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An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines.

A major challenge in cancer vaccine therapy is the efficient delivery of antigens and adjuvants to stimulate a controlled yet robust tumour-specific T-cell response. Here, we describe a structurally well defined DNA nanodevice vaccine generated by precisely assembling two types of molecular adjuvants and an antigen peptide within the inner cavity of a tubular DNA nanostructure that can be activated in the subcellular environment to trigger T-cell activation and cancer cytotoxicity. The integration of low pH-responsive DNA 'locking strands' outside the nanostructures enables the opening of the vaccine in lysosomes in antigen-presenting cells, exposing adjuvants and antigens to activate a strong immune response. The DNA nanodevice vaccine elicited a potent antigen-specific T-cell response, with subsequent tumour regression in mouse cancer models. Nanodevice vaccination generated long-term T-cell responses that potently protected the mice against tumour rechallenge.

Objective: Salivagram is one of the imaging modalities to detect pulmonary aspiration in children. This study aims to optimize the classification of pulmonary aspiration detected by salivagram with a semi-quantitative analytical method., Methods: This is a retrospective study involving 737 patients (471 males, 266 females; aged 1 month to 8 years; mean age 5.3 months, median age 3.0 months old) with suspected pulmonary aspiration, who had salivagram done between January 2018 and June 2019. Positive cases were divided into 10 groups (Grade 1, R2, L2, R2L2, R3, L3, R3L2, R2L3, R3L3, and 4) according to the scintigraphic findings. Aspiration index was determined as the ratio of the count in the respiratory tract to the total count in the image field of view and compared among different groups using the receiver operating characteristics (ROC) curve analysis., Results: A total of 180 cases had positive scintigraphic findings of various grades of aspiration (24.4%, 180/737). There is a high consistency among the two independent nuclear medicine physicians involved in the study, in determining both the disease gradings (κ = 0.919;95% CI: 0.915-0.923) and aspiration index (ICC = 0.994;95% CI: 0.993-0.996). There is no significant difference (p > 0.05) in aspiration index among the gradings in "mild" group (grade 1, R2, L2, L2R2), and "moderate" group (grade R3, R3L2, R3L3). After dividing the different grades into "mild", "moderate" and "severe" groups, the aspiration index of "mild" group is 4.40 ± 2.01, that of "moderate" group is 16.43 ± 8.20, and that of "severe" group is 46.94 ± 14.81. Difference in groups was statistically significant (p < 0.0001). In ROC curve analysis, AUC of "mild" and "moderate" groups is 0.970 and that of "moderate" and "severe" groups is 0.943; the cut-off value with highest diagnostic efficiency is 6.75 between "mild" and "moderate" groups and 38.00 between "moderate" and "severe" groups., Conclusions: We introduced a semi-quantitative analytical method in pulmonary aspiration on salivagram, to optimize and supplement to the current classification of pulmonary aspiration.

Objective: Salivagrams are commonly used for detecting pulmonary aspiration. However, conventional dynamic imaging is relatively time-consuming and could be difficult to perform in children with poor compliance. We analyzed the characteristics of conventional dynamic imaging to obtain a simple protocol suitable for use in children., Methods: We conducted a retrospective analysis of salivagram data from 1163 patients (783 males, 380 females; age, 1 month to 9.0 years; mean age, 5.7 months) obtained in the past 4.5 years (January 2014 to June 2018). The various timepoint images were used for diagnosis. The positivity rate, missed diagnosis rate, and sensitivity were calculated and compared., Results: Dynamic imaging revealed 353 cases of pulmonary aspiration (248 males, 105 females; age, 1 month to 4.5 years; mean age, 6.2 months). The positivity rate was 30.4% (353/1163), and 95.8% (338/353) of patients presented with continuous positive images after pulmonary aspiration. Only 4.2% (15/353) of positive cases showed clearance of pulmonary aspiration. The positivity rates were 11.8%, 18.2%, 21.9%, 25.0%, 27.0%, and 29.2% at 5, 10, 15, 20, 25, and 30 minutes, respectively. About 4.2% (15/353) of positive cases on earlier images showed clearance of pulmonary aspiration on later images, which indicate both early 15-minute and later 30-minute images were necessary., Conclusions: Two static images acquired at 15 and 30 minutes might be an effective alternative to conventional salivagram, which mandates dynamic imaging.

In the present paper, agarose acetate (AGA) nanofibrous membranes containing different weight percentages of β-tricalcium phosphate (β-TCP) were successfully developed through electrospinning. The fibers in the nanofibrous membranes had a rough surface due to the β-TCP particles which were uniformly dispersed within or on the surface of AGA fibers. Rat-bone marrow-derived mesenchymal stem cells (rBMSCs) were cultured on the AGA based nanofibrous membranes while showed a good adhesion and proliferation. It was found that more rBMSCs were differentiated to osteoblast-like cells on the β-TCP containing nanofibrous membranes compared with the single AGA membrane, and more alkaline phosphatase (ALP) and mineralized matrix could be detected when rBMSCs were cultured on the β-TCP containing nanofibrous membranes. The nanofibrous membranes were implanted into Sprague-Dawley (SD) rats for biocompatibility test. Gross examination and histological analysis of the AGA based nanofibrous membranes results showed that there was less inflammatory response. All of experimental results suggested that the AGA based nanofibrous membranes had the great potential application in bone tissue engineering., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite the importance and promise of cancer vaccines for broader prevention and treatment of cancer, limited clinical responses are observed, suggesting that key rational designs are required for inducing potent immune responses against cancer. Here we report a mesoporous silicon vector (MSV) as a multi-functional microparticle for formulating an efficient cancer vaccine composed of B16 melanoma derived-tyrosinase related protein 2 (TRP2) peptide and dual toll-like receptor (TLR) agonists. We demonstrated that MSV microparticles protected the peptide from rapid degradation for prolonged antigen presentation to immune cells. Moreover, MSV enabled co-delivery of two different TLR agonists [CpG oligonucleotide and monophosphoryl lipid A (MPLA)] along with TRP2 peptide into the same dendritic cell (DC), thus increasing the efficiency and capacity of DCs to induce potent TRP2-specifc CD8 + T cell responses against B16 melanoma. Furthermore, this MSV-based DC vaccine could significantly prolong the median survival of tumor-bearing mice by orchestrating effective host immune responses involving CD8 + T cells, CD4 + T cells and macrophages. Our study provides rational and potentially translational approach to develop durable and potent immunotherapy for patients with cancer by delivering various combinations of tumor antigens, neoantigens and innate immune agonists., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ara h 2 is considered a major allergen in peanut. Due to the difficulty of separation, Ara h 2 had not been fully studied. Immunoaffinity chromatography (IAC) column can separate target protein with high selectivity, which made it possible to purify Ara h 2 from different samples. In this study, IAC method was developed to purify Ara h 2 and its effect was evaluated. By coupling polyclonal antibody (pAb) on CNBr-activated Sepharose 4B, the column for specific extraction was constructed. The coupling efficiency of the IAC column was higher than 90%, which made the capacity of column reached 0.56 mg per 0.15 g medium (dry weight). The recovery of Ara h 2 ranged from 93% to 100% for different concentrations of pure Ara h 2 solutions in 15 min. After using a column 10 times, about 88% of the column capacity remained. When applied to extract Ara h 2 from raw peanut protein extract and boiled peanut protein extract, the IAC column could recovery 94% and 88% target protein from the mixture. SDS-PAGE and Western blotting analysis confirmed the purified protein was Ara h 2, its purity reached about 90%. Significantly, the IAC column could capture dimer of Ara h 2, which made it feasible to prepared derivative of protein after processing., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Meckel's diverticulum scintigraphy (MDS) is a common method for diagnosing ectopic gastric mucosa (EGM), but atypical images are difficult to diagnose. This study aimed to improve the understanding of the existing diagnostic criteria through a review of confirmed cases., Subjects and Methods: A total of 352 patients underwent MDS. Among 120 patients with a positive diagnosis, 106 underwent surgery. This study analyzed the imaging presentation, surgical records, and pathological results. The existing diagnostic criteria included the location, shape, and radioactive appearance of the lesions. Data from surgical records with typical or atypical images were compared., Results: One hundred cases (100/106) were surgically confirmed to be Meckel's diverticulum (MD). The remaining 6 were intestinal polyps, intestinal duplication, duodenal ulcer, non-Hodgkin's lymphoma (NHL) and hiatal hernia. Out of the 100 MD cases, 93 had complete operation records and 59/93 of the MDS 63.4% MD were located in the right lower quadrant, and 81.7% had a round shape in the scintiscan. The onset of the lesions activity in 96.8% (90/93) of the cases corresponded with the onset of the gastric activity. The radioactivity of 97.8% (91/93) of the lesions gradually increased during the examination. There were no significant differences between the typical and atypical scintiscan images: in the distance of MD from the ileocecal valve, in the MD length, and the basal diameter of MD for lesions at different scintiscans (P>0.05), or of different shapes (P>0.05)., Conclusion: Location in the right lower quadrant and round shape of the lesions are not the primary diagnostic factors for Meckel's diverticulum. The establishment of the diagnosis of MD requires careful consideration of other imaging characteristics such as: a) The onset of lesions' radioactivity to correspond with the onset of the gastric activity and b) The lesions' radioactivity to gradually increase during the scan procedure.

Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Nanomaterial-mediated photothermal therapy has shown great potential to fulfill the unmet medical needs for treatment of tumors. In this study, a rod-like gold nanoshell capsule, which can offer both photothermal therapy and chemotherapy, is synthesized and applied for the treatment of melanoma. This nano-platform is made by developing a gold nanoshell on rod-like mesoporous silica nanoparticles with different aspect ratios, and it was found that the aspect ratio significantly influenced the cellular uptake and tumor distribution of the nanoparticles. The gold nanoshell capsules with a moderate aspect ratio are found to be efficiently taken up by melanoma cells and are able to penetrate tumor tissues, resulting in the effective ablation of highly malignant melanomas when used along with mild laser irradiation and a single treatment. This study demonstrates that the optimization of the aspect ratio is indispensable to further development of this nanoplatform for antitumor therapy., From the Clinical Editor: The combination of hyperthermia and chemotherapeutic agents has been investigated as a new approach for the treatment of malignant melanoma. It appears that the aspect ratio may play an important role in the treatment efficacy. In this article, the authors studied how the AR influenced the cellular uptake and the optimal AR for antitumor effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The catalytic cracking method of PAHs for the pyrolysis gaseous products is proposed to control their pollution to the environment. In this study, the Py-GC-MS is used to investigate in situ the catalytic effect of CaO and Fe2O3 on the 16 PAHs from Pingshuo coal pyrolysis under different catalytic temperatures and catalyst particle sizes. The results demonstrate that Fe2O3 is effective than that of CaO for catalytic cracking of 16 PAHs and that their catalytic temperature corresponding to the maximum PAHs cracking rates is different. The PAHs cracking rate is up to 60.59% for Fe2O3 at 600°C and is 52.88% at 700°C for CaO. The catalytic temperature and particle size of the catalysts have a significant effect on PAHs cracking rate and CaO will lose the capability of decreasing 16 PAHs when the temperature is higher than 900°C. The possible cracking process of 16 PAHs is deduced by elaborately analyzing the cracking effect of the two catalysts on 16 different species of PAHs.

Cyclooxygenase-2 (COX-2) overexpression has been associated with the grade, prognosis and recurrence of transitional cell carcinoma (TCC) of the bladder. In this study, sulforaphane, a dietary isothiocyanate, down-regulated COX-2 expression in human bladder transitional cancer T24 cells at both transcriptional- and translational levels. Sulforaphane (5-20 microM) induced nuclear translocation of NF-kappaB and reduced its binding to the COX-2 promoter, a key mechanism for suppressing COX-2 expression by sulforaphane. Moreover, sulforaphane increased expression of p38 and phosphorylated-p38 protein. A specific inhibitor of p38 MAPK, SB202190, was used to further investigate its pivotal role in sulforaphane-mediated down-regulation of COX-2. Exposure of T24 cells to SB202190 1 hour prior to sulforaphane treatment abolished the effect of sulforaphane on COX-2 mRNA down-regulation, but enhanced COX-2 transcription. Furthermore, SB202190 alone induced NF-kappaB translocation to the nucleus, promoted NF-kappaB binding to the COX-2 promoter and resulted in up-regulation of COX-2 expression. Taken together, these data suggest that p38 is essential in sulforaphane-mediated COX-2 suppression and provide new insights into the molecular mechanisms of sulforaphane in the chemoprevention of bladder cancer.

Objective: To compare the immunoenhancement of six polysaccharides on the murine immunological cells in vitro., Methods: The immunoenhancement of the polysaccharide on the murine splenocytes were tested by MTt assay. The effects of polysaceharides on IgG secretion of spleen lymphocytes were detected by ELISA. The activation of peritoneal macrophages were tested by the method of neutral red phagocytosis assay. The phagocytic activity of spleen NK cells were detected by the method of LDH., Results: Lentinan and Ganoderan could promote spleen lymphocyte proliferation with ConA significantly. Astragalan, Ganoderan and Lentinan had stronger function in promoting the IgG secretion and proliferation of spleen lymphocyte with LPS. Lichenan and Astragalan could significantly enhance activation of peritoneal macrophages and splenic NK., Conclusion: The immuno-regulation mechanism and effects of six polysaccharides were indivadually variable. The polysaccharide aiming at different effect targets could be combined into the most immunopotentiating agent by the most appropriate doses ratio.