructure and secreted cytokines of epithelial cells and the polarization of macrophages were analyzed to investigate the regulation of local cellular immune function by US-mediated AmB-NPs treatment. Results: Polymeric AmB-NPs display excellent sonodynamic performance with massive singlet oxygen (1O2) generation. US-mediated AmB-NPs could rapidly transport through mucus and promote permeability in biofilms, which exhibited excellent eradicating ability to C. albicans biofilms. Furthermore, in the vaginal epithelial cells (VECs)-associated C. albicans biofilm model, the mp-SDT scheme showed the strongest biofilm eradication effect, with up to 98% biofilm re-formation inhibition rate, improved the ultrastructural damage, promoted local immune defense enhancement of VECs, and regulated the polarization of macrophages to the M1 phenotype to enhance macrophage-associated antifungal immune responses. In addition, mp-SDT treatment exhibited excellent therapeutic efficacy against C. albicans-induced rabbit vaginitis, promoted the recovery of mucosal epithelial ultrastructure, and contributed to the reshaping of a healthier vaginal microbiome. Conclusion: The synergistic anti-biofilm strategies of mp-SDT effectively eradicated C. albicans biofilm and simultaneously regulated local antifungal immunity enhancement, which may provide a new approach to treat refractory drug-resistant biofilm-associated mucosal candidiasis.

Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA-IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial.

Background: Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. Methods: We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). Findings: From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Interpretation: Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial.

BACKGROUND: Radiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). PATIENTS AND METHODS: We did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT03668730. RESULTS: One patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%-94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8-46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%-98.9%) with a median follow-up of 43.9 months (IQR 40.2-46.2). The most common late toxicity was grade 1-2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. CONCLUSION: Reduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.

Clostridium beijerinckii mutant with high inhibitor tolerance obtained by low-energy ion implantation.

Clostridium beijerinckii mutant strain IB4, which has a high level of inhibitor tolerance, was screened by low-energy ion implantation and used for butanol fermentation from a non-detoxified hemicellulosic hydrolysate of corn fiber treated with dilute sulfuric acid (SAHHC). Evaluation of toxicity showed C. beijerinckii IB4 had a higher level of tolerance than parent strain C. beijerinckii NCIMB 8052 for five out of six phenolic compounds tested (the exception was vanillin). Using glucose as carbon source, C. beijerinckii IB4 produced 9.1 g l(-1) of butanol with an acetone/butanol/ethanol (ABE) yield of 0.41 g g(-1). When non-detoxified SAHHC was used as carbon source, C. beijerinckii NCIMB 8052 grew well but ABE production was inhibited. By contrast, C. beijerinckii IB4 produced 9.5 g l(-1) of ABE with a yield of 0.34 g g(-1), including 2.2 g l(-1) acetone, 6.8 g l(-1) butanol, and 0.5 g l(-1) ethanol. The remarkable fermentation and inhibitor tolerance of C. beijerinckii IB4 appears promising for ABE production from lignocellulosic materials.

Incorporation of green emission polymer dots into pyropheophorbide-α enhance the PDT effect and biocompatibility.

BACKGROUND: A green emission up-conversion carbon-based polymer dots (CPDs) owned excellent photophysical properties and good solubility. Most photosensitizers (PS) are hydrophobic which limits their application in biomedicine. Herein we synthesized and integrated green emitting CPDs into pyropheophorbide-α (PPa) to improve the overall properties of the PS. MATERIAL AND METHODS: The nano-agent was incorporated through amide condensation and electrostatic interaction. The structure, size and morphology of the prepared conjugates were determined by FTIR, TEM, DLS, TGA, 1HNMR, Uv-vis, and fluorescence spectrophotometry. The dark and light toxicity, as well as cellular uptake, was also monitored on the human esophageal cancer cell line (Eca-109). RESULTS: Our results illustrate that the conjugation improved the PDT efficacy by increasing the ROS generation. The nano-hybrids showed pH sensitivity as well as good hemocompatibility as the hemolysis ratio was decreased when treated with nano-conjugates. PPa-CPD1 and PPa-CPD2 had the pH response and stronger ability to absorb light and produce fluorescence in an acidic environment (pH 4.0 and pH 5.0) The synthesized nano-hybrids doesnot affect the clotting time. An increase in the absorbance wavelengths was observed. The results of MTT assay showed that dark toxicity was reduced after conjugation. CONCLUSION: This CPDs-based drug enhanced tumor-inhibition efficiency as well as low dark toxicity in vitro, showing significant application potential for PDT-based treatment.

Preparation, in vitro and in vivo Evaluation of Thermosensitive in situ Gel Loaded with Ibuprofen-Solid Lipid Nanoparticles for Rectal Delivery.

Background: Ibuprofen (IBU), a nonsteroidal anti-inflammatory drug, shows poor gastrointestinal absorption due to its low solubility, which limits its clinical application. Objective: In the present study, we aimed to develop thermosensitive gel-mediated ibuprofen-solid lipid nanoparticles (IBU-SLN-ISG) to improve the dissolution and bioavailability of IBU after rectal delivery. Methods: IBU-loaded SLNs (IBU-SLNs) were developed and optimized applying Box-Behnken design. The optimized IBU-SLNs were characterized by physicochemical parameters and morphology. Then, the optimized IBU-SLNs was incorporated into the gel and characterized for gel properties and rheology and investigated its release in vitro, pharmacokinetics in vivo, rectal irritation and rectal retention time. Results: The optimized SLNs had an EE of 90.74 ± 1.40%, DL of 11.36 ± 1.20%, MPS of 166.77 ± 2.26 nm, PDI of 0.27 ± 0.08, and ZP of -21.00 ± 0.59 mV. The FTIR spectra confirmed successful encapsulation of the drug inside the nanoparticle as only peaks responsible for the lipid could be identified. This corroborated well with XRD spectra, which showed a completely amorphous state of the IBU-SLNs as compared to the crystalline nature of the pure drug. The gelation temperature of the prepared IBU-SLN-ISG was 33.30 ± 0.78°C, the gelation time was 14.67 ± 2.52 s, the gel strength was 54.00 ± 1.41 s, and the mucoadhesion was (11.54±0.37) × 102dyne/cm2. The in vitro results of IBU-SLNs and IBU-SLN-ISG showed a biphasic release pattern with initial burst release followed by sustained release. More importantly, IBU-SLN-ISG produced much better absorption of IBU and improved bioavailability in rats. In addition, IBU-SLN-ISG caused no irritation or damage to rectal tissues, and could be retained in the rectum for a long time. Conclusion: Thermosensitive in situ gel loaded with IBU-solid lipid nanoparticles might be further developed as a more convenient and effective rectal dosage form.

Deintensified Chemoradiotherapy for Pretreatment Epstein-Barr Virus DNA-Selected Low-Risk Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase II Randomized Noninferiority Trial.

PURPOSE: Cumulative doses of 200 mg/m2 for concurrent cisplatin (DDP) were indicated by retrospective studies as sufficient in conferring survival benefit for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We performed an open-label, phase II, randomized, controlled trial to test the noninferiority of a two-cycle 100 mg/m2 concurrent DDP regimen over three-cycle in patients with low-risk LA-NPC with pretreatment Epstein-Barr virus DNA levels < 4,000 copies/mL. PATIENTS AND METHODS: Eligible patients were randomly assigned 1:1 to receive two cycles or three cycles concurrent DDP-based chemoradiotherapy. The primary end point was 3-year progression-free survival (PFS). The secondary end points included overall survival, distant metastasis-free survival, locoregional relapse-free survival, etc. RESULTS: Between September 2016 and October 2018, 332 patients were enrolled, with 166 in each arm. After a median follow-up of 37.7 months, the estimated 3-year PFS rates were 88.0% in the two-cycle group and 90.4% in the three-cycle group, with a difference of 2.4% (95% CI, -4.3 to 9.1, Pnoninferiority = .014). No differences were observed between groups in terms of PFS, overall survival, and the cumulative incidences of locoregional relapse and distant metastasis. Patients in the three-cycle group developed significantly more grade 3-4 mucositis (41 [24.8%] v 25 [15.1%]), hyponatremia (26 [15.8%] v 14 [8.4%]), and dermatitis (9 [5.5%] v 2 [1.2%]). The overall all-grade and grade 3-4 toxicity burdens were heavier in three-cycle group (T-scores, 12.33 v 10.57, P < .001 for all grades; 1.76 v 1.44, P = .05 for grade 3-4). Patients in the three-cycle group also showed more all-grade hearing impairment, dry mouth and skin fibrosis, and impaired long-term quality of life. CONCLUSION: Intensity-modulated radiotherapy plus two cycles of concurrent 100 mg/m2 DDP could be an alternative treatment option for patients with low-risk LA-NPC.

Characterization of different biodegradable scaffolds in tissue engineering.

The aim of the present study was to compare the characteristics of acellular dermal matrix (ADM), small intestinal submucosa (SIS) and Bio­Gide scaffolds with acellular vascular matrix (ACVM)­0.25% human­like collagen I (HLC­I) scaffold in tissue engineering blood vessels. The ACVM­0.25% HLC­I scaffold was prepared and compared with ADM, SIS and Bio­Gide scaffolds via hematoxylin and eosin (H&E) staining, Masson staining and scanning electron microscope (SEM) observations. Primary human gingival fibroblasts (HGFs) were cultured and identified. Then, the experiment was established via the seeding of HGFs on different scaffolds for 1, 4 and 7 days. The compatibility of four different scaffolds with HGFs was evaluated by H&E staining, SEM observation and Cell Counting Kit­8 assay. Then, a series of experiments were conducted to evaluate water absorption capacities, mechanical abilities, the ultra­microstructure and the cytotoxicity of the four scaffolds. The ACVM­0.25% HLC­I scaffold was revealed to exhibit the best cell proliferation and good cell architecture. ADM and Bio­Gide scaffolds exhibited good mechanical stability but cell proliferation was reduced when compared with the ACVM­0.25% HLC­I scaffold. In addition, SIS scaffolds exhibited the worst cell proliferation. The ACVM­0.25% HLC­I scaffold exhibited the best water absorption, followed by the SIS and Bio­Gide scaffolds, and then the ADM scaffold. In conclusion, the ACVM­0.25% HLC­I scaffold has good mechanical properties as a tissue engineering scaffold and the present results suggest that it has better biological characterization when compared with other scaffold types.

Increasing the anticancer performance of bufalin (BUF) by introducing an endosome-escaping polymer and tumor-targeting peptide in the design of a polymeric prodrug.

A well-defined multifunctional brush-type polymeric prodrug covalently linked with an anticancer drug (bufalin, BUF), a tumor-targeting peptide (RGD), and an endosome-escaping polymer, poly(N,N-diethylaminoethyl methacrylate-co-butyl methacrylate (P(DEA-co-BMA)), was developed. Its anticancer performance against colon cancer was investigated in vitro and in vivo. Reversible addition-fragmentation transfer (RAFT) polymerization of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), 2-((3-(tert-butoxy)-3-oxopropyl)thio)ethyl methacrylate (BSTMA), and 2-(2-bromoisobutyryloxy)ethylmethacrylate (BIEM) afforded the multifunctional random copolymer, P(OEGMA-co-BSTMA-co-BIEM), in which hydrophilic POEGMA can stabilize nanoparticles in water, PBSTMA can be converted into carboxyl groups, and PBIEM can be employed as a macromolecular atom radical transfer polymerization (ATRP) initiator. The ATRP of DEA and BMA using P(OEGMA-co-BSTMA-co-BIEM) as a macromolecular ATRP initiator led to the formation of the pH-responsive brush-type copolymer, P(OEGMA-co-BSTMA)-g-P(DEA-co- BMA). After hydrolysis by trifluoroacetic acid and post-functionalization the final polymeric prodrug, P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA), was obtained with a drug content of ∼7.8 wt%. P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA) can be assembled into nanoparticles (BUF- NP-RGD) in aqueous solution with a diameter of 148.4 ±â€¯0.7 nm and a zeta potential of -7.6 ±â€¯0.4 mV. BUF-NP-RGD exhibited controlled drug release in the presence of esterase. Additionally, P(OEGMA-co- BSMA)-g-P(DEA-co-BMA) showed a significant hemolysis effect at a pH comparable to that of endosomes/lysosomes. Cell viability and a tumor-bearing nude mouse model were employed to evaluate the anticancer efficacy of BUF-NP-RGD. It was revealed that BUF-NP-RGD showed improved anticancer performance compared with that of free BUF both in vitro and in vivo. Histological and immunochemical analysis further demonstrated that BUF-NP-RGD exhibited improved cell apoptosis, angiogenesis inhibition, and an anti-proliferation effect.

Type I Interferon Induced and Antagonized by Foot-and-Mouth Disease Virus.

Viral infections trigger the innate immune system, serving as the first line of defense, and are characterized by the production of type I interferon (IFN). Type I IFN is expressed in a broad spectrum of cells and tissues in the host and includes various subtypes (IFN-α, IFN-ß, IFN-δ, IFN-ε, IFN-κ, IFN-τ, IFN-ω, IFN-ν, and IFN-ζ). Since the discovery of type I IFN, our knowledge of the biology of type I IFN has accumulated immensely, and we now have a substantial amount of information on the molecular mechanisms of the response and induction of type I IFN, as well as the strategies utilized by viruses to evade the type I IFN response. Foot-and-mouth disease virus (FMDV) can selectively alter cellular pathways to promote viral replication and evade antiviral immune activation of type I IFN. RNA molecules generated by FMDV are sensed by the cellular receptor for pathogen-associated molecular patterns (PAMPs). FMDV preferentially activates different sensor molecules and various signal transduction pathways. Based on knowledge of the virus or RNA pathogen specificity as well as the function-structure relationship of RNA sensing, it is necessary to summarize numerous signaling adaptors that are reported to participate in the regulation of IFN gene activation.