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Journal of Cancer Research and Clinical... May 2024Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not...
PURPOSE
Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not all patients benefit from adjuvant treatment: many patients show disease recurrence despite therapy, while those without recurrence harbor the risk for potentially irreversible adverse events. Biomarkers to select patients benefitting most from adjuvant therapy are currently lacking. As body composition assessment using CT images has shown promising results as a prognostic biomarker in stage IV melanoma, we aim to study the applicability of body composition parameters also in adjuvant melanoma treatment.
METHODS
We analyze body composition features via CT scans in a retrospective cohort of 109 patients with resected stage IIB-IV melanoma receiving an adjuvant first-line treatment with ICB in our department. In this analysis, we focus on the impact of body composition, especially the presence of low skeletal muscle mass (LSMM), on patients' survival and occurrence of adverse events (AEs).
RESULTS
In uni- and multivariate analyses, we identify an association between CT-measured LSMM and melanoma-specific survival in patients treated with adjuvant ICB. Furthermore, LSMM is associated with a lower risk for therapy-related AEs, especially hypothyroidism, fatigue, and xerostomia. Conventional serological biomarkers e.g. S100 and LDH and measures of adipose tissue compartments did not show a correlation with survival or the occurrence of AEs.
CONCLUSIONS
LSMM constitutes a novel biomarker for melanoma-specific survival in patients treated with adjuvant ICB.
Topics: Humans; Melanoma; Male; Female; Retrospective Studies; Middle Aged; Immune Checkpoint Inhibitors; Aged; Muscle, Skeletal; Adult; Body Composition; Chemotherapy, Adjuvant; Prognosis; Aged, 80 and over; Skin Neoplasms; Tomography, X-Ray Computed
PubMed: 38796605
DOI: 10.1007/s00432-024-05812-4 -
European Journal of Pharmaceutics and... Jul 2024Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of...
Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of bacteria, especially in Gram-negatives. There, the lipopolysaccharides (LPS) layer is a unique component of the outer leaflet of the outer membrane which is highly impermeable and prevents antibiotics from passing passively into the intracellular compartments. Biodynamers, a novel class of dynamically bio-responsive polymers, may open new perspectives to overcome this particular barrier by accommodating various secondary structures and form supramolecular structures in such bacterial microenvironments. Generally, bio-responsive polymers are not only candidates as bio-active molecules against bacteria but also carriers via their interactions with the cargo. Based on their dynamicity, design flexibility, biodegradability, biocompatibility, and pH-responsiveness, we investigated the potential of two peptide-based biodynamers for improving antimicrobial drug delivery. By a range of experimental methods, we discovered a greater affinity of Arg-biodynamers for bacterial membranes than for mammalian membranes as well as an enhanced LPS targeting on the bacterial membrane, opening perspectives for enhancing the delivery of antimicrobials across the Gram-negative bacterial cell envelope. This could be explained by the change of the secondary structure of Arg-biodynamers into a predominant β-sheet character in the LPS microenvironment, by contrast to the α-helical structure typically observed for most lipid membrane-permeabilizing peptides. In comparison to poly-L-arginine, the intrinsic antibacterial activity of Arg-biodynamers was nearly unchanged, but its toxicity against mammalian cells was >128-fold reduced. When used in bacterio as an antibiotic potentiator, however, Arg-biodynamers improved the minimum inhibitory concentration (MIC) against Escherichia coli by 32 times compared to colistin alone. Similar effect has also been observed in two stains of Pseudomonas aeruginosa. Arg-biodynamers may therefore represent an interesting option as an adjuvant for antibiotics against Gram-negative bacteria and to overcome antimicrobial resistance.
Topics: Lipopolysaccharides; Anti-Bacterial Agents; Gram-Negative Bacteria; Microbial Sensitivity Tests; Bacterial Outer Membrane; Humans; Escherichia coli; Polymers; Arginine; Drug Delivery Systems
PubMed: 38795784
DOI: 10.1016/j.ejpb.2024.114336 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Despite past efforts towards therapeutical innovation, cancer remains a highly incident and lethal disease, with current treatments lacking efficiency and leading to...
Despite past efforts towards therapeutical innovation, cancer remains a highly incident and lethal disease, with current treatments lacking efficiency and leading to severe side effects. Hence, it is imperative to develop new, more efficient, and safer therapies. Bee venom has proven to have multiple and synergistic bioactivities, including antitumor effects. Nevertheless, some toxic effects have been associated with its administration. To tackle these issues, in this work, bee venom-loaded niosomes were developed, for cancer treatment. The vesicles had a small (150 nm) and homogeneous (polydispersity index of 0.162) particle size, and revealed good therapeutic efficacy in in vitro gastric, colorectal, breast, lung, and cervical cancer models (inhibitory concentrations between 12.37 ng/mL and 14.72 ng/mL). Additionally, they also revealed substantial anti-inflammatory activity (inhibitory concentration of 28.98 ng/mL), effects complementary to direct antitumor activity. Niosome safety was also assessed, both in vitro (skin, liver, and kidney cells) and ex vivo (hen's egg chorioallantoic membrane), and results showed that compound encapsulation increased its safety. Hence, small, and homogeneous bee venom-loaded niosomes were successfully developed, with substantial anticancer and anti-inflammatory effects, making them potentially promising primary or adjuvant cancer therapies. Future research should focus on evaluating the potential of the developed platform in in vivo models.
PubMed: 38794142
DOI: 10.3390/ph17050572 -
Vaccines May 2024MF59 and AS03 are squalene emulsion-based vaccine adjuvants with similar compositions and droplet sizes. Despite their broad use in licensed influenza vaccines, few...
MF59 and AS03 are squalene emulsion-based vaccine adjuvants with similar compositions and droplet sizes. Despite their broad use in licensed influenza vaccines, few studies compared their adjuvant effects and action mechanisms side by side. Considering the majority of adjuvants act on dendritic cells (DCs) to achieve their adjuvant effects, this study compared MF59 and AS03-like adjuvants (AddaVax and AddaS03, respectively) to enhance antigen uptake, DC maturation, ovalbumin (OVA) and seasonal influenza vaccine-induced immune responses. Considering MF59 was reported to activate MyD88 to mediate its adjuvant effects, this study also investigated whether the above-explored adjuvant effects of AddaVax and AddaS03 depended on MyD88. We found AddaVax more potently enhanced antigen uptake at the local injection site, while AddaS03 more potently enhanced antigen uptake in the draining lymph nodes. AddaS03 but not AddaVax stimulated DC maturation. Adjuvant-enhanced antigen uptake was MyD88 independent, while AddaS03-induced DC maturation was MyD88 dependent. AddaVax and AddaS03 similarly enhanced OVA-induced IgG and subtype IgG1 antibody responses as well as influenza vaccine-induced hemagglutination inhibition antibody titers, whileAddaS03 more potently enhanced OVA-specific IgG2c antibody responses. Both adjuvants depended on MyD88 to enhance vaccine-induced antibody responses, while AddaVax depended more on MyD88 to achieve its adjuvant effects. Our study reveals similarities and differences of the two squalene emulsion-based vaccine adjuvants, contributing to our improved understanding of their action mechanisms.
PubMed: 38793782
DOI: 10.3390/vaccines12050531 -
Journal of Medicinal Chemistry Jun 2024TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity...
TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound showed the most potent activity on hTLR7 with an EC of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that is a promising candidate as a vaccine adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.
Topics: Toll-Like Receptor 7; Animals; Administration, Intranasal; Mice; Drug Design; Humans; Influenza Vaccines; Purines; Adjuvants, Vaccine; Structure-Activity Relationship; Mice, Inbred BALB C; Female; Orthomyxoviridae Infections; Cytokines; RAW 264.7 Cells; Adjuvants, Immunologic
PubMed: 38787938
DOI: 10.1021/acs.jmedchem.4c00489 -
ACS Applied Bio Materials May 2024The oral and nasal cavities serve as critical gateways for infectious pathogens, with microorganisms primarily gaining entry through these routes. Our first line of... (Review)
Review
The oral and nasal cavities serve as critical gateways for infectious pathogens, with microorganisms primarily gaining entry through these routes. Our first line of defense against these invaders is the mucosal membrane, a protective barrier that shields the body's internal systems from infection while also contributing to vital functions like air and nutrient intake. One of the key features of this mucosal barrier is its ability to protect the physiological system from pathogens. Additionally, mucosal tolerance plays a crucial role in maintaining homeostasis by regulating the pH and water balance within the body. Recognizing the importance of the mucosal barrier, researchers have developed various mucosal formulations to enhance the immune response. Mucosal vaccines, for example, deliver antigens directly to mucosal tissues, triggering local immune stimulation and ultimately inducing systemic immunity. Studies have shown that lipid-based formulations such as liposomes and virosomes can effectively elicit both local and systemic immune responses. Furthermore, mucoadhesive polymeric particles, with their prolonged delivery to target sites, have demonstrated an enhanced immune response. This Review delves into the critical role of material selection and delivery approaches in optimizing mucosal immunity.
PubMed: 38787767
DOI: 10.1021/acsabm.4c00395 -
Scientific Reports May 2024Cyprinid herpesvirus is a causative agent of a destructive disease in common and koi carp (Cyprinus carpio), which leads to substantial global financial losses in...
Cyprinid herpesvirus is a causative agent of a destructive disease in common and koi carp (Cyprinus carpio), which leads to substantial global financial losses in aquaculture industries. Among the strains of C. herpesvirus, C. herpesvirus 1 (CyHV-1) and C. herpesvirus 3 (CyHV-3) are known as highly pathogenic to carp fishes in Europe, Asia, and Africa. To date, no effective vaccine has been developed to combat these viruses. This study aimed to develop unique multi-epitope subunit vaccines targeting the CyHV-1 and CyHV-3 using a reverse vaccinology approach. The study began with a comprehensive literature review to identify the most critical proteins, which were then subjected to in silico analyses to predict highly antigenic epitopes. These analyses involved assessing antigenicity, transmembrane topology screening, allergenecity, toxicity, and molecular docking approaches. We constructed two multi-epitope-based vaccines incorporating a suitable adjuvant and appropriate linkers. It revealed that both the vaccines are non-toxic and immunogenic. The tertiary structures of the vaccine proteins were generated, refined, and validated to ensure their suitability. The binding affinity between the vaccine constructs and TLR3 and TLR5 receptors were assessed by molecular docking studies. Molecular dynamics simulations indicated that vaccine construct V1 exhibited greater stability with both TLR3 and TLR5 based on RMSD analysis. Hydrogen bond analysis revealed a stronger binding affinity between the vaccine constructs and TLR5 compared to TLR3. Furthermore, MM-PBSA analysis suggested that both vaccine constructs exhibited a better affinity for TLR5. Considering all aspects, the results suggest that in silico development of CyHV vaccines incorporating multiple epitopes holds promise for management of diseases caused by CyHV-1 and CyHV-3. However, further in vivo trials are highly recommended to validate the efficacies of these vaccines.
Topics: Animals; Vaccines, Subunit; Carps; Herpesviridae; Fish Diseases; Herpesviridae Infections; Molecular Docking Simulation; Viral Vaccines; Epitopes; Computational Biology; Herpesvirus Vaccines; Immunoinformatics
PubMed: 38782944
DOI: 10.1038/s41598-024-61074-7 -
Biochemical and Biophysical Research... Aug 2024Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor...
PURPOSE
Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms.
METHODS
In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins.
RESULTS
Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2.
CONCLUSION
These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.
Topics: Animals; TRPV Cation Channels; Neuronal Plasticity; Male; Brain-Derived Neurotrophic Factor; Stress, Psychological; Hippocampus; Rats; Rats, Sprague-Dawley; MAP Kinase Signaling System; Cyclic AMP Response Element-Binding Protein; Depression; Chronic Disease; Probenecid
PubMed: 38776831
DOI: 10.1016/j.bbrc.2024.150128 -
ACS Omega May 2024Lingzhu Pulvis is a classic formulation for treating febrile convulsions in children. However, essential oil (AT-EO) in this prescription is prone to volatilization and...
Lingzhu Pulvis is a classic formulation for treating febrile convulsions in children. However, essential oil (AT-EO) in this prescription is prone to volatilization and oxidation, compromising the efficacy and quality control of this formulation. Herein, based on the concept of "combination of medicine and adjuvant", Pickering emulsion technology was applied to enhance the stability of AT-EO using modified amber as a stabilizer. Amber was a resinous medicinal powder in Lingzhu Pulvis and was modified into a suitable stabilizer for Pickering emulsion through surface modification. A thermal stability study indicated that Pickering emulsion, stabilized by modified amber, exhibited a higher retention rate of AT-EO and lower levels of peroxide value and malondialdehyde content compared to those of the pure AT-EO group after heat treatment at 40 °C for 1, 3, and 8 h. Additionally, component analysis in content and composition revealed that the volatile components of AT-EO in the Pickering emulsion were more stable during the thermal treatment process. This study convincingly illustrates the potential of a Pickering emulsion stabilized with modified medicinal powders to improve the thermal stability of the essential oil.
PubMed: 38764633
DOI: 10.1021/acsomega.3c08110 -
Vaccine May 2024Mucosal vaccination presents a promising complement to parenteral vaccination. Bacterium-like particles (BLPs), peptidoglycan structures prepared from lactic acid...
Mucosal vaccination presents a promising complement to parenteral vaccination. Bacterium-like particles (BLPs), peptidoglycan structures prepared from lactic acid bacteria, are explored as potential nasal vaccine adjuvants for respiratory infections. To date, studies on BLP-adjuvanted nasal vaccines against intestinal infections have remained limited. In this study, we demonstrated the efficacy of intranasal BLP-adjuvanted vaccination in controlling intestinal infections using the Citrobacter rodentium (C. rodentium) model in C57BL/6 mice. Intranasal vaccination of Intimin, an adhesin critical for intimate bacterial adhesion to colonic epithelial cells, combined with BLP (BLP+I) elicited robust Intimin-specific intestinal secretory IgA production, reduced bacterial load in feces and almost completely inhibited colonic hyperplasia, a characteristic symptom of C. rodentium infection in mice. Conversely, parenteral vaccination with Alhydrogel-adjuvanted Intimin failed to induce intestinal Intimin-specific IgA production, resulting in poor protection against C. rodentium infection. This underscores the pivotal role of mucosal IgA responses elicited by intranasal immunization in its protective efficacy. As this study did not delineate the precise protective mechanism conferred by BLP+I intranasal immunization against C. rodentium infection, further elucidation of the mechanisms underlying intranasal BLP+I immunization is required.
PubMed: 38763852
DOI: 10.1016/j.vaccine.2024.05.023