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In vitro models, such as primary cells and continuous cell lines routinely used for evaluating drug candidates, have limitations in their translational relevance to human diseases. Organotypic cultures are increasingly being used to assess therapeutics for various cancers and infectious diseases. Monitoring drug cytotoxicity in cell cultures is crucial in drug development, and several commercially available kits for cytotoxicity assessment offer distinct advantages and limitations. Given the complexity of organoid cultures, including donor-driven variability, we investigated drug-treated, tissue stem cell-derived human intestinal organoid responses with commonly used cell cytotoxicity assay kits. Using seven different compounds, we compared the cytotoxicity assay performance of two different leaky membrane-based and two metabolism-based assays. Significant variability was seen in reported viability outcomes across assays and organoid lines. High baseline activity of lactate dehydrogenase (LDH) in four human intestinal organoid lines required modification of the standard LDH assay protocol. Additionally, the LDH assay reported unique resilience to damage in a genetically-modified line contrasting results compared to other assays. This study highlights factors that can impact the measurement of cell cytotoxicity in intestinal organoid models, which are emerging as valuable new tools for research and pre-clinical drug testing and suggest the need for using multiple assay types to ensure reliable cytotoxicity assessment. [ABSTRACT FROM AUTHOR]

The requirements of augmented signal contrast provided by nanoparticle tags in biosensor microscopy-based point-of-care technologies for cancer and infectious disease diagnostics can be addressed through metallo-dielectric nanoarchitectures that enhance optical scattering and absorption to provide digital resolution detection of single tags with simple instrumentation. Photonic Resonator Interferometric Scattering Microscopy (PRISM) enables label-free visualization of nanometer-scale analytes such as extracellular vesicles and virions, and its applicability can be extended to biomolecular analyte counting through nanoparticle tags. Here, we present template-free, linker-less cryosoret nano-assemblies fabricated via adiabatic cooling (−196 °C) as plasmonic nano-antennas that provide high scattering contrast in PRISM. Plasmonic Ag and Au nanomaterials and their cryosorets are evaluated through imaging experiments and simulations based on the finite element method to understand the photo-plasmonic coupling effect at the surface of a photonic crystal (PC) interface. The Ag and Au cryosorets provide at most 8.29-fold and 6.77-fold higher signal contrast compared to their singlet counterpart. Through the simulations, the averaged field magnitude enhancements of 2.77-fold and 3.68-fold are observed for Ag and Au cryosorets when interfacing with PCs compared to bare glass substrates. The hybrid coupling between the localized Mie and delocalized Bragg plasmons of cryosorets and the underlying PC's guided mode resonance provides insights for developing nano-assembly-based nano-tags for biosensing applications. [ABSTRACT FROM AUTHOR]

Cancer is a multifaceted genetic disease characterized by the acquisition of several essential hallmarks. Notably, certain cancers exhibit horizontal transmissibility, observed across mammalian species and diverse bivalves, the latter referred to as hemic neoplasia. Within this complex landscape, epigenetic mechanisms such as histone modifications and cytosine methylation emerge as fundamental contributors to the pathogenesis of these transmissible cancers. Our study delves into the epigenetic landscape of Cerastoderma edule, focusing on whole-genome methylation and hydroxymethylation profiles in heathy specimens and transmissible neoplasias by means of Nanopore long-read sequencing. Our results unveiled a global hypomethylation in the neoplastic specimens compared to their healthy counterparts, emphasizing the role of DNA methylation in these tumorigenic processes. Furthermore, we verified that intragenic CpG methylation positively correlated with gene expression, emphasizing its role in modulating transcription in healthy and neoplastic cockles, as also highlighted by some up-methylated oncogenic genes. Hydroxymethylation levels were significantly more elevated in the neoplastic samples, particularly within satellites and complex repeats, likely related to structural functions. Additionally, our analysis also revealed distinct methylation and activity patterns in retrotransposons, providing additional insights into bivalve neoplastic processes. Altogether, these findings contribute to understanding the epigenetic dynamics of bivalve neoplasias and shed light on the roles of DNA methylation and hydroxymethylation in tumorigenesis. Understanding these epigenetic alterations holds promise for advancing our broader understanding of cancer epigenetics. [ABSTRACT FROM AUTHOR]

Five types of round cell tumors found in dogs are mast cell tumors (MCT), lymphoma, plasma cell tumors, histiocytoma, and transmissible venereal tumors (TVT). This study focuses on the occurrence and cytopathology of these tumors in dogs of Meerut, Uttar Pradesh (India), spanning the period from 2018 to 2022. A total of 147 samples were gathered from different sites of dogs, notably 95 samples from vaginal specimens, 24 from nodular skin swellings, 7 samples from penile growths, 5 from lymph nodes, and 16 were from various skin lesions. The analysis of these samples revealed 4 cases of lymphoma, 3 cases of MCT, and 28 cases of TVT. In lymphoma, one case was identified as cutaneous lymphoma, while three cases were associated with lymph nodes. Cutaneous lymphoma exhibited numerous small and medium-sized lymphocytes. Lymph node samples exhibited a substantial presence of large-sized and medium-sized lymphocytes. TVT emerged as the most prevalent round cell tumor, observed in both genital and extragenital forms. Extragenital TVT predominantly affected the skin. In mast cell tumors, cells demonstrated round characteristics, with a notable granules in the cytoplasm and infiltration of eosinophils. Minimal anisocytosis and anisokaryosis, coupled with a high nuclear-to-cytoplasmic ratio, were evident in these tumors. [ABSTRACT FROM AUTHOR]

A robust, well-functioning immune system is the cornerstone of good health. Various factors may influence the immune system's effectiveness, potentially leading to immune system failure. This review aims to provide an overview of the structure and action of immunomodulators isolated from African medicinal plants. The research was conducted according to PRISMA guidelines. Full-text access research articles published in English up to December 2023, including plant characteristics, isolated phytochemicals, and immuno-modulatory activities, were screened. The chemical structures of the isolated compounds were generated using ChemDraw® (version 12.0.1076), and convergent and distinctive signaling pathways were highlighted. These phytochemicals with demonstrated immunostimulatory activity include alkaloids (berberine, piperine, magnoflorine), polysaccharides (pectin, glucan, acemannan, CALB-4, GMP90-1), glycosides (syringin, cordifolioside, tinocordiside, aucubin), phenolic compounds (ferulic acid, vanillic acid, eupalitin), flavonoids (curcumin, centaurein, kaempferin, luteolin, guajaverin, etc.), terpenoids (oleanolic acid, ursolic acid, betulinic acid, boswellic acids, corosolic acid, nimbidin, andrographolides). These discussed compounds exert their effects through various mechanisms, targeting the modulation of MAPKs, PI3K-Akt, and NF-kB. These mechanisms can support the traditional use of medicinal plants to treat immune-related diseases. The outcomes of this overview are to provoke structural action optimization, to orient research on particular natural chemicals for managing inflammatory, infectious diseases and cancers, or to boost vaccine immunogenicity. [ABSTRACT FROM AUTHOR]

Summary: NK cells are short‐lived innate lymphocytes that can mediate antigen‐independent responses to infection and cancer. However, studies from the past two decades have shown that NK cells can acquire transcriptional and epigenetic modifications during inflammation that result in increased survival and lifespan. These findings blur the lines between the innate and adaptive arms of the immune system, and suggest that the homeostatic mechanisms that govern the persistence of innate immune cells are malleable. Indeed, recent studies have shown that NK cells undergo continuous and strictly regulated adaptations controlling their survival during development, tissue residency, and following inflammation. In this review, we summarize our current understanding of the critical factors regulating NK cell survival throughout their lifespan, with a specific emphasis on the epigenetic modifications that regulate the survival of NK cells in various contexts. A precise understanding of the molecular mechanisms that govern NK cell survival will be important to enhance therapies for cancer and infectious diseases. [ABSTRACT FROM AUTHOR]

Carbon dots (CDs) are novel carbon-based nanomaterials that have been used as photosensitizer-mediated photodynamic therapy (PDT) in recent years due to their good photosensitizing activity. Photosensitizers (PSs) are main components of PDT that can produce large amounts of reactive oxygen species (ROS) when stimulated by light source, which have the advantages of low drug resistance and high therapeutic efficiency. CDs can generate ROS efficiently under irradiation and therefore have been extensively studied in disease local phototherapy. In tumor therapy, CDs can be used as PSs or PS carriers to participate in PDT and play an extremely important role. In bacterial infectious diseases, CDs exhibit high bactericidal activity as CDs are effective in disrupting bacterial cell membranes leading to bacterial death upon photoactivation. We focus on recent advances in the therapy of cancer and bacteria with CDs, and also briefly summarize the mechanisms and requirements for PSs in PDT of cancer, bacteria and other diseases. We also discuss the role CDs play in combination therapy and the potential for future applications against other pathogens. [ABSTRACT FROM AUTHOR]

This document is a summary of a special issue of the International Journal of Molecular Sciences titled "Digestive Inflammation and New Therapeutical Targets." The issue focuses on chronic inflammatory gastrointestinal diseases (CIGDs), which can affect various parts of the gastrointestinal tract. These diseases, such as hepatitis, pancreatitis, and intestinal bowel diseases, are characterized by dysregulated immune systems, imbalances between pro- and anti-inflammatory processes, disruptions of epithelial barrier function, and involvement of microbiota or viruses. CIGDs are also associated with an increased risk of developing cancer in organs like the stomach, liver, and colon. The special issue includes articles on topics such as sex differences in inflammatory bowel disease, the role of gut microbiota in diverticular disease, alternative therapies for inflammatory bowel diseases, the potential benefits of PPAR-γ activation in IBD patients, the role of long non-coding RNAs in IBD and Johne's disease, and the cellular and molecular aspects of pancreatic acinar-to-ductal metaplasia. These studies contribute to a better understanding of CIGDs and offer potential avenues for improved treatment approaches. [Extracted from the article]

Diagnostic assays utilizing fluorescent reporters in the context of low abundance biomarkers for cancer and infectious disease can reach lower limits of detection through efficient collection of emitted photons into an optical sensor. In this work, we present the rational design, fabrication, and application of one-dimensional photonic crystal (PC) grating interfaces to accomplish a cost-effective prism-free, metal-free, and objective-free platform for augmentation of fluorescence emission collection efficiency. Guided mode resonance (GMR) of the PC is engineered to match the laser excitation (532 nm) and emission maximum (580 nm) of the radiating dipoles to arrive at optimized conditions. The photo-plasmonic hybrid nano-engineering using silver nanoparticles presented >110-fold steering fluorescence enhancement enabling placement of the sample between the excitation source and detector that are in a straight line. From the experimental and simulation inferences, we propose a radiating GMR model by scrutinizing the polarized emission properties of the hybrid substrate, in accordance with the radiating plasmon model. The augmented fluorescence intensity realized here with a simple detection instrument provides sub-nanomolar sensitivity to provide a path toward point-of-care scenarios. [ABSTRACT FROM AUTHOR]

Recent advances in mRNA technology and its delivery have enabled mRNA-based therapeutics to enter a new era in medicine. The rapid, potent, and transient nature of mRNA-encoded proteins, without the need to enter the nucleus or the risk of genomic integration, makes them desirable tools for treatment of a range of diseases, from infectious diseases to cancer and monogenic disorders. The rapid pace and ease of mass-scale manufacturability of mRNA-based therapeutics supported the global response to the COVID-19 pandemic. Nonetheless, challenges remain with regards to mRNA stability, duration of expression, delivery efficiency, and targetability, to broaden the applicability of mRNA therapeutics beyond COVID-19 vaccines. By learning from the rapidly expanding preclinical and clinical studies, we can optimise the mRNA platform to meet the clinical needs of each disease. Here, we will summarise the recent advances in mRNA technology; its use in vaccines, immunotherapeutics, protein replacement therapy, and genomic editing; and its delivery to desired specific cell types and organs for development of a new generation of targeted mRNA-based therapeutics. [ABSTRACT FROM AUTHOR]

Coevolution is common and frequently governs host-pathogen interaction outcomes. Phenotypes underlying these interactions often manifest as the combined products of the genomes of interacting species, yet traditional quantitative trait mapping approaches ignore these intergenomic interactions. Devil facial tumor disease (DFTD), an infectious cancer afflicting Tasmanian devils (Sarcophilus harrisii), has decimated devil populations due to universal host susceptibility and a fatality rate approaching 100%. Here, we used a recently developed joint genome-wide association study (i.e., co-GWAS) approach, 15 y of mark-recapture data, and 960 genomes to identify intergenomic signatures of coevolution between devils and DFTD. Using a traditional GWA approach, we found that both devil and DFTD genomes explained a substantial proportion of variance in how quickly susceptible devils became infected, although genomic architectures differed across devils and DFTD; the devil genome had fewer loci of large effect whereas the DFTD genome had a more polygenic architecture. Using a co-GWA approach, devil-DFTD intergenomic interactions explained ~3× more variation in how quickly susceptible devils became infected than either genome alone, and the top genotype-by-genotype interactions were significantly enriched for cancer genes and signatures of selection. A devil regulatory mutation was associated with differential expression of a candidate cancer gene and showed putative allele matching effects with two DFTD coding sequence variants. Our results highlight the need to account for intergenomic interactions when investigating host-pathogen (co)evolution and emphasize the importance of such interactions when considering devil management strategies. [ABSTRACT FROM AUTHOR]

In seeking alternative cancer treatments, antimicrobial peptides (AMPs), sourced from various life forms, emerge as promising contenders. These endogenous peptides, also known as host defense peptides (HDPs), play crucial roles in immune defenses against infections and exhibit potential in combating cancers. With their diverse defensive functions, plant-derived AMPs, such as thionins and defensins, offer a rich repertoire of antimicrobial properties. Insects, amphibians, and animals contribute unique AMPs like cecropins, temporins, and cathelicidins, showcasing broad-spectrum activities against bacteria, fungi, and viruses. Understanding these natural peptides holds significant potential for developing effective and targeted therapies against cancer and infectious diseases. Antimicrobial peptides (AMPs) exhibit diverse structural characteristics, including α-helical, β-sheet, extended, and loop peptides. Environmental conditions influence their structure, connecting to changes in cell membrane hydrophobicity. AMPs' actions involve direct killing and immune regulation, with additional activities like membrane depolarization. In this review, we focus on antimicrobial peptides that act as anticancer agents and AMPs that exhibit mechanisms akin to antimicrobial activity. Buforin AMPs, particularly Buforin I and II, derived from histone H2A, demonstrate antibacterial and anticancer potential. Buforin IIb and its analogs show promise, with selectivity for cancer cells. Despite the challenges, AMPs offer a unique approach to combat microbial resistance and potential cancer treatment. In various cancer types, including HeLa, breast, lung, ovarian, prostate, and liver cancers, buforins demonstrate inhibitory effects and apoptosis induction. To address limitations like stability and bioavailability, researchers explore buforin-containing bioconjugates, covalently linked with nanoparticles or liposomes. Bioconjugation enhances specificity-controlled release and combats drug resistance, presenting a promising avenue for targeted cancer treatment. Clinical translation awaits further evaluation through in vivo studies and future clinical trials. [ABSTRACT FROM AUTHOR]

Flavonoids and cannabinoids comprise two large families of natural products that contain a chromane moiety in their structure. Their therapeutic potential has been extensively investigated as potential treatments to several diseases, ranging from cancer to infectious and neurodegenerative diseases. Despite their relative structural simplicity, in recent years creative synthetic methodologies were designed to overcome limitations from the previous synthetic strategies applied to these compounds. The aim of this review is to provide a comprehensive overview of all the enantioselective organocatalytic strategies that have been applied to the synthesis of flavonoids and cannabinoids to date. [ABSTRACT FROM AUTHOR]

Since the emergence of a transmissible cancer, devil facial tumour disease (DFT1), in the 1980s, wild Tasmanian devil populations have been in decline. In 2016, a second, independently evolved transmissible cancer (DFT2) was discovered raising concerns for survival of the host species. Here, we applied experimental and modelling frameworks to examine competition dynamics between the two transmissible cancers in vitro. Using representative cell lines for DFT1 and DFT2, we have found that in monoculture, DFT2 grows twice as fast as DFT1 but reaches lower maximum cell densities. Using co‐cultures, we demonstrate that DFT2 outcompetes DFT1: the number of DFT1 cells decreasing over time, never reaching exponential growth. This phenomenon could not be replicated when cells were grown separated by a semi‐permeable membrane, consistent with exertion of mechanical stress on DFT1 cells by DFT2. A logistic model and a Lotka–Volterra competition model were used to interrogate monoculture and co‐culture growth curves, respectively, suggesting DFT2 is a better competitor than DFT1, but also showing that competition outcomes might depend on the initial number of cells, at least in the laboratory. We provide theories how the in vitro results could be translated to observations in the wild and propose that these results may indicate that although DFT2 is currently in a smaller geographic area than DFT1, it could have the potential to outcompete DFT1. Furthermore, we provide a framework for improving the parameterization of epidemiological models applied to these cancer lineages, which will inform future disease management. [ABSTRACT FROM AUTHOR]

Most basic studies directed at how immune responses are regulated employ chemically "simple antigens", usually purified proteins. The target antigens in many clinical situations, such as in autoimmunity, infectious diseases and cancer, are chemically "complex", consisting of several distinct molecules, and they often are part of a replicating entity. We examine here the relationships between how immune responses to complex and simple antigens are regulated. This examination provides a context for considering how immune responses are regulated in those clinical situations involving complex antigens. I have proposed and discuss here a mechanism by which immune responses to the envisaged complex target antigen in remitting/relapsing multiple sclerosis go back and forth between inflammatory and non-inflammatory modes, potentially accounting for the course of this disease. This proposal makes predictions that can be tested by non-invasive means. It also leads to a suggestion for simple, non-invasive treatment. [ABSTRACT FROM AUTHOR]

This document, titled "State-of-the-Art Cancer Immunotherapies," provides an overview of recent advancements in cancer immunotherapy. It discusses the use of adoptive cell transfer (ACT) of chimeric antigen receptor (CAR)-T cells and immune checkpoint inhibitors (ICIs) as effective treatments for cancer. The document also highlights the potential of mRNA vaccines delivered by lipid nanoparticles (LNPs) in cancer treatment. Additionally, it explores the role of cytokines and exosomes in cancer immunotherapy. The authors suggest that these advancements deepen our understanding of human cancer and offer potential strategies for its eradication. [Extracted from the article]

Background: The ocular side effects of cancer chemotherapeutic drugs are relatively uncommon. Nonetheless, the ocular system has a potentially high sensitivity to toxic substances. This study proposed a framework to assess the effect of vincristine chemotherapy on intraocular pressure, tear protein, and oxidative stress in canines with transmissible venereal tumor (TVT). Methods: The study group comprised 10 dogs with TVT, whose diagnosis was based on cytology, and all dogs were treated with vincristine for 4 weeks. Each animal was given a complete ophthalmic examination, followed by a standard Schirmer tear test. Before and 20 min after administering vincristine, intraocular pressure (IOP) was measured in the eyes with a noncontact tonometer. At any of the times mentioned, tear samples were collected using the Schirmer test procedure and were subjected to protein analysis—oxidative stress index (OSI), total antioxidant capacity (TAC), total oxidant status (TOS), nitric oxide (NO), and malondialdehyde (MDA) were determined, and standard statistical analysis was applied. Results: No significant differences were found in protein in tears, but mean Pre and Postinjection IOP revealed a significant decrease in the eyes each week. Also, results indicated significant differences in oxidative stress markers: increased OSI, NO, and MDA, and reduced TAC. Conclusion: The importance of an increase in oxidative stress levels in the tears of vincristine‐treated patients should be taken seriously, as it appears to play a role in the pathogenesis of eye disease. Therefore, during the treatment weeks prior to prescribing vincristine, eye diseases should be evaluated and considered. [ABSTRACT FROM AUTHOR]

The messenger RNA (mRNA) vaccines have progressed from a theoretical concept to a clinical reality over the last few decades. Compared to conventional vaccination methods, these vaccines have a number of benefits, such as substantial potency, rapid growth, inexpensive production, and safe administration. Nevertheless, their usefulness was restricted up to now due to worries about the erratic and ineffective circulation of mRNA in vivo. Thankfully, these worries have largely been allayed by recent technological developments, which have led to the creation of multiple mRNA vaccination platforms for cancer and viral infections. The mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low‐cost manufacturing. The paper will examine the present status of mRNA vaccine technology and suggest future paths for the advancement and application of this exciting vaccine platform as a common therapeutic choice. Significance statement: With the approval of two messenger RNA (mRNA) vaccines for the prevention of infectious diseases, preclinical and clinical research on mRNA vaccines in the fields of infectious diseases and cancers has greatly expanded. The discovery and efficient delivery of highly immunogenic tumor‐specific antigens poses a substantial obstacle to the development of potent anticancer vaccinations. In this article, we want to provide a thorough and in‐depth examination of mRNA vaccines, including their mechanisms of action as well as their uses in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Admixture mapping has been useful in identifying genetic variations linked to phenotypes, adaptation and diseases. Copy number variations (CNVs) represents genomic structural variants spanning large regions of chromosomes reaching several megabases. In this investigation, the "Canary" algorithm was applied to 102 Tunisian samples and 991 individuals from eleven HapMap III populations to genotype 1279 copy number polymorphisms (CNPs). In this present work, we investigate the Tunisian population structure using the CNP makers previously identified among Tunisian. The study revealed that Sub-Saharan African populations exhibited the highest diversity with the highest proportions of allelic CNPs. Among all the African populations, Tunisia showed the least diversity. Individual ancestry proportions computed using STRUCTURE analysis revealed a major European component among Tunisians with lesser contribution from Sub-Saharan Africa and Asia. Population structure analysis indicated the genetic proximity with Europeans and noticeable distance from the Sub-Saharan African and East Asian clusters. Seven genes harbouring Tunisian high-frequent CNPs were identified known to be associated with 9 Mendelian diseases and/or phenotypes. Functional annotation of genes under selection highlighted a noteworthy enrichment of biological processes to receptor pathway and activity as well as glutathione metabolism. Additionally, pathways of potential concern for health such as drug metabolism, infectious diseases and cancers exhibited significant enrichment. The distinctive genetic makeup of the Tunisians might have been influenced by various factors including natural selection and genetic drift, resulting in the development of distinct genetic variations playing roles in specific biological processes. Our research provides a justification for focusing on the exclusive genome organization of this population and uncovers previously overlooked elements of the genome. [ABSTRACT FROM AUTHOR]

Mutant selection windows (MSWs), the range of drug concentrations that select for drug-resistant mutants, have long been used as a model for predicting drug resistance and designing optimal dosing strategies in infectious disease. The canonical MSW model offers comparisons between two subtypes at a time: drug-sensitive and drug-resistant. In contrast, the fitness landscape model with N alleles, which maps genotype to fitness, allows comparisons between N genotypes simultaneously, but does not encode continuous drug response data. In clinical settings, there may be a wide range of drug concentrations selecting for a variety of genotypes in both cancer and infectious diseases. Therefore, there is a need for a more robust model of the pathogen response to therapy to predict resistance and design new therapeutic approaches. Fitness seascapes, which model genotype-by-environment interactions, permit multiple MSW comparisons simultaneously by encoding genotype-specific dose-response data. By comparing dose-response curves, one can visualize the range of drug concentrations where one genotype is selected over another. In this work, we show how N-allele fitness seascapes allow for N * 2N−1 unique MSW comparisons. In spatial drug diffusion models, we demonstrate how fitness seascapes reveal spatially heterogeneous MSWs, extending the MSW model to more fully reflect the selection of drug resistant genotypes. Furthermore, using synthetic data and empirical dose-response data in cancer, we find that the spatial structure of MSWs shapes the evolution of drug resistance in an agent-based model. By simulating a tumor treated with cyclic drug therapy, we find that mutant selection windows introduced by drug diffusion promote the proliferation of drug resistant cells. Our work highlights the importance and utility of considering dose-dependent fitness seascapes in evolutionary medicine. Author summary: Drug resistance in infectious disease and cancer is a major driver of mortality. While undergoing treatment, the population of cells in a tumor or infection may evolve the ability to grow despite the use of previously effective drugs. Researchers hypothesize that the spatial organization of these disease populations may contribute to drug resistance. In this work, we analyze how spatial gradients of drug concentration impact the evolution of drug resistance. We consider a decades-old model called the mutant selection window (MSW), which describes the drug concentration range that selects for drug-resistant cells. We show how extending this model with continuous dose-response data, which describes how different types of cells respond to drug, improves the ability of MSWs to predict evolution. This work helps us understand how the spatial organization of cells, such as the organization of blood vessels within a tumor, may promote drug resistance. In the future, we may use these methods to optimize drug dosing to prevent resistance or leverage known vulnerabilities of drug-resistant cells. [ABSTRACT FROM AUTHOR]

T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response. This class of bispecifics binds specific target peptides presented by human leukocyte antigen on the cell surface via an affinity-enhanced T-cell receptor and can redirect T-cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T-cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimizing the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proofreading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark state. These findings have important implications for the design of anti-CD3-based bispecifics with optimal biophysical parameters for both activity and specificity. These studies demonstrate how to optimize the fundamental process of T-cell activation, both in terms of affinity and binding kinetics to target cell and T-cell epitopes. Current theories of T-cell biology are used to build a mathematical model that explains most features of the data. How the kinetics of target and cluster of differentiation 3 binding regulate T-cell activation in the context of the clinically validated immune mobilizing monoclonal TCRs against cancer platform, which directly targets peptide-human leukocyte antigen complexes. [ABSTRACT FROM AUTHOR]

This article provides information on various parasitic infections, including filariae, leishmania species, malaria, Toxoplasma gondii, and Trypanosoma brucei. It explains the different diseases caused by these parasites, their modes of transmission, and the regions where they are prevalent. The article also discusses the risk of transfusion transmission for some of these parasites and the available treatment options. It emphasizes the importance of screening questions, laboratory tests, and personal protective measures in preventing the transmission of these parasites. [Extracted from the article]

T-cell exhaustion refers to a state of T-cell dysfunction commonly observed in chronic infections and cancer. Immune checkpoint molecules blockading using PD-1 and TIM-3 antibodies have shown promising results in reversing exhaustion, but this approach has several limitations. The treatment of T-cell exhaustion is still facing great challenges, making it imperative to explore new therapeutic strategies. With the development of nanotechnology, nanoparticles have successfully been applied as drug carriers and delivery systems in the treatment of cancer and infectious diseases. Furthermore, nanoparticle-based immunotherapy has emerged as a crucial approach to reverse exhaustion. Here, we have compiled the latest advances in T-cell exhaustion, with a particular focus on the characteristics of exhaustion that can be targeted. Additionally, the emerging nanoparticle-based delivery systems were also reviewed. Moreover, we have discussed, in detail, nanoparticle-based immunotherapies that aim to reverse exhaustion, including targeting immune checkpoint blockades, remodeling the tumor microenvironment, and targeting the metabolism of exhausted T cells, etc. These data could aid in comprehending the immunopathogenesis of exhaustion and accomplishing the objective of preventing and treating chronic diseases or cancer. [ABSTRACT FROM AUTHOR]

The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR. [ABSTRACT FROM AUTHOR]

Developing a green effective approach and a suitable applicative process for increasing the efficiency of microbial nanomaterial synthesis is an emerging prospect for future industrial production. This was accomplished by employing exopolysaccharides (EPS) to obtain potent silver nanoparticles using Penicillium citrinum (EPS−AgNPs) as a reducing and stabilizing agent. EPS−AgNPs were analyzed by UV–Vis spectrophotometry, which showed a peak of absorbance at 420 nm. TEM was used to determine the morphology of the EPS−AgNPs and showed that the particles were 14.4 nm in size, well dispersed, and spherical. The stabilization of (EPS−AgNPs) was caused by amides and amines groups, which were confirmed via Fourier transform infrared. Moreover, the EPS−AgNPs showed excellent antibacterial activities against various human pathogenic bacterial strains in comparison to the potent antibiotics. Additionally, EPS−AgNPs were examined for their anticancer properties. Furthermore, EPS−AgNPs had a significant impact on the ochratoxin production. Finally, our findings confirm the benefits of adopting a bio green technique for the synthesis of antibacterial and detoxifying nanoparticles, which are predicted to provide new pathways for various cancers and infectious microbial diseases treatment. [ABSTRACT FROM AUTHOR]

Abstract—CRISPR/Cas systems are perspective molecular tools for targeted manipulation with genetic materials, such as gene editing, regulation of gene transcription, modification of epigenome etc. While CRISPR/Cas systems proved to be highly effective for correcting genetic disorders and treating infectious diseases and cancers in experimental settings, clinical translation of these results is hampered by the lack of efficient CRISPR/Cas delivery vehicles. Modern synthetic nanovehicles based on organic and inorganic polymers have many disadvantages, including toxicity issues, the lack of targeted delivery, and complex and expensive production pipelines. In turn, exosomes are secreted biological nanoparticles that exhibit high biocompatibility, physico-chemical stability, and the ability to cross biological barriers. Early clinical trials found no toxicity associated with exosome injections. In the recent years, exosomes have been considered as perspective delivery vehicles for CRISPR/Cas systems in vivo. The aim of this study was to analyze the efficacy of CRISPR/Cas stochastic packaging into exosomes for several human cell lines. Here, we show that Cas9 protein is effectively localized into the compartment of intracellular exosome biogenesis, but stochastic packaging of Cas9 into exosomes turns to be very low (~1%). As such, stochastic packaging of Cas9 protein is very ineffective and cannot be used for gene editing purposes. Developing novel tools and technologies for loading CRISPR/Cas systems into exosomes is needed. [ABSTRACT FROM AUTHOR]

SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly–Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases. [ABSTRACT FROM AUTHOR]

In this study, we demonstrate the green synthesis of bimetallic silver-copper nanoparticles (Ag–Cu NPs) using Aerva lanata plant extract. These NPs possess diverse biological properties, including in vitro antioxidant, antibiofilm, and cytotoxic activities. The synthesis involves the reduction of silver nitrate and copper oxide salts mediated by the plant extract, resulting in the formation of crystalline Ag–Cu NPs with a face-centered cubic structure. Characterization techniques confirm the presence of functional groups from the plant extract, acting as stabilizing and reducing agents. The synthesized NPs exhibit uniform-sized spherical morphology ranging from 7 to 12 nm. They demonstrate significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, inhibiting extracellular polysaccharide secretion in a dose-dependent manner. The Ag–Cu NPs also exhibit potent cytotoxic activity against cancerous HeLa cell lines, with an inhibitory concentration (IC50) of 17.63 µg mL−1. Additionally, they demonstrate strong antioxidant potential, including reducing capability and H2O2 radical scavenging activity, particularly at high concentrations (240 µg mL−1). Overall, these results emphasize the potential of A. lanata plant metabolite-driven NPs as effective agents against infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Animal models are essential in medical research for testing drugs and vaccines. These models differ from humans in various respects, so their results are not directly translatable in humans. To address this issue, humanized mice engrafted with functional human cells or tissue can be helpful. We propose using humanized mice that support the engraftment of human hematopoietic stem cells (HSCs) without irradiation to evaluate vaccines that influence patient immunity. For infectious diseases, several types of antigens and adjuvants have been developed and evaluated for vaccination. Peptide vaccines are generally used for their capability to fight cancer and infectious diseases. Evaluation of adjuvants is necessary as they induce inflammation, which is effective for an enhanced immune response but causes adverse effects in some individuals. A trial can be done on humanized mice to check the immunogenicity of a particular adjuvant and peptide combination. Messenger RNA has also emerged as a potential vaccine against viruses. These vaccines need to be tested with human immune cells because they work by producing a particular peptide of the pathogen. Humanized mice with human HSCs that can produce both myeloid and lymphoid cells show a similar immune response that these vaccines will produce in a patient. [ABSTRACT FROM AUTHOR]

The enzyme-linked immunosorbent spot (ELISpot) assay is a powerful in vitro immunoassay that enables cost-effective quantification of antigen-specific T-cell reactivity. It is used widely in the context of cancer and infectious diseases to validate the immunogenicity of predicted epitopes. While technological advances have kept pace with the demand for increased throughput, efforts to increase scale are bottlenecked by current assay design and deconvolution methods, which have remained largely unchanged. Current methods for designing pooled ELISpot experiments offer limited flexibility of assay parameters, lack support for high-throughput scenarios and do not consider peptide identity during pool assignment. We introduce the ACE Configurator for ELISpot (ACE) to address these gaps. ACE generates optimized peptide-pool assignments from highly customizable user inputs and handles the deconvolution of positive peptides using assay readouts. In this study, we present a novel sequence-aware pooling strategy, powered by a fine-tuned ESM-2 model that groups immunologically similar peptides, reducing the number of false positives and subsequent confirmatory assays compared to existing combinatorial approaches. To validate ACE's performance on real-world datasets, we conducted a comprehensive benchmark study, contextualizing design choices with their impact on prediction quality. Our results demonstrate ACE's capacity to further increase precision of identified immunogenic peptides, directly optimizing experimental efficiency. ACE is freely available as an executable with a graphical user interface and command-line interfaces at https://github.com/pirl-unc/ace. [ABSTRACT FROM AUTHOR]

• Cuminaldehyde (CUM), the main bioactive component of Cuminum cyminum, also called 4-isopropylbenzaldehyde, is are used for potent biomedical applications. • CUM for possible anticancer (colon cancer HCT-116 and cervical cancer HeLa cells), antibacterial, and antifungal activities has been investigated. • In addition, the anticancer and antibacterial efficacy of CUM has been verified by molecular docking and in silico/ADMET analysis. Many people have recently been diagnosed with cancer and other multi-resistant infections. These illnesses are now considered among the leading causes of mortality worldwide. In addition, infectious organisms such as microbes and viruses are responsible for around 2 million new cancer cases. Cuminaldehyde (CUM), the main bioactive component of Cuminum cyminum, also called 4-isopropylbenzaldehyde, is the most prevalent in C. cyminum seeds. Extensive research has been conducted on natural compounds in general; however, the investigation of CUM, a unique component of cumin oil, is still in its preliminary phases. Therefore, this study aimed to screen CUM for possible anticancer (colon cancer HCT-116 and cervical cancer HeLa cells), antibacterial, and antifungal activities. The number of DAPI-stained cells was lower in the CUM treatment group compared to the control group. The results showed that the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for Gram-negative bacteria, i.e., Escherichia coli ATCC 25922, multidrug-resistant Pseudomonas aeruginosa (MDR-PA), and multidrug-resistant Acinetobacter baumannii (MDR- A. baumannii), were 6.25/12.5, 12.5/25, and 6.25/12.5 mM, respectively, while the MICs for Gram-positive bacteria Staphylococcus aureus ATCC 25923, and methicillin-resistant S. aureus (MRSA) were 25/50 and 6.25/12.5 mM, respectively. However, MIC and minimum fungicidal concentration (MFC) values against Candida albicans ATCC 14053 were 6.25 and 12.5 mM, respectively. In addition, the anticancer and antibacterial efficacy of CUM has also been analyzed by an in silico molecular docking study, which demonstrated noteworthy binding energy with the sterol 14-alpha demethylase (-5.53 kcal/mol), followed by cyclin-dependent kinase 2 (-5.35 kcal/mol), poly-beta-1,6-N-acetyl-d-glucosamine synthase (-4.90 kcal/mol), GDP-mannose dehydrogenase (-4.35 kcal/mol), and intact bacterial peptidoglycan (-2.65 kcal/mol). Our predicted results need to be further validated through in vitro and in vivo studies before they can be applied to the development of therapeutic compound against cancer and infectious diseases, two of humanity's gravest health issues. [ABSTRACT FROM AUTHOR]

Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute Salmonella Typhimurium (S. Tm) gut infection. However, to date, we lack a comprehensive functional assessment of the different Gasdermins (GSDMA-E) during S. Tm infection in vivo. Here, we used epithelium-specific ablation, bone marrow chimeras, and mouse lines lacking individual Gasdermins, combinations of Gasdermins or even all Gasdermins (GSDMA1-3C1-4DE) at once and performed littermate-controlled oral S. Tm infections in streptomycin-pretreated mice to investigate the impact of all murine Gasdermins. While GSDMA, C, and E appear dispensable, we show that GSDMD i) restricts S. Tm loads in the gut tissue and systemic organs, ii) controls gut inflammation kinetics, and iii) prevents epithelium disruption by 72 h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs). In vivo experiments as well as 3D-, 2D-, and chimeric enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding IECs, affects extrusion kinetics, and promotes overall mucosal barrier capacity. As such, this work identifies a unique multipronged role of GSDMD among the Gasdermins for mucosal tissue defense against a common enteric pathogen. [ABSTRACT FROM AUTHOR]

The Tasmanian devil (Sarcophilus harrisii) is endangered due to the spread of Devil Facial Tumour Disease (DFTD), a contagious cancer with no current treatment options. Here we test whether seven recently characterized Tasmanian devil cathelicidins are involved in cancer regulation. We measured DFTD cell viability in vitro following incubation with each of the seven peptides and describe the effect of each on gene expression in treated cells. Four cathelicidins (Saha-CATH3, 4, 5 and 6) were toxic to DFTD cells and caused general signs of cellular stress. The most toxic peptide (Saha-CATH5) also suppressed the ERBB and YAP1/TAZ signaling pathways, both of which have been identified as important drivers of cancer proliferation. Three cathelicidins induced inflammatory pathways in DFTD cells that may potentially recruit immune cells in vivo. This study suggests that devil cathelicidins have some anti-cancer and inflammatory functions and should be explored further to determine whether they have potential as treatment leads. [ABSTRACT FROM AUTHOR]

Numerous supramolecular platforms inspired by natural self-assembly are exploited as drug delivery systems. The spontaneous arrangement of single building blocks into inorganic and organic structures is determined and controlled by noncovalent forces such as electrostatic interactions, π-π interactions, hydrogen bonds, and van der Waals interactions. This review describes the main structures and characteristics of several building blocks used to obtain stable, self-assembling nanostructures tailored for numerous biological applications. Owing to their versatility, biocompatibility, and controllability, these nanostructures find application in diverse fields ranging from drug/gene delivery, theranostics, tissue engineering, and nanoelectronics. Herein, we described the different approaches used to design and functionalize these nanomaterials to obtain selective drug delivery in a specific disease. In particular, the review highlights the efficiency of these supramolecular structures in applications related to infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes. Females have greater immune responses to diverse antigens than males. Klein and colleagues review how signaling through receptors for estrogens, androgens, and progesterone directly regulate immune responses at the transcriptional level to alter the outcomes of diverse diseases ranging from cancers and autoimmunity to infectious diseases. [ABSTRACT FROM AUTHOR]

Different innate immune pathways converge to Stimulator of interferon genes (STING) and trigger type I interferon responses after recognition of abnormal nucleic acids in the cells. This non-redundant function renders STING a major player in immunosurveillance, and an emerging target for cancer and infectious diseases therapeutics. Beyond somatic mutations that often occur in cancer, the human gene encoding STING protein, TMEM173 (STING1), holds great genetic heterogeneity; R232, HAQ (R71H-G230A-R293Q) and H232 are the most common alleles. Although some of these alleles are likely to be hypomorphic, their function is still debated, due to the available functional assessments, which have been performed in biased biological systems. Here, by using genetic background-matched models, we report on the functional evaluation of R232, HAQ and H232 variants on STING function, and on how these genotypes affect the susceptibility to clinically relevant viruses, thus supporting a potential contributing cause to differences in inter-individual responses to infections. Our findings also demonstrate a novel toll-like receptor-independent role of STING in modulating monocytic cell function and differentiation into macrophages. We further supported the interplay of STING1 variants and human biology by demonstrating how monocytes bearing the H232 allele were impaired in M1/M2 differentiation, interferon response and antigen presentation. Finally, we assessed the response to PD-1 inhibitor in a small cohort of melanoma patients stratified according to STING genotype. Given the contribution of the STING protein in sensing DNA viruses, bacterial pathogens and misplaced cancer DNA, these data may support the development of novel therapeutic options for infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Adoptive cell therapy (ACT) is an innovative approach to combat cancer and infectious diseases using specialised immune cells, such as chimeric antigen receptor T-cells (CAR-Ts), tumour-infiltrating lymphocytes (TILs) and virus-specific T-cells (VSTs). Such therapies are manufactured individually for each patient and can be negatively affected by poor cell quality, often impaired by prior treatments, age, and complex manufacturing. To overcome this, this field is assessing the potential of creating cell therapies from "fit" donors to provide off-the-shelf treatment options. Induced pluripotent cells (iPSCs) have renewable characteristics and offer a solution towards off-the-shelf therapy. iPSCs can be used as an unlimited source to derive different immune cells, including natural killer (NK) cells and T-cells. iPSCs can be further genetically modified and used create different ACTs. In this review, we describe the methodologies for generating such cell therapies from iPSCs and discuss the current advances and challenges with a focus on CAR-T/NK-, TIL- and VST-based therapies. Adoptive cell therapy (ACT) has transformed the treatment landscape for cancer and infectious disease through the investigational use of chimeric antigen receptor T-cells (CAR-Ts), tumour-infiltrating lymphocytes (TILs) and viral-specific T-cells (VSTs). Whilst these represent breakthrough treatments, there are subsets of patients who fail to respond to autologous ACT products. This is frequently due to impaired patient T-cell function or "fitness" as a consequence of prior treatments and age, and can be exacerbated by complex manufacturing protocols. Further, the manufacture of autologous, patient-specific products is time-consuming, expensive and non-standardised. Induced pluripotent stem cells (iPSCs) as an allogeneic alternative to patient-specific products can potentially overcome the issues outlined above. iPSC technology provides an unlimited source of rejuvenated iPSC-derived T-cells (T-iPSCs) or natural killer (NK) cells (NK-iPSCs), and in the context of the growing field of allogeneic ACT, iPSCs have enormous potential as a platform for generating off-the-shelf, standardised, "fit" therapeutics for patients. In this review, we evaluate current and future applications of iPSC technology in the CAR-T/NK, TIL and VST space. We discuss current and next-generation iPSC manufacturing protocols, and report on current iPSC-based adoptive therapy clinical trials to elucidate the potential of this technology as the future of ACT. [ABSTRACT FROM AUTHOR]

Emeritus Professor Margaret Baird forged a luminary career for her pioneering research investigating the role of dendritic cells in cancer and infectious diseases, as an inspirational lecturer at the University of Otago and a role model to many. In this article celebrating the 100‐year anniversary of ICB, we discuss Margaret's career and life journey through the eyes of her family and coauthors, as we explore her many publications in ICB and beyond. [ABSTRACT FROM AUTHOR]

Nucleic acid vaccines have shown promising results in the clinic against infectious diseases and cancers. To robustly improve the vaccine efficacy and safety, we developed an approach to increase the intracellular stability of nucleic acids by transiently inhibiting lysosomal function in targeted tissues using sucrose. To achieve efficient and localized delivery of sucrose in animals, we designed a biomimetic lipid nanoparticle (LNP) to target the delivery of sucrose into mouse muscle cells. Using this approach, viral antigen expression in mouse muscle after DNA vaccination was substantially increased and prolonged without inducing local or systemic inflammation or toxicity. The same change in antigen expression would be achieved if the vaccine dose could be increased by 3,000 folds, which is experimentally and clinically impractical due to material restrictions and severe toxicity that will be induced by such a high dose of nucleic acids. The increase in antigen expression augmented the infiltration and activation of antigen-presenting cells, significantly improved vaccine-elicited humoral and T cell responses, and fully protected mice against the viral challenge at a low dose of vaccine. Based on these observations, we conclude that transient inhibition of lysosome function in target tissue by sucrose LNPs is a safe and potent approach to substantially improve nucleic acid-based vaccines. [ABSTRACT FROM AUTHOR]

Immunotherapy using dendritic cell (DC)‐based vaccination is an established approach for treating cancer and infectious diseases; however, its efficacy is limited. Therefore, targeting the restricted migratory capacity of the DCs may enhance their therapeutic efficacy. In this study, the effect of laponite (Lap) on DCs, which can be internalized into lysosomes and induce cytoskeletal reorganization via the lysosomal reprogramming–calcium flicker axis, is evaluated, and it is found that Lap dramatically improves the in vivo homing ability of these DCs to lymphoid tissues. In addition, Lap improves antigen cross‐presentation by DCs and increases DC‐T‐cell synapse formation, resulting in enhanced antigen‐specific CD8+ T‐cell activation. Furthermore, a Lap‐modified cocktail (Lap@cytokine cocktail [C‐C]) is constructed based on the gold standard, C‐C, as an adjuvant for DC vaccines. Lap@C‐C‐adjuvanted DCs initiated a robust cytotoxic T‐cell immune response against hepatitis B infection, resulting in > 99.6% clearance of viral DNA and successful hepatitis B surface antigen seroconversion. These findings highlight the potential value of Lap as a DC vaccine adjuvant that can regulate DC homing, and provide a basis for the development of effective DC vaccines. [ABSTRACT FROM AUTHOR]

Advances in molecular biology have revolutionized the use of messenger RNA (mRNA) as a therapeutic. The concept of nucleic acid therapy with mRNA originated in 1990 when Wolff et al. reported successful expression of proteins in target organs by direct injection of either plasmid DNA or mRNA. It took decades to bring the transfection efficiency of mRNA closer to that of DNA. The next few decades were dedicated to turning in vitro-transcribed (IVT) mRNA from a promising delivery tool for gene therapy into a full-blown therapeutic modality, which changed the biotech market rapidly. Hundreds of clinical trials are currently underway using mRNA for prophylaxis and therapy of infectious diseases and cancers, in regenerative medicine, and genome editing. The potential of IVT mRNA to induce an innate immune response favors its use for vaccination and immunotherapy. Nonetheless, in non-immunotherapy applications, the intrinsic immunostimulatory activity of mRNA directly hinders the desired therapeutic effect since it can seriously impair the target protein expression. Targeting the same innate immune factors can increase the effectiveness of mRNA therapeutics for some indications and decrease it for others, and vice versa. The review aims to present the innate immunity-related 'barriers' or 'springboards' that may affect the development of immunotherapies and non-immunotherapy applications of mRNA medicines. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that plays a critical role in the pathogenesis of SARS-CoV-2 infection. Through the use of ligands engineered for the receptor, ACE2 imaging has emerged as a valuable tool for preclinical and clinical research. These can be used to visualize the expression and distribution of ACE2 in tissues and cells. A variety of techniques including optical, magnetic resonance, and nuclear medicine contrast agents have been developed and employed in the preclinical setting. Positron-emitting radiotracers for highly sensitive and quantitative tomography have also been translated in the context of SARS-CoV-2-infected and control patients. Together this information can be used to better understand the mechanisms of SARS-CoV-2 infection, the potential roles of ACE2 in homeostasis and disease, and to identify potential therapeutic modulators in infectious disease and cancer. This review summarizes the tools and techniques to detect and delineate ACE2 in this rapidly expanding field. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper describes pathological findings in small ruminants with ovine pulmonary adenocarcinoma, a contagious respiratory tumor caused by the jaagsiekte sheep retrovirus. Infection with JSRV leads to the formation of lung tumors, progressive respiratory failure and, ultimately, the death or culling of the affected animals. OPA has traditionally been divided into two forms: classical and atypical. However, in this study, we examined 27 animals with OPA, and found that most of the observed tumors displayed a mix of characteristics from both the classical and the atypical form, and were classified as mixed. Grossly, the lesions were found mostly in the cranial lobes of the lungs, appearing as firm, flat-to-slightly-raised masses that varied in size and color. Histologically, the cases were categorized based on the predominant architectural patterns, with the mixed pattern being the most common. The objective of this study was to provide a detailed description of the gross and microscopic spectrum of ovine pulmonary adenocarcinoma in small ruminants from Spain, focusing on the mixed form. It is important to note that the mixed form of OPA is less frequently reported, and can be mistaken for other concurrent lung diseases. Ovine pulmonary adenocarcinoma (OPA) is a contagious respiratory tumor of small ruminants, manifesting in chronic weight loss and respiratory failure. Infection with the betaretrovirus jaagsiekte sheep retrovirus (JSRV) is the cause of OPA. Here, we describe the gross and microscopic features of twenty-six sheep and one goat with naturally occurring JSRV-associated OPA. All the animals included in this study had pulmonary lesions morphologically consistent with OPA, but the majority of the observed lesions demonstrated features of both the classical and the atypical form of OPA, and were, therefore, classified grossly as mixed. The gross lesions were located mainly in the cranial pulmonary lobes, were multifocal to coalescing, variable in number and size, flat to slightly raised, firm, and white to grey. Histologically, the cases were classified according to the predominant architectural patterns as lepidic, papillary, acinar, or mixed; the mixed histological pattern was the most prevalent. The aim of this study was to describe the gross and microscopic spectrum of OPA in naturally infected small ruminants from Spain. The mixed form of OPA is less commonly reported, and can be confused with other concurrent pulmonary pathologies (such as BALT hyperplasia in SRLV-associated pneumonia or lungworm granulomas). [ABSTRACT FROM AUTHOR]

Natural products, characterized by huge scaffold diversity, complexity, and bioactivity, have long played a crucial role in drug discovery and development, particularly as anticancer and anti-infective agents. The development of drug resistance is the biggest threat to the successful treatment of cancer and infectious diseases. Furthermore, cancer cells frequently exhibit cross-resistance to a variety of anticancer drugs that are not structurally related, which is termed the multidrug resistance (MDR) phenomenon and is the main cause of cancer relapse and cancer-related death. Despite the great enhancement of cancer treatment in recent decades, chemotherapy is still the standard cancer treatment. [Extracted from the article]

The Golgi membrane protein GOLM1/GP73/GOLPH2 has been found to impact cytokine production in both infectious disease and cancer. In viral infections, GOLM1 levels are increased, and this lowers the production of type I interferons and other inflammatory cytokines. However, elevated GOLM1 expression levels due to mutations are linked to a higher production of interleukin (IL)‐6 during Candida infections, potentially explaining an increased susceptibility to candidemia in individuals carrying these mutations. In cancer, the protease Furin produces a soluble form of GOLM1 that has oncogenic properties by promoting the production of the chemokine CCL2 and suppressing the production of inflammatory cytokines such as IL‐12 and interferon gamma. This review will focus on the role of GOLM1 in cytokine production, highlighting how it can both promote and inhibit cytokine production. It is crucial to understand this in order to effectively target GOLM1 for therapeutic purposes in diseases associated with abnormal cytokine production, including cancer and infectious disease. [ABSTRACT FROM AUTHOR]

Avian leukosis (AL), caused by avian leukosis virus (ALV), is a contagious tumor disease that results in significant economic losses for the poultry industry. Currently, ALV-A, B, J, and K subgroups are the most common in commercial poultry and cause possible coinfections. Therefore, close monitoring is necessary to avoid greater economic losses. In this study, a novel multiplex quantitative polymerase chain reaction (qPCR) assay was developed to detect ALV-A, ALV-B, ALV-J, and ALV-K with limits of detection of 40, 11, 13.7, and 96 copies/µL, respectively, and no cross-reactivity with other ALV subtypes and avian pathogens. We detected 852 cell cultures inoculated with clinical samples using this method, showing good consistency with conventional PCR and ELISA. The most prevalent ALV strain in Hubei Province, China, was still ALV-J (11.74%). Although single infections with ALV-A, ALV-B, and ALV-K were not found, coinfections with different subgroup strains were identified: 0.7% for ALV-A/J, 0.35% for ALV-B/J, 0.25% for ALV-J/K, and 0.12% for ALV-A/B/K and ALV-A/B/J. Therefore, our novel multiplex qPCR may be a useful tool for molecular epidemiology, clinical detection of ALV, and ALV eradication programs. [ABSTRACT FROM AUTHOR]

Since mice do not express a homologue of the human Fc alpha receptor (FcαRI or CD89), a transgenic mouse model was generated in four different backgrounds (C57BL/6, BALB/c, SCID and NXG) expressing the FcαRI under the endogenous human promoter. In this study, we describe previously unknown characteristics of this model, such as the integration site of the FCAR gene, the CD89 expression pattern in healthy male and female mice and in tumor-bearing mice, expression of myeloid activation markers and FcγRs and IgA/CD89-mediated tumor killing capacity. In all mouse strains, CD89 expression is highest in neutrophils, intermediate on other myeloid cells such as eosinophils and DC subsets and inducible on, among others, monocytes, macrophages and Kupffer cells. CD89 expression levels are highest in BALB/c and SCID, lower in C57BL/6 and lowest in NXG mice. Additionally, CD89 expression on myeloid cells is increased in tumor-bearing mice across all mouse strains. Using Targeted Locus Amplification, we determined that the hCD89 transgene has integrated in chromosome 4. Furthermore, we established that wildtype and hCD89 transgenic mice have a similar composition and phenotype of immune cells. Finally, IgA-mediated killing of tumor cells is most potent with neutrophils from BALB/c and C57BL/6 and less with neutrophils from SCID and NXG mice. However, when effector cells from whole blood are used, SCID and BALB/c are most efficient, since these strains have a much higher number of neutrophils. Overall, hCD89 transgenic mice provide a very powerful model to test the efficacy of IgA immunotherapy against infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Background: The neutrophil to lymphocyte*platelet ratio (NLPR) is a new index based on platelets, neutrophils, and lymphocytes associated with the prognosis of patients with infectious diseases and cancer. However, its use in acute ischemic stroke has rarely been reported. This study examined the relationship between levels of systemic immunoinflammatory indices at admission and patient outcomes at different times after onset to assess stroke prognosis by NLPR. Methods: This was a retrospective cohort study. The data from 1222 stroke patients were obtained from multi-parameter intelligent monitoring in the Intensive Care III database(MIMIC- III). Cox proportional risk model was conducted to evaluate the relation between NLPR, all-cause mortality, and ischemic. The results were further verified via a subgroup analysis. Results: After adjusting for multiple covariates, it was found that NLPR was related with all-cause mortality in stroke patients. High NLPR was accompanied by an increase in mortality with longer follow-up (30 days: HR = 1.52, 95% CI = 1.14–2.02,90 days: HR = 1.67, 95% CI = 1.29–2.16, 365 days: HR = 1.56, 95% CI = 1.24–1.96 and 2 years: HR = 1.52, 95% CI = 1.22–1.89). Conclusion: The neutrophil to lymphocyte*platelet ratio (NLPR) are related to long-term adverse outcomes in patients with acute ischemic stroke. Therefore, NLPR is a promising inflammatory index for predicting the long-term prognosis of stroke. [ABSTRACT FROM AUTHOR]

Vaccines comprising innovative adjuvants are rapidly reaching advanced translational stages, such as the authorized nanotechnology adjuvants in mRNA vaccines against COVID-19 worldwide, offering new strategies to effectively combat diseases threatening human health. Adjuvants are vital ingredients in vaccines, which can augment the degree, extensiveness, and longevity of antigen specific immune response. The advances in the modulation of physicochemical properties of nanoplatforms elevate the capability of adjuvants in initiating the innate immune system and adaptive immunity, offering immense potential for developing vaccines against hard-to-target infectious diseases and cancer. In this review, we provide an essential introduction of the basic principles of prophylactic and therapeutic vaccination, key roles of adjuvants in augmenting and shaping immunity to achieve desired outcomes and effectiveness, and the physiochemical properties and action mechanisms of clinically approved adjuvants for humans. We particularly focus on the preclinical and clinical progress of highly immunogenic emerging nanotechnology adjuvants formulated in vaccines for cancer treatment or infectious disease prevention. We deliberate on how the immune system can sense and respond to the physicochemical cues (e.g., chirality, deformability, solubility, topology, and chemical structures) of nanotechnology adjuvants incorporated in the vaccines. Finally, we propose possible strategies to accelerate the clinical implementation of nanotechnology adjuvanted vaccines, such as in-depth elucidation of nano-immuno interactions, antigen identification and optimization by the deployment of high-dimensional multiomics analysis approaches, encouraging close collaborations among scientists from different scientific disciplines and aggressive exploration of novel nanotechnologies. [ABSTRACT FROM AUTHOR]