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Adjuvant is a major supplementary component of vaccines to boost adaptive immune responses. To select an efficient adjuvant from the heat-labile toxin B subunit (LTB) of E. coli , four LTB mutants (numbered LTB26, LTB34, LTB57, and LTB85) were generated by multi-amino acid random replacement. Mice have been intranasally vaccinated with human rotavirus VP8 admixed. Among the four mutants, enzyme-linked immunosorbent assay (ELISA) revealed that LTB26 had enhanced mucosal immune adjuvanticity compared to LTB, showing significantly enhanced immune responses in both serum IgG and mucosal sIgA levels. The 3D modeling analysis suggested that the enhanced immune adjuvanticity of LTB26 might be due to the change of the first LTB α-helix to a β-sheet. The molecular mechanism was studied using transcriptomic and flow cytometric (FCM) analysis. The transcriptomic data demonstrated that LTB26 enhanced immune response by enhancing B cell receptor (BCR) and major histocompatibility complex (MHC) II+-related pathways. Furthermore, LTB26 promoted Th1 and Th2-type immune responses which were confirmed by detecting IFN-γ and IL-4 expression levels. Immunohistochemical analysis demonstrated that LTB26 enhanced both Th1 and Th2 type immunity. Therefore, LTB26 was a potent mucosal immune adjuvant meeting the requirement for use in human clinics in the future. • The adjuvant activity of LTB and its mutants are not as proportional to the GM-binding affinity as previously reported. [ABSTRACT FROM AUTHOR]

Protein deficiency is a major difficulty for human needs in the past few decades, while different types of aquatic species are rich in high quality protein. Therefore, aquaculture is considered as the main developing food production sector globally. Bacterial infections are the main problem for aquaculture, and their outbreaks have a great impact on productivity, and previously indiscriminate use of antibiotics to control them. However, the emergence of multidrug-resistant pathogens might lead to sudden infectious disease outbreaks resulting in serious economic loss. Immunostimulants application is an effective technique to protect and enhance the immune system of aquatic animals and therefore improve aquaculture production. Nutrient immunostimulants such as essential fatty acids, amino acids, vitamins, and minerals are the most important responsibility to improve aquaculture production, as well as the cost of this method, which is effective, non-toxic, and environment friendly. These nutrient immunostimulants are supportive to increase the immune system, antioxidant, antiinflammatory, and infection resistance of aquatic animals. In addition, nutritional feed additives improved feed palatability and the excellence of aquatic products and also enhance gut functions. Some information is available on nutrient immunostimulants in aquaculture applications, and this review provides information on different kinds of nutritional administration used in aquaculture to enhance positive impacts on aquatic animals' health as well as feed quality development. This review will provide theoretical references for the application of nutrient immunostimulants in aquatic feeds. [ABSTRACT FROM AUTHOR]

A nano-immunomodulator modified with N-acetylgalactosamine (GalNAc) on calcium carbonate (CaCO3) was prepared for targeted and responsive immunotherapy. And the immunologic adjuvant (CpG ODNs) and doxorubicin (DOX) were released to synergistically improve immune response for treating orthotopic liver cancer. [ABSTRACT FROM AUTHOR]

Atlantic salmon (Salmo salar) were fed diets containing black soldier fly larvae (BSFL) meal at two inclusion levels for 13 months in open sea-cages. BSFL meal replaced plant-based ingredients and dietary insect meal inclusion levels were at 5% and 10%. A commercial salmon diet was fed as a control diet. Fish were reared from ~173 g to ~ 4 kg andwere randomly distributed into nine open sea-cages with ~6000 salmon/cage (12×12m²; 1900m³). Fish from the sea-cages were sampled at two time points (mid and final samplings) to study the dietary effects of BSFL meal on the general health and welfare. Monthly assessments of sea-lice and gill score were conducted to evaluate the overall well-being of the salmon. The findings from the current study revealed that dietary inclusion of BSFL meal up to 10% did not have any significant effects in general growth, welfare or survival. However, significant positive response was observed in the general skin mucosal, hematological, and gene expression profiles of salmon. Notably, the group of salmon fed with 5% BSFL meal showed a significant decrease in plasma aspartate transaminase and alanine transaminase. Also, a significantly higher expression of interleukin1β in both skin and gill along with upregulation of matrix metallopeptidase9 and mucin18 in gill were observed in salmonfedBSFL at 5%, which aidedinincreased immune responses. A part fromthat, this group had significantly higher mucus secretions, decreased cortisol response and increased number of erythrocytes. Furthermore, the delousing stress had a significant effect on the plasma cortisol, and these responses were independent of the dietary effect. Moreover, these immune responses behaved differently at different fish size and time points, acknowledging the influence of various factors in immune modulation. Overall, the findings from this study showed the effects of dietary BSFL meal to modulate the immune status of salmon. This study aims to fill the existing knowledge gaps regarding the impact of incorporating BSFL meal as a functional feed ingredient into the salmon diet on health and immune status replicating real farm conditions. [ABSTRACT FROM AUTHOR]

Delta inulin, or Advax, is a polysaccharide vaccine adjuvant that significantly enhances vaccine‐mediated immune responses against multiple pathogens and was recently licensed for use in the coronavirus disease 2019 (COVID‐19) vaccine SpikoGen. Although Advax has proven effective as an immune adjuvant, its specific binding targets have not been characterized. In this report, we identify a cellular receptor for Advax recognition. In vitro uptake of Advax particles by macrophage cell lines was substantially greater than that of latex beads of comparable size, suggesting an active uptake mechanism by phagocytic cells. Using a lectin array, Advax particles were recognized by lectins specific for various carbohydrate structures including mannosyl, N‐acetylgalactosamine and galactose moieties. Expression in nonphagocytic cells of dendritic cell–specific intercellular adhesion molecule‐3‐grabbing nonintegrin (DC‐SIGN), a C‐type lectin receptor, resulted in enhanced uptake of fluorescent Advax particles compared with mock‐transfected cells. Advax uptake was reduced with the addition of ethylenediaminetetraacetic acid and mannan to cells, which are known inhibitors of DC‐SIGN function. Finally, a specific blockade of DC‐SIGN using a neutralizing antibody abrogated Advax uptake in DC‐SIGN–expressing cells. Together, these results identify DC‐SIGN as a putative receptor for Advax. Given the known immunomodulatory role of DC‐SIGN, the findings described here have implications for the use of Advax adjuvants in humans and inform future mechanistic studies. [ABSTRACT FROM AUTHOR]

Purpose: To compare disease-free survival (DFS), overall survival (OS), and adverse events (AEs) among muscle-invasive urothelial carcinoma (MIUC) patients receiving adjuvant immune checkpoint inhibitors (ICIs) versus placebo/observation following radical surgery. Methods: This was a systematic review/meta-analysis of all published phase 3 randomized controlled trials. MEDLINE, EMBASE, and Cochrane were searched from inception until April 4, 2024. Pooled hazard ratios (HR) and relative risks (RR), plus confidence intervals (CI), were generated using frequentist random-effects modeling. Results: Three trials were identified: IMvigor010, CheckMate 274, and AMBASSADOR. In the overall cohort, adjuvant ICIs significantly improved DFS by 23% (HR = 0.77, 95% CI = 0.65–0.90). No DFS benefit was observed in patients with upper tract disease (HR = 1.19, 95% CI = 0.86–1.64). The highest magnitude of DFS benefit was observed among patients who had received prior neoadjuvant chemotherapy (HR = 0.69) and pathologic node-positive disease (HR = 0.75). A similar DFS benefit was observed irrespective of tumor PD-L1 status. Pooled OS demonstrated a 13% non-significant benefit (HR = 0.87, 95% CI = 0.75–1.01). Grade ≥ 3 immune-mediated AEs occurred in 8.6% and 2.1% of ICI and placebo/observation patients, respectively (RR = 4.35, 95% CI = 1.02–18.5). AEs leading to treatment discontinuation occurred in 14.3% and 0.9% of patients, respectively. Conclusion: Adjuvant ICIs confer a DFS benefit following radical surgery for MIUC, particularly among node-positive patients and those who received prior neoadjuvant chemotherapy. The lack of benefit for upper tract disease suggests that alternate adjuvant approaches, including chemotherapy, should be considered for these patients. Tumor PD-L1 status is not a predictive biomarker, highlighting the need for biomarkers in this setting. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases (IBDs) are chronic, recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis and Crohn's disease, is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations. Summary: During the last decades, therapeutic goals in IBD evolved toward endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMAs). DMAs include conventional immunosuppressants (thiopurines, methotrexate), biologic drugs (anti-TNF, anti-integrin, and anti-IL-12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with aggressive course of disease and risk factors for poor prognosis should be treated with biologic therapy early, while conventional immunomodulators should be used in those with milder course of disease in the absence of risk factors. Key Messages: Challenges in the treatment of IBD patients include the choice of effective yet safe drug and prevention or overcoming loss of response. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti‐PD‐1 after complete resection. All stages III–IV AM and CM patients receiving adjuvant anti‐PD‐1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence‐free survival (RFS), distant metastasis‐free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5–29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p =.002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07–2.17; p =.019). Two‐year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p =.050). Two‐year OS was significantly lower in AM (71.5% vs. 84.3%; p =.027). The results of this study suggest a poorer outcome of adjuvant‐treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high‐risk AM. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the efficacy and safety of neoadjuvant and adjuvant immunotherapies for non-small cell lung cancer (NSCLC). Methods: Electronic literature searches were conducted in PubMed, OVID, Web of SCI, Embase, Cochrane Library, and the Chinese National Knowledge Infrastructure databases. The deadline for literature update and retrieval is February 16, 2024. Studies presented at meetings were also screened. Randomized controlled trials (RCTs) and single-arm trials were included, and the data were extracted according to the inclusion and exclusion criteria. Data analysis was performed using Stata (16.0) software. Results: A total of 5850 patients in 11 RCTs and 6 single-arm trial studies involving neoadjuvant and/or adjuvant immune checkpoint inhibitor (ICI)-based therapies were included. Regarding neoadjuvant therapy, the overall complication rate after surgery reached 35% (95% CI, 0.21-0.49). Higher rates of pathological complete response (OR = 7.83; 95% CI, 5.95-10.31; P <.001) and major pathological response (OR = 5.13; 95% CI, 3.56-7.40; P <.001) were found in the resectable NSCLC patients who received neoadjuvant therapy with ICIs combined with chemotherapy compared with patients treated with chemotherapy alone. Of note, compared with chemotherapy, neoadjuvant ICIs combined with chemotherapy significantly improved the overall survival (OS) (HR = 0.65; 95% CI, 0.52-0.82; P <.001) and event-free survival (EFS) (HR = 0.59; 95% CI, 0.52-0.67; P <.001) in patients with resectable NSCLC. Regarding adjuvant therapy, a lower risk of disease progression or death (HR = 0.78; 95% CI, 0.69-0.90; P <.001) was found in the adjuvant ICI group compared with the adjuvant chemotherapy-alone group. In terms of safety, perioperative immunotherapy combined with chemotherapy did not increase toxicity compared with chemotherapy alone. Conclusion: In patients with resectable NSCLC, perioperative immunotherapy was safe and efficacious. Perioperative immunotherapy combined with chemotherapy improved the pathologic response and EFS/DFS/OS over chemotherapy alone without increasing toxicity. [ABSTRACT FROM AUTHOR]

Agonists of Toll like receptors (TLRs) have attracted interest as adjuvants and immune modulators. A crystal structure of TLR4/MD2 with E. coli LPS indicates that the fatty acid at C‐2 of the lipid A component of LPS induces dimerization of two TLR4‐MD2 complexes, which in turn initiates cell signaling leading to the production of (pro)inflammatory cytokines. To probe the importance of the (R)‐3‐hydroxymyristate at C‐2 of lipid A, a range of bis‐ and mono‐phosphoryl lipid A derivatives with different modifications at C‐2 were prepared by a strategy in which 2‐methylnaphthyl ethers were employed as permanent protecting group that could be readily removed by catalytic hydrogenation. The C‐2 amine was protected as 9‐fluorenylmethyloxycarbamate, which at a later stage could be removed to give a free amine that was modified by different fatty acids. LPS and the synthetic lipid As induced the same cytokines, however, large differences in activity were observed. A compound having a hexanoyl moiety at C‐2 still showed agonistic properties, but further shortening to a butanoyl abolished activity. The modifications had a larger influence on monophosphoryl lipid As. The lipid As having a butanoyl moiety at C‐2 could selectively antagonize TRIF associated cytokines induced by LPS or lipid A. [ABSTRACT FROM AUTHOR]

Background: Administering adjuvant therapy following liver resection is crucial for patients with hepatocellular carcinoma (HCC) exhibiting high-risk recurrence factors. Immune checkpoint inhibitors (ICIs) are effective against unresectableHCC; however, their effectiveness and safety for this specific patient group remain uncertain. Methods: We conducted an extensive literature search across four scholarly databases to identify relevant studies. Our primary endpoints were overall survival (OS), recurrence-free survival (RFS), and adverse events (AEs). OS and RFS were quantified using hazard ratios (HRs), whereas the 1-, 2-, and 3-year OS and RFS rates were expressed as risk ratios (RRs). Additionally, the incidence of AEs was calculated. Results: Our meta-analysis included 11 studies (N = 3,219 patients), comprising two randomized controlled trials (RCTs) and nine retrospective studies. Among these, eight studies reported HRs for OS, showing a statistically significant improvement in OS among patients receiving adjuvant ICIs (HR, 0.60; 95% confidence interval [CI], 0.45-0.80; p < 0.0001). All included studies reported HRs for RFS, indicating a favorable impact of adjuvant ICIs (HR, 0.62; 95% CI, 0.52-0.73; p < 0.0001). Moreover, aggregated data demonstrated improved 1- and 2-year OS and RFS rates with adjuvant ICIs. The incidence rate of AEs of any grade was 0.70 (95% CI, 0.49-0.91), with grade 3 or above AEs occurring at a rate of 0.12 (95% CI, 0.05-0.20). Conclusion: Adjuvant ICI therapy can enhance both OS and RFS rates in patients with HCC exhibiting high-risk recurrence factors, with manageable AEs. [ABSTRACT FROM AUTHOR]

Background: Glioma is the main subtype of primary central nervous system (CNS) tumor with high malignancy and poor prognosis under current therapeutic approaches. Glycolysis and suppressive tumor microenvironment (TME) are key markers of glioma with great importance for aggressive features of glioma and inferior clinical outcomes. Hexokinase 3 (HK3) is an important rate-limiting enzyme in glycolysis, but its function in glioma remains unknown. Methods: This study comprehensively assessed the expression distribution and immunological effect of HK3 via pan-cancer analysis based on datasets from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA). Furthermore, it explored the malignant phenotype and genomic landscape between low-HK3 and high-HK3 expression groups in gliomas from Chinese Glioma Genome Atlas (CGGA) and TCGA. Moreover, data from the TIMER website predicted the relationship between macrophage infiltration and HK3 expression. Also, single-cell sequencing data were used to validate the relationship. Results: For pan-cancer patients, HK3 was expressed in various cancers. The results showed that HK3 was highly expressed in gliomas and positively correlated with tumor-infiltrating immune cells (TIICs), immune checkpoints, immunomodulators, and chemokines. Meanwhile, HK3 expression was highest in normal immune cells and tissues. In gliomas, the expression of HK3 was found to be closely correlated with the malignant clinical characteristics and the infiltration of macrophages. Also, HK3 was proven to be positively associated with macrophage through single-cell sequencing data and immunohistochemistry techniques. Finally, it is predicted that samples with high HK3 expression are often malignant entities and also significant genomic aberrations of driver oncogenes. Conclusions: This is the first comprehensive research to figure out the relationship between HK3 and TME characteristics in gliomas. HK3 is positively associated with macrophage infiltration and can induce the immunosuppressive TME and malignant phenotype of gliomas. [ABSTRACT FROM AUTHOR]

The objective of this study was to explore the effects of black seed (Nigella sativa) and AQUA-IMMUNOPROTECT® on growth, feed utilization, serum constituents, and disease resistance against vibriosis in gilthead sea bream juveniles. The research involved three groups: TC (control) received a basal diet, TSI (received a basal diet with 2% AQUA-IMMUNOPROTECT®), and TNS (received a basal diet with 2% N. sativa). The experiment period extended for 2 months. Results revealed a significant rise in erythrogram (RBCs, HB, and PCV %), leucogram (total differential leucocytic count), serum total protein, and globulin in gilthead sea bream treated with 2% Nigella sativa supplemented diets after an 8-week trial. No substantial variations were found in liver enzymes, urea, uric acid, and creatinine between the groups. Respiratory burst activity was notably greater in the N. sativa group after 2 months of feeding compared to the other groups. In the experimental challenge, the control group experienced higher mortality rates than the other groups following an IP injection of V. harveyi at a dose of 106 CFU per 0.5 ml/fish (106 fish/challenge). Overall, the findings of this research indicate that N. sativa can enhance non-specific immunity and minimize susceptibility and pathogenicity to V. harveyi in gilthead sea bream. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemo-immunotherapy, in which chemotherapeutic drugs activate immune system to suppress tumor growth and metastases, has great potential for clinical application. However, insufficient immunogenic cell death and serious side effects caused by tumor multidrug resistance and non-specific drug distribution, as well as inadequate and dysfunctional immune cells, greatly impair the effectiveness of chemo-immunotherapy. Herein, taking advantage of the functional diversity and structural programmability of nucleic acids, a DNA-based bioorthogonal nanoagonist is constructed to initiate and augment immune responses for robust chemo-immunotherapy. Benefiting from polyvalent targeting and template effects of DNA, the tailor-made nanoagonist shows prior bioorthogonal catalytic performance. Chemotherapeutic drug is bioorthogonally synthesized in situ under the catalysis of the nanoagonist, maximizing immunogenic cell death and minimizing systemic toxicity. The large amount of antigen and damage-associated molecular patterns released from dying tumor cells effectively initiates antitumor immunity. Meanwhile, the integration of high density of immunologic adjuvant can more effectively stimulate immune cells. The combination of bioorthogonal catalytic drug synthesis and immunostimulatory effect of DNA adjuvant not only destroys local primary tumors, but also eliminates distal metastasis. Moreover, the nanoagonist triggered the immune memory effect. The work extends the application of bioorthogonal chemistry to immunotherapy and provides a safe and powerful strategy for cancer chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this analysis was to assess the prognostic value of the post-treatment serum CA 125 level in each member of a group of advanced endometrial cancer (aEC) patients in comparison to other clinical and pathological parameters. Material and methods: Records of 266 patients treated at the Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch between the years 2006 and 2018 were included in the study. Follow-up ranged from 1 to 138 months. Progression free survival (PFS) and overall survival (OS) were set as the endpoints. The tests chi-squared, Fisher, log-rank, Mann-Whitney, Kruskal-Wallis and Cox proportional hazard ratio were used for statistical analyses. Results: In the analysed group, there was a significant association between an elevated serum CA 125 level following adjuvant treatment and shorter PFS and OS. After setting a cut-off value for CA 125 there was a statistically significant correlation between the marker and PFS and OS. Multivariate analysis indicated that the post-treatment serum CA 125 level is an independent prognostic factor of the course of aEC. Conclusions: The post-treatment serum CA 125 level correlates significantly with both PFS and OS in each patient with aEC. The marker is an independent prognostic factor in this group. A low post-treatment level of the marker is a strong indicator of good 5-year survival, with 82% of patients reaching 5-year OS. [ABSTRACT FROM AUTHOR]

Ultrasound‐generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti‐tumor efficacy as an in‐situ vaccine. However, the use of TLR7/8 agonists can cause severe inflammatory responses. In this study, we present a novel tumor‐targeting nano‐adjuvant termed aPDL1‐PLG/R848 NPs, which are composed of aPDL1 antibody, Fc‐III‐4C peptide linker (Fc‐linker) and poly(L‐glutamic acid)‐grafted‐R848. Under ultrasound irradiation, antigen‐presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants. The strategy inhibits primary tumor growth and induces a strong antigen‐specific immune memory effect to prevent tumor recurrence in vivo. This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy. [ABSTRACT FROM AUTHOR]

Nanodrugs capable of aggregating in the tumor microenvironment (TME) have demonstrated great efficiency in improving the therapeutic outcome. Among various approaches, the strategy utilizing electrostatic interaction as a driving force to achieve intratumor aggregation of nanodrugs has attracted great attention. However, the great difference between the two nanodrugs with varied physicochemical properties makes their synchronous transport in blood circulation and equal‐opportunity tumor uptake impossible, which significantly detracts from the beneficial effects of nanodrug aggregation inside tumors. We herein propose a new strategy to construct a pair of extremely similar nanodrugs, referred to as "twins‐like nanodrugs (TLNs)", which have identical physicochemical properties including the same morphology, size, and electroneutrality to render them the same blood circulation time and tumor entrance. The 1:1 mixture of TLNs (TLNs‐Mix) intravenously injected into a mouse model efficiently accumulates in tumor sites and then transfers to oppositely charged nanodrugs for electrostatic interaction‐driven coalescence via responding to matrix metalloproteinase‐2 (MMP‐2) enriched in tumor. In addition to enhanced tumor retention, the thus‐formed micron‐sized aggregates show high echo intensity essential for ultrasound imaging as well as ultrasound‐triggered penetrative drug delivery. Owing to their distinctive features, the TLNs‐Mix carrying sonosensitizer, immune adjuvant, and ultrasound contrast agent exert potent sonodynamic immunotherapy against hypovascular hepatoma, demonstrating their great potential in treating solid malignancies. [ABSTRACT FROM AUTHOR]

To better understand the role of pHsp90 adjuvant in immune response modulation, we proposed the use of the Receptor Binding Domain (RBD) of the Spike protein of SARS-CoV2, the principal candidate in the design of subunit vaccines. We evaluated the humoral and cellular immune responses against RBD through the strategy "protein mixture" (Adjuvant + Antigen). The rRBD adjuvanted with rAtHsp81.2 group showed a higher increase of the anti-rRBD IgG1, while the rRBD adjuvanted with rNbHsp90.3 group showed a significant increase in anti-rRBD IgG2b/2a. These results were consistent with the cellular immune response analysis. Spleen cell cultures from rRBD + rNbHsp90.3-immunized mice showed significantly increased IFN-γ production. In contrast, spleen cell cultures from rRBD + rAtHsp81.2-immunized mice showed significantly increased IL-4 levels. Finally, vaccines adjuvanted with rNbHsp90.3 induced higher neutralizing antibody responses compared to those adjuvanted with rAtHsp81.2. To know whether both chaperones must form complexes to generate an effective immune response, we performed co-immunoprecipitation (co-IP) assays. The results indicated that the greater neutralizing capacity observed in the rRBD adjuvanted with rNbHsp90.3 group would be given by the rRBD-rNbHsp90.3 interaction rather than by the quality of the immune response triggered by the adjuvants. These results, together with our previous results, provide a comparative benchmark of these two novel and safe vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV2 subunit vaccines. Furthermore, these results revealed differences in the ability to modulate the immune response between these two pHsp90s, highlighting the importance of adjuvant selection for future rational vaccine and adjuvant design. [ABSTRACT FROM AUTHOR]

This study provides an in-depth review of bentonite, focusing on its applications in Korea's biomedical and cosmetic sectors. It delves into bentonite's chemical properties, which make it a valuable resource in various industries, particularly in the health and beauty industries. We discuss bentonite's antimicrobial properties, showcasing its effectiveness against a wide range of pathogens and its potential as a biomedicine adjuvant to boost immune responses. Despite its benefits, the review also addresses the need for caution due to its possible side effects when used in human therapy. In the cosmetics industry, bentonite is prized for its ability to absorb impurities, making it a popular ingredient in products from leading brands. The review highlights the ongoing research and development efforts aiming to further explore bentonite's capabilities and applications, underlining the material's significant contribution to advancing Korea's innovation in the biomedical and cosmetic fields. This review suggests that with more research, bentonite's full potential can be unlocked, offering new opportunities for these industries. [ABSTRACT FROM AUTHOR]

Skin is the body's largest organ and serves as a protective barrier from physical, thermal, and mechanical environmental challenges. Alongside, the skin hosts key immune system players, such as the professional antigen-presenting cells (APCs) like the Langerhans cells in the epidermis and circulating macrophages in the blood. Further, the literature supports that the APCs can be activated by antigen or vaccine delivery via multiple routes of administration through the skin. Once activated, the stimulated APCs drain to the associated lymph nodes and gain access to the lymphatic system. This further allows the APCs to engage with the adaptive immune system and activate cellular and humoral immune responses. Thus, vaccine delivery via skin offers advantages such as reliable antigen delivery, superior immunogenicity, and convenient delivery. Several preclinical and clinical studies have demonstrated the significance of vaccine delivery using various routes of administration via skin. However, such vaccines often employ adjuvant/(s), along with the antigen of interest. Adjuvants augment the immune response to a vaccine antigen and improve the therapeutic efficacy. Due to these reasons, adjuvants have been successfully used with infectious disease vaccines, cancer immunotherapy, and immune-mediated diseases. To capture these developments, this review will summarize preclinical and clinical study results of vaccine delivery via skin in the presence of adjuvants. A focused discussion regarding the FDA-approved adjuvants will address the experiences of using such adjuvant-containing vaccines. In addition, the challenges and regulatory concerns with these adjuvants will be discussed. Finally, the review will share the prospects of adjuvant-containing vaccines delivered via skin. [Display omitted] • Role of various routes of vaccine administration via skin. • Skin offers reliable antigen delivery and yields superior immune responses. • Adjuvants as immune response enhancers for infectious disease, cancer vaccines. • Preclinical and clinical studies with FDA-approved adjuvants and cutaneous vaccines. • Regulatory considerations for adjuvanted vaccines delivered via skin. [ABSTRACT FROM AUTHOR]

Immunotherapy faces insufficient immune activation and limited immune effectiveness. Herein, we report a smart DNA hydrogel that enables the release of multivalent functional units at the tumor site to enhance the efficacy of immunotherapy. The smart DNA hydrogel was assembled from two types of ultra‐long DNA chains synthesized via rolling circle amplification. One DNA chain contained immune adjuvant CpG oligonucleotides and polyaptamers for loading natural killer cell‐derived exosomes; the other chain contained multivalent G‐quadruplex for loading photodynamic agents. DNA chains formed DNA hydrogel through base‐pairing. HhaI restriction endonuclease sites were designed between functional units. Upon stimuli in the tumor sites, the hydrogel was effectively cleaved by the released HhaI and disassembled into functional units. Natural killer cell‐derived exosomes played an anti‐tumor role, and the CpG oligonucleotide activated antigen‐presenting cells to enhance the immunotherapy. Besides the tumor‐killing effect of photodynamic therapy, the generated cellular debris acted as an immune antigen to further enhance the immunotherapeutic effect. In a mouse melanoma orthotopic model, the smart DNA hydrogel as a localized therapeutic agent, achieved a remarkable tumor suppression rate of 91.2 %. The smart DNA hydrogel exhibited enhanced efficacy of synergistic immunotherapy and photodynamic therapy, expanding the application of DNA materials in biomedicine. [ABSTRACT FROM AUTHOR]

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffoldbased cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemoimmunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors. [ABSTRACT FROM AUTHOR]

Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumorassociated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models. [ABSTRACT FROM AUTHOR]

Cyclic dinucleotides (CDNs) are cyclic molecules consisting of two nucleoside monophosphates linked by two phosphodiester bonds, which act as a second messenger and bind to the interferon gene stimulating factor (STING) to activate the downstream signaling pathway and ultimately induce interferon secretion, initiating an anti-infective immune response. Cyclic dinucleotides and their analogs are lead compounds in the immunotherapy of infectious diseases and tumors, as well as immune adjuvants with promising applications. Many agonists of pathogen recognition receptors have been developed as effective adjuvants to optimize vaccine immunogenicity and efficacy. In this work, the binding mechanism of human-derived interferon gene-stimulating protein and its isoforms with cyclic dinucleotides and their analogs was theoretically investigated using computer simulations and combined with experimental results in the hope of providing guidance for the subsequent synthesis of cyclic dinucleotide analogs. [ABSTRACT FROM AUTHOR]

Despite the fact that immunotherapy has significantly improved the prognosis of melanoma patients, the non-response rate of monoimmunotherapy is considerably high due to insufficient tumor immunogenicity. Therefore, it is necessary to develop alternative methods of combination therapy with enhanced antitumor efficiency and less systemic toxicity. In this study, we reported a cancer cell membrane-coated zeolitic imidazole framework-8 (ZIF-8) encapsulating pyroptosis-inducer oxaliplatin (OXA) and immunomodulator imiquimod (R837) for chemoimmunotherapy. With the assistance of DNA methyltransferase inhibitor decitabine (DCT), upregulated Gasdermin E (GSDME) was cleaved by OXA-activated caspase-3, further inducing tumor cell pyroptosis, then localized antitumor immunity was enhanced by immune adjuvant R837, followed by triggering systemic antitumor immune responses. These results provided a proof-of-concept for the use of cell membrane-coated biomimetic nanoparticles as a promising drug carrier of combination therapy and a potential insight for pyroptosis-based melanoma chemo-immunotherapy. [Display omitted] • The functionalized synthetic nanoparticles coated with cancer cell membrane are novel biomimetic nanoplatforms, which could improve drug uptake by tumor cells and prolong drug retention time in tumor tissue. • Combination therapy firstly upregulates the expression of GSDME in tumor cells, secondly induces cell pyroptosis, and finally enhances the immune response induced by cell pyroptosis. • Local administration is safer and could reduce the side effects of chemotherapy compared with systemic administration. [ABSTRACT FROM AUTHOR]

Sungkai leaf extract (Peronema canescens Jack.) has been used traditionally to cure various diseases. This research aimed to determine the immunostimulant effect of sungkai leaf extract using the carbon clearance method, the total leukocyte cell count, and the percentage of leukocyte cell types. Twenty-five male mice divided into 5 groups were used for this study. The extract was administered orally for 6 days at 25, 50, and 100 mg/kgbw, Na CMC 0.5% as negative control, and Stimuno 50 mg/kgbw as a comparison (positive control) group. The phagocytic index, total leukocytes, and the percentage of leukocyte cell types were determined on the 7th day. The phagocytotic index value was analysed by one-way ANOVA followed by Duncan's post-hoc test. The increase in phagocytosis index showed that the effect of each dose was significantly different (p< 0.05) compared to the control group. The highest phagocytosis index was obtained from a 100 mg/kg bw dose. There was a significant difference (p<0.05) in the total leukocyte cell count and the percentage of leukocyte cell type. Sungkai leaf extract (Peronema canescens Jack.) had an immunostimulant effect on male white mice (Mus musculus L.). [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effect of histological subtype on oncological outcome and adjuvant platinum-based chemotherapy response in patients with epithelial ovarian cancer (EOC). Material and methods: The study group was created with stage II–IV EOC patients. Progression-free survival (PFS) and disease-specific survival (DSS) estimates were determined by using the Kaplan–Meier method. The log-rank test and cox proportional hazards model were performed. Results: A total 396 patients were included the study. Tumor type was serous in 332 (83.8%). Two hundred and thirty-one patients (58.3%) had maximal cytoreduction. Three hundred and twenty-seven (82.6%) patients received complete clinical response. Refractory disease was present in 69 (17.4%) patients. In patients with complete clinical response, 183 (56%) patients recurred. Five-year PFS was 32% in serous group and 31% in non-serous group (p = 0.755). Five-year DSS was 78% in serous group and 87% in non-serous group (p = 0.084). On multivariate analysis, recurrence rates 1.959 times (95% CI: 1.224–3.085; p = 0.004), death rates 2.624 times (95% CI: 1.328–5.185; p = 0.005) higher in patients with optimal cytoreduction than patients with maximal cytoreduction, respectively. Conclusions: Although the rate of maximal cytoreduction was higher in patients with non-serous tumor type, the rate of refractory disease was higher after adjuvant chemotherapy. However, the recurrence rate was higher in serous tumor type. Survival rates were similar in serous and non-serous tumor types. Maximal cytoreduction was an independent predictor factor for survival. Maximal cytoreduction should be the main target in EOC. [ABSTRACT FROM AUTHOR]

Bacillus subtilis, a probiotic bacterium with engineering potential, is widely used for the expression of exogenous proteins. In this study, we utilized the integrative plasmid pDG364 to integrate the hemagglutinin–neuraminidase (HN) gene from Newcastle disease virus (NDV) into the genome of the B. subtilis 168 model strain. We successfully constructed a recombinant B. subtilis strain (designated B. subtilis RH) that displays a truncated HN antigen fragment on the surface of its spores and further evaluated its immunogenic effects in mice. Using ELISA, we quantified the levels of IgG in serum and secretory IgA (sIgA) in intestinal contents. The results revealed that the recombinant B. subtilis RH elicited robust specific mucosal and humoral immune responses in mice. Furthermore, B. subtilis RH demonstrated potential mucosal immune adjuvant properties by fostering the development of immune organs and augmenting the number of lymphocytes in the small intestinal villi. Additionally, the strain significantly upregulated the relative expression of inflammatory cytokines such as IL-1β, IL-6, IL-10, TNF-α, and IFN-γ in the small intestinal mucosa. In conclusion, the B. subtilis RH strain developed in this study exhibits promising mucosal immunogenic effects. It holds potential as a candidate for an anti-NDV mucosal subunit vaccine and offers a novel preventive strategy for the poultry industry against this disease. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is characterized by high rates of recurrence, especially in patients with residual disease after neoadjuvant chemotherapy (NAC). Capecitabine is being used as standard adjuvant treatment in residual TNBC. We aimed to investigate the real-life data regarding the efficacy of capecitabine in residual TNBC. In this retrospective multicenter study, TNBC patients with residual disease were evaluated. Patients, who received standard anthracycline and taxane-based NAC and adjuvant capecitabine were eligible. Overall survival (OS), disease free survival (DFS) and toxicity were analyzed. 170 TNBC patients with residual disease were included. Of these, 62.9% were premenopausal. At the time of analysis, the recurrence rate was 30% and death rate was 18%. The 3-year DFS and OS were 66% and 74%, respectively. In patients treated with adjuvant capecitabine, residual node positive disease stood out as an independent predictor of DFS (p = 0.024) and OS (p = 0.032). Undergoing mastectomy and the presence of T2 residual tumor was independent predictors of DFS (p = 0.016) and OS (p = 0.006), respectively. The efficacy of capecitabine was found lower compared to previous studies. Selected patients may have further benefit from addition of capecitabine. The toxicity associated with capecitabine was found lower than anticipated. [ABSTRACT FROM AUTHOR]

Trained immunity defines the long‐term memory of innate immunity based on innate immune signalling, metabolic changes and epigenetic rewiring of trained innate immune cells, which are characterised by elevated inflammatory responses towards secondary stimuli. The activation of this non‐specific protection‐mediated memory in innate immune cells was identified to benefit host defences as well as play a detrimental role in inflammatory diseases. In this review, we focused on summing up the current progress about the inducers, effector cells, molecular mechanisms and protective effects of trained immunity that have been identified in both mammals and teleost fish, and discussing the future research and application of trained immunity in aquaculture. Revealing the mechanisms of trained immunity will not only provide a novel aspect for understanding the evolution of innate immune memory and their longer‐term protections, but also contribute to the rational design and evaluation of immunopotentiators, adjuvants and potential vaccines in aquaculture. [ABSTRACT FROM AUTHOR]

Immunostimulants were widely used in aquafeed due to their multiple important functions, including promoting growth, enhancing non‐specific defence mechanisms and resisting infectious diseases. But the efficiencies of the positive effects of immunostimulants were affected by the duration of the administration and their dose. Short‐term and normal‐dose of immunostimulants promoted the growth and enhance non‐specific immunity of aquatic animals. However, improper use led to several immune disorders, including immune tolerance, immune exhaustion and over‐immunity. The application of two immunostimulant diets in rotation technique and the intermittent use of immune stimulant diets may solve the problems associated with immune disorders, but this application method will be limited by both species and immunostimulants. The occurrence of immune disorders is accompanied by different degrees of gut microbiota dysbiosis, especially significantly up‐regulated the abundance of Proteobacteria. Besides, the gut symbiotic microbiota plays a significant role in host immunity. Consequently, the regulation of gut microbiota may be an effective way to modulate immune disorders caused by improper use of polysaccharide immunostimulants. Regulating the gut microbiota not only solves the negative effects caused by improper use of immunostimulants without restrictions on both species and immunostimulants, but also has the advantage of simplicity and convenience compared to conventional approaches. In summary, this article reviews the possible negative effects caused by improper use of immunostimulants on aquatic animals and compares regular approaches with regulating gut microbiota. And gut microbiota maybe be used as a therapeutic target to improve immune disorders caused by immunostimulants in aquatic animals. [ABSTRACT FROM AUTHOR]

Background: This study aimed to develop a vaccine for controlling salmonellosis, a zoonotic disease affecting both humans and chicken, by employing Fe2O3 ferrous iron oxide (FNPs), silicon dioxide (SiNPs), carboxymethyl chitosan (C.CS NPs), and FNPs-chitosan (FCNPs) nanocomposite as immunological adjuvants. The immune response of vaccinated chicken was assessed through ELISA and challenge tests. Results: The hydrodynamic diameters of Fe2O3, Fe2O3-CS, C.CS, and SiO2 NPs were found to be 81.95 ± 14.95, 137.1 ± 20.5, 32.86 ± 14.05, and 15.64 ± 3.6 nm, respectively. The incorporation of nanoparticles into the vaccine formulation significantly enhanced its efficacy by eliciting a robust immune response. According to the study, FNPs, SiNPs, C.CS NPs, and FCNPs can be used as immunological adjuvants to strengthen chicken's immune systems and help prevent salmonellosis. By gradually raising antibody titers, all five vaccine formulations successfully stimulated an immunological response against Salmonella in vaccinated chicken. The size of the immunological response, however, differed amongst the various vaccination formulations. The SiNPs group had the highest antibody titer, followed by the locally administered vaccine. Conclusions: These findings suggest that the use of silicon dioxide SiNPs as a vaccine delivery system could enhance the immune response to Salmonella in chicken. Overall, the study demonstrates that the use of adjuvanted vaccines with nanomaterials, particularly SiNPs, has significantly increased the protection rate from 67 to 93.3% when compared to the locally used vaccine, which had a protection rate of 83%. [ABSTRACT FROM AUTHOR]

Vaccination is a valid strategy to prevent and control newly emerging and reemerging infectious diseases in humans and animals. However, synthetic and recombinant antigens are poor immunogenic to stimulate efficient and protective host immune response. Immunostimulants are indispensable factors of vaccines, which can promote to trigger fast, robust, and long-lasting immune responses. Importantly, immunotherapy with immunostimulants is increasing proved to be an effective and promising treatment of cancer, which could enhance the function of the immune system against tumor cells. Pattern recognition receptors (PRRs) play vital roles in inflammation and are central to innate and adaptive immune responses. Toll-like receptors (TLRs)-targeting immunostimulants have become one of the hotspots in adjuvant research and cancer therapy. Bacterial-origin immunoreactive molecules are usually the ligands of PRRs, which could be fast recognized by PRRs and activate immune response to eliminate pathogens. Varieties of bacterial immunoreactive molecules and bacterial component-mimicking molecules have been successfully used in vaccines and clinical therapy so far. This work provides a comprehensive review of the development, current state, mechanisms, and applications of bacterial-origin immunostimulants. The exploration of bacterial immunoreactive molecules, along with their corresponding mechanisms, holds immense significance in deepening our understanding of bacterial pathogenicity and in the development of promising immunostimulants. [ABSTRACT FROM AUTHOR]

H9N2 avian influenza poses a significant public health risk, necessitating effective vaccines for mass immunization. Oral inactivated vaccines offer advantages like the ease of administration, but their efficacy often requires enhancement through mucosal adjuvants. In a previous study, we established a novel complex of polysaccharide from Atractylodes macrocephala Koidz binding with zinc oxide nanoparticles (AMP-ZnONPs) and preliminarily demonstrated its immune-enhancing function. This work aimed to evaluate the efficacy of AMP-ZnONPs as adjuvants in an oral H9N2-inactivated vaccine and the vaccine's impact on intestinal mucosal immunity. In this study, mice were orally vaccinated on days 0 and 14 after adapting to the environment. AMP-ZnONPs significantly improved HI titers, the levels of specific IgG, IgG1 and IgG2a in serum and sIgA in intestinal lavage fluid; increased the number of B-1 and B-2 cells and dendritic cell populations; and enhanced the mRNA expression of intestinal homing factors and immune-related cytokines. Interestingly, AMP-ZnONPs were more likely to affect B-1 cells than B-2 cells. AMP-ZnONPs showed mucosal immune enhancement that was comparable to positive control (cholera toxin, CT), but not to the side effect of weight loss caused by CT. Compared to the whole-inactivated H9N2 virus (WIV) group, the WIV + AMP-ZnONP and WIV + CT groups exhibited opposite shifts in gut microbial abundance. AMP-ZnONPs serve as an effective and safe mucosal adjuvant for oral WIV, improving cellular, humoral and mucosal immunity and microbiota in the gastrointestinal tract, avoiding the related undesired effects of CT. [ABSTRACT FROM AUTHOR]

Vaccination is the most effective tool for paratuberculosis control. Currently, available vaccines prevent the progression of clinical disease in most animals but do not fully protect them against infection and induce the formation of an injection site granuloma. The precise mechanisms that operate in response to vaccination and granuloma development, as well as the effect that adjuvants could trigger, have not been fully investigated. Therefore, this study aimed to investigate the injection site granulomas induced by two inactivated paratuberculosis vaccines, which differ in the adjuvant employed. Two groups of 45-day-old lambs were immunized with two commercially available vaccines--one (n = 4) with Gudair® and the other (n = 4) with Silirum®. A third group (n = 4) was not vaccinated and served as control. The peripheral humoral response was assessed throughout the study by a commercial anti- Mycobacterium avium subspecies paratuberculosis (Map) antibody indirect ELISA, and the cellular immune response was assessed similarly by the IFN-g release and comparative intradermal tests. The injection site granulomas were measured during the experiment and sampled at 75 days post-vaccination (dpv) when the animals were euthanized. The tissue damage, antigen and adjuvant distribution, and the presence and amount of immune cells were then determined and assessed by immunohistochemicalmethods. Antibodies against Map antigens; a general macrophage marker (Iba1), M1 (iNOS), and M2 (CD204) macrophages; T (CD3), B (CD20), and gd T lymphocytes, proteins MHC-II and NRAMP1, and cytokines IL-4, IL-10, TNF, and IFN-g were employed. Silirum® elicited a stronger peripheral cellular immune response than Gudair®, while the latter induced larger granulomas and more tissue damage at the site of injection. Additionally, adjuvant and Map antigen distribution throughout the granulomatous inflammatory infiltrate, as well as the NRAMP1 cell expression, which is linked to antigen phagocytosis, were highly irregular. In Silirum® induced granulomas, a higher number of MHC-II and TNF-expressing cells and a lower number of M2 macrophages suggested an improved antigen presentation, which could be due to the better antigen distribution and reduced tissue damage induced by this vaccine. [ABSTRACT FROM AUTHOR]

Background: In recent years, biosafety and green food safety standards have increased the demand for immune enhancers and adjuvants. In the present study, recombinant food-grade Lactococcus lactis (r-L. lactis-Tα1-IFN) expressing thymosin Tα1 and chicken interferon fusion protein was constructed. Results: The in vitro interactions with macrophages revealed a mixture of recombinant r-L. lactis-Tα1-IFN could significantly activate both macrophage J774-Dual™ NF-κB and interferon regulator (IRF) signaling pathways. In vitro interactions with chicken peripheral blood mononuclear cells (PBMCs) demonstrated that a mixture of recombinant r-L. lactis-Tα1-IFN significantly enhanced the expression levels of interferon (IFN)-γ, interleukin (IL)-10, CD80, and CD86 proteins in chicken PBMCs. Animal experiments displayed that injecting a lysis mixture of recombinant r-L. lactis-Tα1-IFN could significantly activate the proliferation of T cells and antigen-presenting cells in chicken PBMCs. Moreover, 16S analysis of intestinal microbiota demonstrated that injection of the lysis mixture of recombinant r-L. lactis-Tα1-IFN could significantly improve the structure and composition of chicken intestinal microbiota, with a significant increase in probiotic genera, such as Lactobacillus spp. Results of animal experiments using the lysis mixture of recombinant r-L. lactis-Tα1-IFN as an immune adjuvant for inactivated chicken Newcastle disease vaccine showed that the serum antibody titers of the experimental group were significantly higher than those of the vaccine control group, and the expression levels of cytokines IFN-γ and IL-2 were significantly higher than those of the vaccine control group. Conclusion: These results indicate that food-safe recombinant r-L. lactis-Tα1-IFN has potential as a vaccine immune booster and immune adjuvant. This study lays the foundation for the development of natural green novel animal immune booster or immune adjuvant. [ABSTRACT FROM AUTHOR]

Do different medico-scientific understandings of autoimmune inflammation, whose carriers disobediently promote the therapeutic use of immunostimulants, have the potential to destabilize the hegemony of the standard palliative treatment based on immunosuppression? Here I explore whether and how medical paradigms in Brazil develop and expand around immunopathologies through practices of exclusion and inclusion in the context of global circulation of knowledges, therapies, and regulatory frameworks. While focusing on concurrent immunotherapeutic models within biomedicine, I discuss aspects of legal-epistemological frictions that animate controversies in which distinct ways of co-producing medical evidence affect and are affected by the biomedical establishment. [ABSTRACT FROM AUTHOR]

Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 (Gal10) protein, an abundant protein in eosinophils. Although mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by Chil3 and Chil4 and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is one of the mainstays of cancer therapy and has been used for treating 65–75% of patients with solid tumors. However, radiotherapy of tumors has two limitations: high-dose X-rays damage adjacent normal tissue and tumor metastases cannot be prevented. Results: Therefore, to overcome the two limitations of radiotherapy, a multifunctional core–shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer were fabricated by assembling Au8NCs on the surface of a bifunctional nanoimmunomodulator R837/BMS nanocore using nanoprecipitation followed by electrostatic assembly. Formed R837/BMS@Au8 NP composed of R837, BMS-1, and Au8 clusters. Au8NC can enhance X-ray absorption at the tumor site to reduce X-ray dose and releases a large number of tumor-associated antigens under X-ray irradiation. With the help of immune adjuvant R837, dendritic cells can effectively process and present tumor-associated antigens to activate effector T cells, meanwhile, a small-molecule PD-L1 inhibitor BMS-1 can block PD-1/PD-L1 pathway to reactivate cytotoxic T lymphocyte, resulting in a strong systemic antitumor immune response that is beneficial for limiting tumor metastasis. According to in vivo and in vitro experiments, radioimmunotherapy based on R837/BMS@Au8 nanoparticles can increase calreticulin expression on of cancer cells, reactive oxygen species generation, and DNA breakage and decrease colony formation. The results revealed that distant tumors were 78.2% inhibited depending on radioimmunotherapy of primary tumors. Therefore, the use of a novel radiosensitizer R837/BMS@Au8 NPs realizes low-dose radiotherapy combined with immunotherapy against advanced cancer. Conclusion: In conclusion, the multifunctional core–shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer effectively limiting tumor metastasis and decrease X-ray dose to 1 Gy, providing an efective strategy for the construction of nanosystems with radiosensitizing function. [ABSTRACT FROM AUTHOR]

Micro/Nano-scale particles are widely used as vaccine adjuvants to enhance immune response and improve antigen stability. While aluminum salt is one of the most common adjuvants approved for human use, its immunostimulatory capacity is suboptimal. In this study, we modified risedronate, an immunostimulant and anti-osteoporotic drug, to create zinc salt particle-based risedronate (Zn-RS), also termed particulate risedronate. Compared to soluble risedronate, micronanoparticled Zn-RS adjuvant demonstrated increased recruitment of innate cells, enhanced antigen uptake locally, and a similar antigen depot effect as aluminum salt. Furthermore, Zn-RS adjuvant directly and quickly stimulated immune cells, accelerated the formulation of germinal centers in lymph nodes, and facilitated the rapid production of antibodies. Importantly, Zn-RS adjuvant exhibited superior performance in both young and aged mice, effectively protecting against respiratory diseases such as SARS-CoV-2 challenge. Consequently, particulate risedronate showed great potential as an immune-enhancing vaccine adjuvant, particularly beneficial for vaccines targeting the susceptible elderly. [Display omitted] • Risedronate in particulate form enhances antibody production compared to soluble form. • Particulate risedronate adjuvant (Zn-RS) promotes antigen uptake and retention in local. • Zn-RS adjuvant enhances antigen presentation and immune cell communication. • Zn-RS adjuvanted vaccines generate broad-spectrum humoral and strong T cell responses. • Single vaccination with Zn-RS adjuvanted vaccine confers protection against SARS-CoV-2 challenge. [ABSTRACT FROM AUTHOR]

Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatment-related deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3–4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741. 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1·76, 95% CI 0·95–3·25; p=0·073), consistent across immune checkpoint blockade subtype (I 2=0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15·0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3–4 treatment-related adverse events (OR 2·73, 95% CI 1·98–3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45–5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88–3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04–15·63; p=0·044) and grade 3–4 adverse events (5·31, 3·08–9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38–3·29; p=0·84) or grade 3–4 adverse events (1·17, 0·90–1·51; p=0·23). The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3–4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings. None. [ABSTRACT FROM AUTHOR]

The products of the Panatechnology series are completely natural, obtained by finely grinding rock meal and adding other natural ingredients. They can be applied as complex foliar and soil fertilizers and as agents increasing the natural immunity of plants. The aim of the investigation was to determine the potential effect of these products on some aphids in apple and peach orchards. The study was conducted in 2022 and 2023 in conventional orchards of apples and peaches, in the experimental fields of the Agricultural University – Plovdiv. Several leaf treatments were carried out with products from the Panamin and Panatop series (Immuno Save; Panamin Suspension, etc.) as a comprehensive program to improve plant resistance and growth during the spring period. The experiments have shown that Panamin and Panatop immunostimulants can reduce the rate of attack of some aphids on apple and peach trees to some extent but cannot completely prevent the danger of these pests, especially in a year suitable for their development. [ABSTRACT FROM AUTHOR]

Adjuvant immune checkpoint inhibitor therapies have radically altered the treatment landscape for renal cell carcinoma and urothelial carcinoma. However, studies have reported negative data regarding adjuvant immune checkpoint inhibitor therapies. Thus, this study aimed to assess the role of adjuvant immune checkpoint inhibitor therapy for both renal cell carcinoma and urothelial carcinoma. A systematic review and network meta‐analysis were conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Multiple databases were searched for articles published as of February 2023. Studies were deemed eligible if they evaluated disease‐free survival in patients with renal cell carcinoma and urothelial carcinoma receiving adjuvant immune checkpoint inhibitor therapy. Five studies met the inclusion criteria. In a network meta‐analysis, pembrolizumab was shown to be the most effective regimen for patients with renal cell carcinoma, whereas nivolumab was found to be the most effective regimen for patients with urothelial carcinoma. Additionally, these results were consistently observed in a sub‐analysis of the T stage. The present analysis provides findings that support the usefulness of adjuvant nivolumab therapy in urothelial carcinoma and adjuvant pembrolizumab therapy in renal cell carcinoma, in agreement with the currently available guidelines. However, the caveat is that the randomized controlled trials included in this analysis differed in important respects despite being similar in study design. Therefore, with these differences in mind, care needs to be taken when selecting patients for these immune checkpoint inhibitor therapies to maximize their benefits. [ABSTRACT FROM AUTHOR]

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Monocytes (Mos) are believed to play important roles during the generation of immune response. In our previous study, CVC1302, a complex of PRRs agonists, was demonstrated to recruit Mo into lymph nodes (LNs) in order to present antigen and secret chemokines (CXCL9 and CXCL10), which attracted antigen-specific CD4+ T cells. As it is known that Mos in mice are divided into two main Mo subsets (Ly6C+ Mo and Ly6C− Mo), we aimed to clarify the CVC1302-recruiting Mo subset and functions in the establishment of immunity. In this study, we found that CVC1302 attracted both Ly6C+ Mo and Ly6C− Mo into draining LNs, which infiltrated from different origins, injection muscles and high endothelial venule (HEV), respectively. We also found that the numbers of OVA+ Ly6C+ Mo in the draining LNs were significantly higher compared with OVA+ Ly6C− Mo. However, the levels of CXCL9 and CXCL10 produced by Ly6C− Mo were significantly higher than Ly6C+ Mo, which plays important roles in attracting antigen-specific CD4+ T cells. Under the analysis of their functions in initiating immune responses, we found that the ability of the Ly6C+ monocyte was mainly capturing and presenting antigens, otherwise; the ability of the Ly6C− monocyte was mainly secreting CXCL9 and CXCL10, which attracted antigen-specific CD4+ T cells through CXCR3. These results will provide new insights into the development of new immunopotentiators and vaccines. [ABSTRACT FROM AUTHOR]

Background: The imperative need for effective vaccines against viral diseases has intensified research on adjuvants to enhance immune responses. Toll-like receptor (TLR) agonists, such as Imiquimod, Resiquimod, and CpG oligodeoxynucleotides (CpG ODN), are some crucial components in vaccine formulations. This study investigated the molecular interactions and binding affinities of TLR4, TLR7/8, and TLR9 agonists, through in silico techniques. Methods: The three-dimensional structure of human TLR9 was predicted using Iterative Threading ASSEmbly Refinement. Homology modeling was employed using a multi-step approach to generate the human TLR9 model including template identification, ab initio modeling, iterative refinement, and final model generation of the crystallographic structure. Molecular docking and simulation studies were performed using AutoDock Vina, HDOCK, and GROningen MAchine for Chemical Simulations tools. The molecular docking study revealed binding sites and binding affinities of adjuvants in the binding regions of target TLRs. Molecular dynamics simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area calculations ascertain the stability and binding energies of the TLR-adjuvant complexes. Results: Results indicate distinct interactions, with Resiquimod showing superior affinity toward TLR7. QS21, on the other hand, emerged as a potent TLR4 agonist, while CpG ODN 2006 binds specifically to TLR9. The study proposes a strategic combination of QS21, Resiquimod, and CpG ODN 2006 as a potential adjuvant system, offering a multifaceted approach to enhance vaccine efficacy. Conclusions: This study furnishes preliminary data and establishes the foundational framework for subsequent inquiries encompassing both in vitro and in vivo studies concerning vaccine adjuvant systems. [ABSTRACT FROM AUTHOR]

Objective: Estrogen receptor (ER) inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor vα (ERα). Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score (-12 kcal/mol) compared to the established ER inhibitor, tamoxifen (-10 kcal/mol). Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapide's heightened binding affinity of -380.727 kJ/mol, surpassing tamoxifen's binding affinity of -352.029 kJ/mol. Conclusion: This comprehensive computational exploration underscores lomitapide's potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapide's promise as a novel ER inhibi tor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapide's reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies. [ABSTRACT FROM AUTHOR]

The perception of circulating granulocytes as cells with a predetermined immune response mainly triggered by pathogens is evolving, recognizing their functional heterogeneity and adaptability, particularly within the neutrophil subset. The involvement of these cells in the pathophysiology of autoimmune uveitis has become increasingly clear, yet their exact role remains elusive. We used an equine model for autoimmune-mediated recurrent pan-uveitis to investigate early responses of granulocytes in different inflammatory environments. For this purpose, we performed differential proteomics on granulocytes from healthy and diseased horses stimulated with IL8, LPS, or PMA. Compared to healthy horses, granulocytes from the recurrent uveitis model significantly changed the cellular abundance of 384 proteins, with a considerable number of specific changes for each stimulant. To gain more insight into the functional impact of these stimulant-specific proteome changes in ERU pathogenesis, we used Ingenuity Pathway Analysis for pathway enrichment. This resulted in specific reaction patterns for each stimulant, with IL8 predominantly promoting Class I MHC-mediated antigen processing and presentation, LPS enhancing processes in phospholipid biosynthesis, and PMA, clearly inducing neutrophil degranulation. These findings shed light on the remarkably differentiated responses of neutrophils, offering valuable insights into their functional heterogeneity in a T-cell-driven disease. Raw data are available via ProteomeXchange with identifier PXD013648. [ABSTRACT FROM AUTHOR]

Immune adjuvants are immune modulators that have been developed in the context of infectious vaccinations. There is currently a growing interest in immune adjuvants due to the development of immunotherapy against cancers. Immune adjuvant mechanisms of action are focused on the initiation and amplification of the inflammatory response leading to the innate immune response, followed by the adaptive immune response. The main activity lies in the support of antigen presentation and the maturation and functions of dendritic cells. Most immune adjuvants are associated with a vaccine or incorporated into the new generation of mRNA vaccines. Few immune adjuvants are used as drugs. Hydroxyapatite (HA) ceramics and azoximer bromide (AZB) are overlooked molecules that were used in early clinical trials, which demonstrated clinical efficacy and excellent tolerance profiles. HA combined in an autologous vaccine was previously developed in the veterinary field for use in canine spontaneous lymphomas. AZB, an original immune modulator derived from a class of heterochain aliphatic polyamines that is licensed in Russia, the Commonwealth of Independent States, and Slovakia for infectious and inflammatory diseases, is and now being developed for use in cancer with promising results. These two immune adjuvants can be combined in various immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Our findings showed T3 stage bladder cancer can be divided into two different perivesical fat invasive patterns: fibrous-surrounded pattern and nonfibrous-surrounded. Perivesical fat invasion pattern demonstrated potential clinical significance as a survival predictor. Perivesical fat invasion patterns can predict which patients may benefit from adjuvant chemotherapy with greater clinical significance than the current T3 substage. Background: The prognostic value of the distinction between microscopic (pT3a) and macroscopic (pT3b) perivesical fat invasions remains a subject of debate. To explore whether the pattern of perivesical fat invasion can serve as a prognostic factor to better subgroup T3 stage bladder cancer. Materials and Methods: One hundred and forty-nine patients diagnosed with T3 stage bladder cancer at Sun Yat-sen University Cancer Center (SYSUCC) were selected for the experimental cohort in this study. Ninety-seven T3 stage bladder cancer patients with pathological slices at the Cancer Genome Atlas (TCGA) were selected as validation cohort in this study. The perivesical fat invasive pattern was examined with hematoxylin and eosin-stained pathological slides by two pathologists independently. Two different perivesical fat invasive patterns, fibrous-surrounded (FS) pattern, and nonfibrous-surrounded (NFS) pattern were assessed. Results: Perivesical fat invasion pattern had a significant influence on overall survival in T3 stage bladder cancer. Compared to the NFS pattern, the FS pattern was related to a better prognosis in both the SYSUCC cohort and TCGA cohort. The patients with NFS pattern tumor who underwent cisplatin-based adjuvant chemotherapy experienced an obvious improvement compared to observation after radical cystectomy in overall survival in the SYSUCC cohort. Conclusion: The perivesical fat invasion pattern could predict prognosis and clinically different chemotherapeutic survival outcomes in patients with T3 stage bladder cancer after radical cystectomy. [ABSTRACT FROM AUTHOR]