Cancer vaccines promote immune responses and establish anti-tumor immune memory. Eliminating cancer cells by vaccination requires cellular immunity-based adjuvants and tumor-related antigens. However, commonly used aluminum-based adjuvants are insufficient in inducing strong cellular immune responses, thus necessitating additional immune stimulants. To address this limitation, we report the development of layer-by-layer (LBL) assembled aluminum nanoparticles (LBL-AlNPs) using ovalbumin as a model antigen and chitosan as a cellular immune enhancer. The LBL technique enable improved the antigen loading and controlled release by incorporating chitosan layers. The effect of the number of layers in the LBL-AlNPs and the optimum number of layers was determined by evaluating their physicochemical properties. As the number of layers increased, the antigen release rate decreased. The LBL-AlNPs were stable under physiological environment for 14 days. In particular, the LBL-AlNPs with two layers (LBL-AlNP-2L) exhibited 3.9-fold and 2.4-fold higher IL-2 secretion, indicating enhanced antigen cross-presentation, compared to LBL-AlNP-1L and 3L, respectively. Furthermore, cellular uptake was increased by 1.8-fold and 1.5-foldcompared to the same groups. Significantly, in vivo studies demonstrated that LBL-AlNP-2L promoted a better immune response, including increased IFN- gamma production (2.4fold vs free OVA) after immunization and ultimately suppressed tumor growth when tumors in the immunized model were challenged. Consequently, these findings suggest that LBL-AlNP-2L can be considered as a promising cancer vaccine.

We consider the dispersion managed nonlinear Schrodinger equations with quintic and cubic nonlinearities in one and two dimensions, respectively. We prove the global well-posedness and scattering in L2x for small initial data employing the Up and Vp spaces.

We consider the variational problem with a mass constraint arising from the two-dimensional dispersion managed nonlinear Schrödinger equation with power-law type nonlinearity. We prove a threshold phenomenon with respect to mass for the existence of minimizers for all possible powers of nonlinearities, including at the threshold itself. This threshold is closely related to the best constant for the Gagliardo-Nirenberg-Strichartz type inequality whose extremizers are found as a byproduct.

We consider the Gabitov-Turitsyn equation or the dispersion managed nonlinear Schr\"odinger equation of a power-type nonlinearity \[ i\partial_t u+ d_\text{av} \partial_x^2u+\int_0^1 e^{-ir\partial_x^2}\big(|e^{ir\partial_x^2}u|^{p-1}e^{ir\partial_x^2}u\big)dr=0 \] and prove the global existence versus finite time blowup dichotomy for the mass-supercritical cases, that is, $p>9$.

The influenza virus poses a global health burden. Currently, an annual vaccine is used to reduce influenza virus-associated morbidity and mortality. Most influenza vaccines have been developed to elicit neutralizing Abs against influenza virus. These Abs primarily target immunodominant epitopes derived from hemagglutinin (HA) or neuraminidase (NA) of the influenza virus incorporated in vaccines. However, HA and NA are highly variable proteins that are prone to antigenic changes, which can reduce vaccine efficacy. Therefore, it is essential to develop universal vaccines that target immunodominant epitopes derived from conserved regions of the influenza virus, enabling cross-protection among different virus variants. The internal proteins of the influenza virus serve as ideal targets for universal vaccines. These internal proteins are presented by MHC class I molecules on Ag-presenting cells, such as dendritic cells, and recognized by CD8 T cells, which elicit CD8 T cell responses, reducing the likelihood of disease and influenza viral spread by inducing virus-infected cell apoptosis. In this review, we highlight the importance of CD8 T cell-mediated immunity against influenza viruses and that of viral epitopes for developing CD8 T cell-based influenza vaccines.

Cancer, a key factor in declining global life expectancy, has driven the integration of chemotherapy and immunotherapy to address multidrug resistance and influence the tumor microenvironment. We developed a novel vaccine delivery carrier, a chitosan-coated polylactic acid/poloxamer nanoparticle (CPP NP), designed to co-encapsulate an anticancer drug and antigen without any chemical conjugation process, enabling effective and synergistic cancer chemo-immunotherapy. The CPP NP achieved synergistic efficacy through paclitaxel (PTX), an immunogenic cell death-inducing chemotherapeutic agent; ovalbumin (OVA), which promotes dendritic cell maturation; and enhanced cellular uptake facilitated by chitosan. The PTX and OVA-loaded CPP NPs (PTX/OVA@CPP NPs) were stable in PBS for four weeks and resuspended well after lyophilization without any cryoprotectants. Moreover, PTX and OVA from the NPs exhibited a sustained release rate and pH-responsive release pattern within different cellular microenvironments. Importantly, PTX@CPP NPs exhibited much higher anticancer efficacy across various cancer cell lines, even multidrug-resistant cells, compared to free PTX and PTX@PP NPs without the chitosan coating. In antigen-presenting cells, OVA@CPP NPs led to higher IL-2 secretion and cellular uptake compared to free OVA and OVA@PP NPs. Furthermore, in a tumor-bearing mouse model, PTX/OVA@CPP NPs exhibited strong synergistic tumor suppression and triggered OVA antigen-specific responses, promoting an antitumor immune response. These findings demonstrate that PTX/OVA@CPP NPs show potential as new chemo-immunotherapeutic agents for effective cancer treatment.

We consider the dispersion managed nonlinear Schrödinger equation with power-law nonlinearity and its discrete version of equations with step size h∈(0,1]. We prove that the solutions of the discrete equations strongly converge in L2(R) to the solution of the dispersion managed NLS as h→0 after showing the global well-posedness of the discrete equations.

Teicoplanin (TP) is a glycopeptide antibiotic used for Gram-positive bacterial infections, and it has been reported to inhibit SARS-CoV-2 and Ebola virus entry through cathepsin inhibition. Given that TP can inhibit viruses belonging to different virus families, we aimed to expand the potential targets of TP to determine whether TP can be developed as a broad-spectrum antiviral agent. Considering the original indication of TP, we first determined the effects of TP against viruses that cause respiratory tract infections and found that TP inhibits enveloped and non-enveloped RNA viruses, namely: human and avian influenza viruses; representative coronaviruses including porcine epidemic diarrhea virus (PEDV), human coronavirus OC43 (HCoV-OC43), and SARS-CoV-2; measles virus; human respiratory syncytial virus A2; and enterovirus 71 (EV-71). Representative flaviviruses, Zika virus (ZIKV) and dengue virus serotype 2 (DENV2), were also susceptible to inhibition by TP. In contrast, TP did not attenuate infection of human adenovirus 5, a non-enveloped DNA virus. Addition of TP at the endocytosis stage but not at the attachment/binding stage of PEDV infection reduced PEDV production in vitro, indicating cathepsin inhibition. Meanwhile, addition of TP during either the attachment/binding or the endocytosis stage of ZIKV infection reduced ZIKV particle production in host cells, and in silico modeling suggested that TP has potential binding pockets in the envelope proteins of ZIKV and DENV2. These results show that TP can be developed as a broad-spectrum antiviral especially against RNA viruses, with potentially different targets in the replication cycle of various viruses. ### Competing Interest Statement The authors have declared no competing interest.

Background: Vaccination is an effective disease prevention strategy involving immune cell stimulation and formation in response to foreign substances. However, the poor immunogenicity and deliverability of certain antigens necessitate novel methods to establish continuous immunity. Therefore, for efficient antigen delivering and simultaneously performing as a nanoadjuvant, herein, we prepared core (polylactic acid)-shell (poloxamer) thermoresponsive nanosponges (TNSs). Methods: By simple nanoprecipitation, we prepared the thermoresponsive nanosponges (TNSs) with core-to-shell ratios of 1:2 and 1:20. Thereafter, antigens (ovalbumin, OVA) were loaded into TNSs by swelling behavior. Results: The TNSs were prepared with different sizes using differing core-to-shell ratios: TNS1:2 (160 nm) and TNS1:20 (67 nm). When loaded with the model antigen ovalbumin (OVA), TNS1:2 (289 nm) showed a seven-fold higher IL-2 secretion response cross-presentation ability than TNS1:20 (74 nm) and was used in subsequent experiments. TNS1:2 promoted dendritic cell maturation and exhibited high OVA encapsulation (optimal loading: 50 wt%), sufficient long-term stability, and controlled OVA release under physiological conditions. It was not toxic to dendritic cells even at high concentrations. Compared to free OVA, 50 wt% OVA loaded TNS1:2 exhibited better cellular uptake and a superior ability to elicit immune cell IL-2 secretion. The OVA antigen-specific activation of immune cells in mice was examined by monitoring serum IgG levels, cross-presentation to splenocyte CD8+ T-cells, and IFN-gamma cytokine levels. Conclusions: The results highlight TNSs as promising nanoadjuvants and carriers for antigen delivery in vaccine applications.

We consider a nonlocal and nonlinear minimization problem, with a parameter > 0, related to the dispersion managed nonlinear Schro"\dinger equation having a positive average dispersion. The minimizers converge, up to shifts and boosts, to a minimizer for the limit problem associated with the nonlinear Schro"\dinger equation in H1(R) as \varepsilon \rightarrow 0. Furthermore, the uniqueness of a minimizer for the minimization problem, up to shifts and boosts, is shown when \varepsilon is small enough.

We prove local and global well–posedness results for the Gabitov–Turitsyn or dispersion managed nonlinear Schrödinger equation with a large class of nonlinearities and arbitrary average dispersion on L2(R) and H1(R) for zero and non–zero average dispersions, respectively. Moreover, when the average dispersion is non–negative, we show that the set of ground states is orbitally stable. This covers the case of non–saturated and saturated nonlinear polarizations and yields, for saturated nonlinearities, the first proof of orbital stability.

The excessive production of reactive oxygen species (ROS) causes harmful effects, including biomolecular damage and inflammation. ROS due to ultraviolet rays, blue light, and fine dust harm the skin, causing urban-related aging. Therefore, a strong antioxidant that relieves oxidative stress in the skin and removes ROS is required. Idebenone (IB) is a powerful antioxidant but is poorly soluble and thus has low solubility in water, resulting in low bioavailability. In this study, IB-loaded nanoparticles (IB@NPs) were synthesized by loading IB without an organic solvent into nanoparticles that can provide high loading efficiency and stability for solubilization. Indeed, the synthesized IB@NPs exhibited long-term stability through dynamic light scattering, methylene blue staining, and redispersion assays, and IB@NPs prepared with a 5 wt% IB loading content were found to be optimal. The antioxidant activity of IB@NPs evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was significantly higher than that of unloaded IB. In addition, IB@NPs showed excellent biocompatibility, inhibited oxidative damage to mouse NIH-3T3 fibroblasts, and reduced intracellular ROS generation according to an in vitro DPPH antioxidant assay. Most notably, IB@NPs significantly promoted wound healing in vitro, as demonstrated by scratch assays. Therefore, as carriers with excellent stability, IB@NPs have potential cosmetic and pharmaceutical applications.

AbstractBackgroundVaccination with tumor peptide epitopes associated with major histocompatibility complex class I molecules is an attractive approach directed at inducing tumor-specific cytotoxic T lymphocytes (CTLs). However, challenges remain in improving the therapeutic efficacy of peptide epitope vaccines, including the low immunogenicity of peptide epitopes and insufficient stimulation of innate immune componentsin vivo. To overcome this, we aimed to develop and test an innovative strategy that elicits potent CTL responses against tumor epitopes. The essential feature of this strategy is vaccination using tumor epitope-loaded nanoparticles (NPs) in combination with polyinosinic-polycytidylic acid (poly-IC) and anti-PD1 monoclonal antibody (mAb).MethodsCarboxylated NPs were prepared using poly(lactic-co-glycolic acid) and poly(ethylene/maleic anhydride), covalently conjugated with anti-H-2KbmAbs, and then attached to H-2Kb molecules isolated from the tumor mass (H-2b). Native peptides associated with the H-2Kbmolecules of H-2Kb-attached NPs were exchanged with tumor peptide epitopes. The tumor-specific CTL-inducing and anti-tumor activities of the tumor epitope-loaded NPs were examined in mice bearing EG7-OVA thymoma or B16-F10 melanoma. In addition, the anti-tumor therapeutic efficacy of the NPs was examined in combination with poly-IC, anti-PD1 mAb, or both.ResultsTumor peptide epitope-loaded NPs efficiently induced tumor-specific CTLs when used to immunize tumor-bearing mice as well as normal mice. This activity of the NPs significantly was increased when co-administered with poly-IC. Accordingly, the NPs exerted significant anti-tumor effects in mice implanted with EG7-OVA thymoma or B16-F10 melanoma, and the anti-tumor activity of the NPs was significantly increased when applied in combination with poly-IC. The most potent anti-tumor activity was observed when the NPs were co-administered with both poly-IC and anti-PD1 mAb.ConclusionsImmunization with tumor epitope-loaded NPs in combination with poly-IC and anti-PD1 mAb in tumor-bearing mice can be a powerful means to induce tumor-specific CTLs with therapeutic anti-tumor activity.

We consider the dispersion managed power-law nonlinear Schrödinger (DM NLS) equations with a small parameter ɛ > 0 and the averaged equation, which are used in optical fiber communications. We prove that the solutions of DM NLS equations converge to the solution of the averaged equation in H1(R) as ɛ goes to zero. Meanwhile, in the positive average dispersion, we obtain the global existence of the solution to DM NLS equation in H1(R) for sufficiently small ɛ > 0, even when the exponent of the nonlinearity is beyond the mass-critical power.

Vaccination with tumor peptide epitopes associated with MHC class I molecules is an attractive approach directed at inducing tumor-specific CTLs. However, challenges remain in improving the therapeutic efficacy of peptide epitope vaccines, including the low immunogenicity of peptide epitopes and insufficient stimulation of innate immune components in vivo. To overcome this, we aimed to develop and test an innovative strategy that elicits potent CTL responses against tumor epitopes. The essential feature of this strategy is vaccination using tumor epitope-loaded nanoparticles (NPs) in combination with polyinosinic-polycytidylic acid (poly-IC) and anti-PD1 mAb. Carboxylated NPs were prepared using poly(lactic-co-glycolic acid) and poly(ethylene/maleic anhydride), covalently conjugated with anti-H-2Kb mAbs, and then attached to H-2Kb molecules isolated from the tumor mass (H-2b). Native peptides associated with the H-2Kb molecules of H-2Kb-attached NPs were exchanged with tumor peptide epitopes. Tumor peptide epitope-loaded NPs efficiently induced tumor-specific CTLs when used to immunize tumor-bearing mice as well as normal mice. This activity of the NPs significantly was increased when co-administered with poly-IC. Accordingly, the NPs exerted significant anti-tumor effects in mice implanted with EG7-OVA thymoma or B16-F10 melanoma, and the anti-tumor activity of the NPs was significantly increased when applied in combination with poly-IC. The most potent anti-tumor activity was observed when the NPs were co-administered with both poly-IC and anti-PD1 mAb. Immunization with tumor epitope-loaded NPs in combination with poly-IC and anti-PD1 mAb in tumor-bearing mice can be a powerful means to induce tumor-specific CTLs with therapeutic anti-tumor activity.

Tumor peptides associated with MHC class I molecules or their synthetic variants have attracted great attention for their potential use as vaccines to induce tumor-specific CTLs. However, the outcome of clinical trials of peptide-based tumor vaccines has been disappointing. There are various reasons for this lack of success, such as difficulties in delivering the peptides specifically to professional Ag-presenting cells, short peptide half-life in vivo, and limited peptide immunogenicity. We report here a novel peptide vaccination strategy that efficiently induces peptide-specific CTLs. Nanoparticles (NPs) were fabricated from a biodegradable polymer, poly(D,L-lactic-co-glycolic acid), attached to H-2Kb molecules, and then the natural peptide epitopes associated with the H-2Kb molecules were exchanged with a model tumor peptide, SIINFEKL (OVA257-268). These NPs were efficiently phagocytosed by immature dendritic cells (DCs), inducing DC maturation and activation. In addition, the DCs that phagocytosed SIINFEKL-pulsed NPs potently activated SIINFEKL-H-2Kb complex-specific CD8+ T cells via cross-presentation of SIINFEKL. In vivo studies showed that intravenous administration of SIINFEKL-pulsed NPs effectively generated SIINFEKL-specific CD8+ T cells in both normal and tumor-bearing mice. Furthermore, intravenous administration of SIINFEKL-pulsed NPs into EG7.OVA tumor-bearing mice almost completely inhibited the tumor growth. These results demonstrate that vaccination with polymeric NPs coated with tumor peptide-MHC-I complexes is a novel strategy for efficient induction of tumor-specific CTLs.

We show the global well-posedness of the nonlinear Schrödinger equation with periodically varying coefficients and a small parameter ɛ > 0, which is used in optical-fiber communications. We also prove that the solutions converge to the solution for the Gabitov–Turitsyn or averaged equation as ɛ tends to zero.

We study behavior of numerical solutions for a nonlinear eigenvalue problem on R-n that is reduced from a dispersion managed nonlinear Schrodinger equation. The solution operator of the free Schrodinger equation in the eigenvalue problem is implemented via the finite difference scheme, and the primary nonlinear eigenvalue problem is numerically solved via Picard iteration. Through numerical simulations, the results known only theoretically, for example the number of eigenpairs for one dimensional problem, are verified. Furthermore several new characteristics of the eigenpairs, including the existence of eigenpairs inherent in zero average dispersion two dimensional problem, are observed and analyzed.

The global burden of bone-related diseases is increasing in the aging society; thus, improved bone targeted imaging for their early identification and treatment are needed. In this study, we screened novel peptide ligands for hydroxyapatite, a major inorganic component of teeth and bones, and identified a peptide enabling in vivo bone targeting and real-time fluorescence bone detection. To isolate peptides highly specific for hydroxyapatite, we used negative and positive selection from a randomized 8-mer peptide phage library and identified hydroxyapatite-specific peptides (HA-pep2, HA-pep3, and HA-pep7). Among these three peptides, HA-pep3 showed the highest binding capacity and superior dissociation constant towards hydroxyapatite surfaces over time (~ 88.3% retained on hydroxyapatite after two weeks). Furthermore, HA-pep3 was highly specific for hydroxyapatite compared to other calcium salt-based materials. Using this superior specificity, HA-pep3 showed higher accumulation in skull, spine, and joints in comparison with scrambled control peptide during real-time whole-body imaging. Ex vivo analysis of the major organs and bone from mice demonstrated that the fluorescence intensity in bone was about 3.32 folds higher in the case of HA-pep3 than the one exhibited by the scrambled control peptide. Our study identified a novel approach for targeting ligands for bone specific imaging and can be useful for drug delivery applications.

The purpose of this study was to investigate the effects of either chrysin or exercise on the inflammasome and thermogenic markers in the livers of high-fat fed mice. C57BL/6 mice were randomly assigned to four groups: normal diet control (NC; n=5), high-fat diet control (HC; n=5), high-fat diet with chrysin (Hch; n=5), and high-fat diet with moderate exercise (HME; n=5). The mice were fed a high-fat diet (60% of calories from fat) or normal diet (18% of calories from fat). Chrysin was supplemented orally as 50mg/kg/day dissolved in a 0.1ml solution of dimethyl sulfoxide. The exercised mice ran on a treadmill at 12-20 m/min for 30-60 min/day, 5 times/week, for 16 weeks. After the intervention, the epididymal fat and liver weights were significantly decreased in the HME group compared with HC and Hch groups. The adipocyte size was effectively decreased in the Hch and HME groups compared with the HC group. The inflammasome markers NLRP3, IL-1β, and caspase1 were significantly decreased in the Hch and HME groups compared with the HC group. The thermogenic markers PGC-1α and BMP7 were significantly lower in the HC than in the NC group. However, the HME group showed an increase in the thermogenic markers. In conclusion, chrysin and moderate exercise have positive effects on obese metabolic complications induced by high-fat diets by reducing inflammasome genes. However, chrysin supplementation had no effect on thermogenic gene expression. Moderate exercise would therefore seem to be more effective in controlling obesity-induced metabolic deregulation.