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Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immunerelated genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as the fourth leading cause of cancer-related deaths in the United States, marked by challenging treatment and dismal prognoses. As immunotherapy emerges as a promising avenue for mitigating PDAC's malignant progression, a comprehensive understanding of the tumor's immunosuppressive characteristics becomes imperative. This paper systematically delves into the intricate immunosuppressive network within PDAC, spotlighting the significant crosstalk between immunosuppressive cells and factors in the hypoxic acidic pancreatic tumor microenvironment. By elucidating these mechanisms, we aim to provide insights into potential immunotherapy strategies and treatment targets, laying the groundwork for future studies on PDAC immunosuppression. Recognizing the profound impact of immunosuppression on PDAC invasion and metastasis, this discussion aims to catalyze the development of more effective and targeted immunotherapies for PDAC patients. [ABSTRACT FROM AUTHOR]

Recurrent miscarriage, poses a significant challenge for many couples globally, the causes of which are not fully understood. Recent studies have shown the intricate link between uterine inflammation and recurrent miscarriages. While inflammation is essential during early pregnancy stages, especially in embryo implantation, an imbalance can lead to miscarriage. Key inflammatory mediators and an imbalance in immune cells can significantly alter and contribute to recurrent miscarriages. Lifestyle factors like smoking and obesity exacerbate inflammatory responses, increasing miscarriage risks. Understanding the interaction between the uterine environment, immune cell imbalances, and recurrent miscarriages is essential for devising effective treatments. This paper presents the latest data on inflammation's role in recurrent miscarriage, emphasizing the significance of diagnosing chronic endometritis and immune imbalances, offering practical recommendations for treatment and diagnosis. [ABSTRACT FROM AUTHOR]

This document is an editorial published in Frontiers in Immunology titled "Interdependencies and interfaces in bone regeneration - the immune status at its core." The editorial discusses the importance of understanding the immune reaction in bone healing and regeneration. It highlights the interdependencies and interfaces between the immune system and other factors such as mechanics, metabolism, revascularization, and aging. The editorial also mentions that this Research Topic includes nine papers from authors around the world, covering various aspects of bone regeneration. [Extracted from the article]

Hematopoietic stem cells (HSCs) undergo self-renewal and differentiation in the bone marrow, which is tightly regulated by cues from the microenvironment. The gut microbiota, a dynamic community residing on the mucosal surface of vertebrates, plays a crucial role in maintaining host health. Recent evidence suggests that the gut microbiota influences HSCs differentiation by modulating the bone marrow microenvironment through microbial products. This paper comprehensively analyzes the impact of the gut microbiota on hematopoiesis and its effect on HSCs fate and differentiation by modifying the bone marrow microenvironment, including mechanical properties, inflammatory signals, bone marrow stromal cells, and metabolites. Furthermore, we discuss the involvement of the gut microbiota in the development of hematologic malignancies, such as leukemia, multiple myeloma, and lymphoma. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) produces some of the most malignant tumors in the world, with high morbidity and mortality. Tumor immune microenvironment (TIME), a component of the tumor microenvironment (TME), are critical in tumor development, immune escape, and drug resistance. The TIME is composed of various immune cells, immune cytokines, etc, which are important biological characteristics and determinants of tumor progression and outcomes. In this paper, we reviewed the recently published literature and discussed the potential uses of natural products in regulating TIME. We observed that a total of 37 natural compounds have been reported to exert anti-cancer effects by targeting the TIME. In different classes of natural products, terpenoids are the most frequently mentioned compounds. TAMs are one of the most investigated immune cells about therapies with natural products in TIME, with 9 natural products acting through it. 17 natural products exhibit anti-cancer properties in LC by modulating PD-1 and PD-L1 protein activity. These natural products have been extensively evaluated in animal and cellular LC models, but their clinical trials in LC patients are lacking. Based on the current review, we have revealed that the mechanisms of LC can be treated with natural products through TIME intervention, resulting in a new perspective and potential therapeutic drugs. [ABSTRACT FROM AUTHOR]

Is it possible to have an available vaccine that eradicates cancer? Starting from this question, this article tries to verify the state of the art, proposing a different approach to the issue. The variety of cancers and different and often unknown causes of cancer impede, except in some cited cases, the creation of a classical vaccine directed at the causative agent. The efforts of the scientific community are oriented toward stimulating the immune systems of patients, thereby preventing immune evasion, and heightening chemotherapeutic agents effects against cancer. However, the results are not decisive, because without any warning signs, metastasis often occurs. The purpose of this paper is to elaborate on a vaccine that must be administered to a patient in order to prevent metastasis; metastasis is an event that leads to death, and thus, preventing it could transform cancer into a chronic disease. We underline the fact that the field has not been studied in depth, and that the complexity of metastatic processes should not be underestimated. Then, with the aim of identifying the target of a cancer vaccine, we draw attention to the presence of the paradoxical actions of different mechanisms, pathways, molecules, and immune and non-immune cells characteristic of the tumor microenvironment at the primary site and pre-metastatic niche in order to exclude possible vaccine candidates that have opposite effects/behaviors; after a meticulous evaluation, we propose possible targets to develop a metastasis-targeting vaccine. We conclude that a change in the current concept of a cancer vaccine is needed, and the efforts of the scientific community should be redirected toward a metastasis-targeting vaccine, with the increasing hope of eradicating cancer. [ABSTRACT FROM AUTHOR]

Fish, comprising over 27,000 species, represent the oldest vertebrate group and possess both innate and adaptive immune systems. The susceptibility of most wild fish to parasitic infections and related diseases is well-established. Among all vertebrates, the digestive tract creates a remarkably favorable and nutrient-rich environment, which, in turn, renders it susceptible to microparasites and macroparasites. Consequently, metazoan parasites emerge as important disease agents, impacting both wild and farmed fish and resulting in substantial economic losses. Given their status as pathogenic organisms, these parasites warrant considerable attention. Helminths, a general term encompassing worms, constitute one of the most important groups of metazoan parasites in fish. This group includes various species of platyhelminthes (digeneans, cestodes), nematodes, and acanthocephalans. In addition, myxozoans, microscopic metazoan endoparasites, are found in water-dwelling invertebrates and vertebrate hosts. It is worth noting that several innate immune cells within the fish alimentary canal and certain visceral organs (e.g., liver, spleen, and gonads) play active roles in the immune response against parasites. These immune cells include macrophages, neutrophils, rodlet cells, and mast cells also known as eosinophilic granular cells. At the site of intestinal infection, helminths often impact mucous cells number and alter mucus composition. This paper presents an overview of the state of the art on the occurrence and characteristics of innate immune cells in the digestive tract and other visceral organs in different fishparasite systems. The data, coming especially from studies employed immunohistochemical, histopathological, and ultrastructural analyses, provide evidence supporting the involvement of teleost innate immune cells in modulating inflammatory responses to metazoan and protozoan parasitic infections. [ABSTRACT FROM AUTHOR]

Cholestasis is a common clinical event in which bile formation and excretion are blocked, leading to retention of bile acids or bile salts; whether it occurs intra- or extrahepatically, primary or secondary, its pathogenesis is still unclear and is influenced by a combination of factors. In a variety of inflammatory and immune cells such as neutrophils, macrophages (intrahepatic macrophages are also known as Kupffer cells), mast cells, NK cells, and even T cells in humoral immunity and B cells in cellular immunity, inflammation can be a "second strike" against cholestatic liver injury. These cells, stimulated by a variety of factors such as bile acids, inflammatory chemokines, and complement, can be activated and accumulate in the cholestatic liver, and with the involvement of inflammatory mediators and modulation by cytokines, can lead to destruction of hepatocytes and bile duct epithelial cells and exacerbate (and occasionally retard) the progression of cholestatic liver disease. In this paper, we summarized the new research advances proposed so far regarding the relationship between inflammation and cholestasis, aiming to provide reference for researchers and clinicians in the field of cholestatic liver injury research. [ABSTRACT FROM AUTHOR]

The use of reactive oxygen species (ROS) to target cancer cells has become a hot topic in tumor therapy. Although ROS has strong cytotoxicity against tumor cells, the key issue currently is how to generate a large amount of ROS within tumor cells. Organic/inorganic hybrid nanoreactor materials combine the advantages of organic and inorganic components and can amplify cancer treatment by increasing targeting and material self-action. The multifunctional organic / inorganic hybrid nanoreactor is helpful to overcome the shortcomings of current reactive oxygen species in cancer treatment. It can realize the combination of in situ dynamic therapy and immunotherapy strategies, and has a synergistic anti-tumor effect. This paper reviews the research progress of organic/inorganic hybrid nanoreactor materials using tumor components to amplify reactive oxygen species for cancer treatment. The article reviews the tumor treatment strategies of nanohybrids from the perspectives of cancer cells, immune cells, tumor microenvironment, as well as 3D printing and electrospinning techniques, which are different from traditional nanomaterial technologies, and will arouse interest among scientists in tumor therapy and nanomedicine. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic reprogramming in immune cells is diverse and distinctive in terms of complexity and flexibility in response to heterogeneous pathogenic stimuli. We studied the carbohydrate metabolic changes in immune cells in different types of infectious diseases. This could help build reasonable strategies when understanding the diagnostics, prognostics, and biological relevance of immune cells under alternative metabolic burdens. Methods: Search and analysis were conducted on published peer-reviewed papers on immune cell metabolism of a single pathogen infection from the four known types (bacteria, fungi, parasites, and viruses). Out of the 131 selected papers based on the PIC algorithm (pathogen type/immune cell/carbohydrate metabolism), 30 explored immune cell metabolic changes in well-studied bacterial infections, 17 were on fungal infections of known medical importance, and 12 and 57 were on parasitic and viral infections, respectively. Results and Discussion: While carbohydrate metabolism in immune cells is signaled by glycolytic shift during a bacterial or viral infection, it is widely evident that effector surface proteins are expressed on the surface of parasites and fungi to modulate metabolism in these cells. Conclusions: Carbohydrate metabolism in immune cells can be categorized according to the pathogen or the disease type. Accordingly, this classification can be used to adopt new strategies in disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Cancer, the most deadly disease, is known as a recent dilemma worldwide. Presently different treatments are used for curing cancers, especially solid cancers. Because of the immune-enhancing functions of cytokine, IL-21 as a cytokine may have new possibilities to manipulate the immune system in disease conditions, as it stimulates NK and CTL functions and drives IgG antibody production. Indeed, IL-21 has been revealed to elicit antitumor-immune responses in several tumor models. Combining IL-21 with other agents, which target tumor cells, immune-regulatory circuits, or other immune-enhancing molecules enhances this activity. The exciting breakthrough in the results obtained in pre-clinical situations has led to the early outset of present developing clinical trials in cancer patients. In the paper, we have reviewed the function of IL-21 in solid tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Dietary plant polysaccharides, one of the main sources of natural polysaccharides, possess significant cancer prevention activity and potential development value in the food and medicine fields. The anti-tumor mechanisms of plant polysaccharides are mainly elaborated from three perspectives: enhancing immunoregulation, inhibiting tumor cell growth and inhibiting tumor cell invasion and metastasis. The immune system plays a key role in cancer progression, and immunomodulation is considered a significant pathway for cancer prevention or treatment. Although much progress has been made in revealing the relationship between the cancer prevention activity of polysaccharides and immunoregulation, huge challenges are still met in the research and development of polysaccharides. Results suggest that certain polysaccharide types and glycosidic linkage forms significantly affect the biological activity of polysaccharides in immunoregulation. At present, the in vitro anti-tumor effects and immunoregulation of dietary polysaccharides are widely reported in articles; however, the anti-tumor effects and in vivo immunoregulation of dietary polysaccharides are still deserving of further investigation. In this paper, aspects of the mechanisms behind dietary polysaccharides' cancer prevention activity achieved through immunoregulation, the role of immune cells in cancer progression, the role of the mediatory relationship between the gut microbiota and dietary polysaccharides in immunoregulation and cancer prevention are systematically summarized, with the aim of encouraging future research on the use of dietary polysaccharides for cancer prevention. [ABSTRACT FROM AUTHOR]

Wenshe Sun,1– 3,* Shaowei Xie,4,* Shi Feng Liu,1,* Xiaokun Hu,1 Dongming Xing1,2 1The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China; 2Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, People’s Republic of China; 3Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 4Department of Ultrasound, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaokun Hu; Dongming Xing, The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China, Email huxiaokun770@163.com; xdm_tsinghua@163.comAbstract: Typical physiological characteristics of tumors, such as weak acidity, low oxygen content, and upregulation of certain enzymes in the tumor microenvironment (TME), provide survival advantages when exposed to targeted attacks by drugs and responsive nanomedicines. Consequently, cancer treatment has significantly progressed in recent years. However, the evolution and adaptation of tumor characteristics still pose many challenges for current treatment methods. Therefore, efficient and precise cancer treatments require an understanding of the heterogeneity degree of various factors in cancer cells during tumor evolution to exploit the typical TME characteristics and manage the mutation process. The highly heterogeneous tumor and infiltrating stromal cells, immune cells, and extracellular components collectively form a unique TME, which plays a crucial role in tumor malignancy, including proliferation, invasion, metastasis, and immune escape. Therefore, the development of new treatment methods that can adapt to the evolutionary characteristics of tumors has become an intense focus in current cancer treatment research. This paper explores the latest understanding of cancer evolution, focusing on how tumors use new antigens to shape their “new faces”; how immune system cells, such as cytotoxic T cells, regulatory T cells, macrophages, and natural killer cells, help tumors become “invisible”, that is, immune escape; whether the diverse cancer-associated fibroblasts provide support and coordination for tumors; and whether it is possible to attack tumors in reverse. This paper discusses the limitations of targeted therapy driven by tumor evolution factors and explores future strategies and the potential of intelligent nanomedicines, including the systematic coordination of tumor evolution factors and adaptive methods, to meet this therapeutic challenge.Keywords: smart nanomedicine, tumor evolution, immune cells, fibroblasts

Despite recent advances in the mathematical modeling of biological processes and real-world situations raised in the day-to-day life phase, some phenomena such as immune cell populations remain poorly understood. The mathematical modeling of complex phenomena such as immune cell populations using nonlinear differential equations seems to be a quite promising and appropriate tool to model such complex and nonlinear phenomena. Fractional differential equations have recently gained a significant deal of attention and demonstrated their relevance in modeling real phenomena rather than their counterpart, classical (integer) derivative differential equations. We report in this paper a mathematical approach susceptible to answering some relevant questions regarding the side effects of ionizing radiation (IR) on DNA with a particular focus on double-strand breaks (DSBs), leading to the destruction of the cell population. A theoretical elucidation of the population memory was carried out within the framework of fractional differential equations (FODEs). Using FODEs, the mathematical approach presented herein ensures connections between fractional calculus and the nonlocal feature of the fractional order of immune cell populations by taking into account the memory trace and genetic qualities that are capable of integrating all previous actions and considering the system's long-term history. An illustration of both fractional modeling, which provides an excellent framework for the description of memory and hereditary properties of immune cell populations, is elucidated. The mathematics presented in this research hold promise for modeling real-life phenomena and paves the way for obtaining accurate model parameters resulting from the mathematical modeling. Finally, the numerical simulations are conducted for the analytical approach presented herein to elucidate the effect of various parameters that govern the influence of ionizing irradiation on DNA in immune cell populations as well as the evolution of cell population dynamics, and the results are presented using plots and contrasted with previous theoretical findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors are not masses of cancer cells alone but made up of cancer cells, other cells including fibroblasts, macrophages, endothelial cells, as well as secreted factors, blood vessels and the extracellular matrix (ECM). This comprehensive review presents new findings on the role of each component of the tumor cell surroundings and the effect on the success of cancer drugs. We show in this paper that the tumor cell's surroundings are not simply 'bystanders' but are actively involved in tumor growth and can cause resistance to treatment. Initially, cells and ECM around tumor cells do not promote their growth but over time, tumor cells 'convert' their surroundings to promote their growth. An increase in tumor size means tumor cells must overcome a lack of oxygen and nutrients, be able to remove waste and form secondary tumors. A better knowledge of tumor cells and their surrounding means better drugs for tumor cells and their surroundings. Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation. [ABSTRACT FROM AUTHOR]

The existence of malignant tumors has been a threat to human life, health, and safety. Although the rapid development of radiotherapy, drug therapy, surgery, and local therapy has improved the quality of life of tumor patients, there are still somerisks. Natural compounds arewidely usedincancerbecause they are easy to obtain, have a good curative effects and have no obvious side effects, and play a vital role in the prevention and treatment of various cancers. Phenolic, flavonoids, terpenoids, alkaloids, and other natural components of traditional Chinese medicine have certain anti-tumor activities, which can promote apoptosis, antiproliferation, anti-metastasis, inhibit angiogenesis, change the morphology of cancer cells and regulate immune function, etc., and have positive effects on breast cancer, liver cancer, lungcancer, gastric cancer, rectal cancer andsoon. To better understand the effects of natural compounds on cancer, this paper screened out four important pathways closely related to cancer, including cell deathandimmunogenic celldeath, immunecells in the tumormicroenvironment, inflammation and related pathways and tumor metastasis, and systematically elaborated the effects of natural compounds on cancer. [ABSTRACT FROM AUTHOR]

WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met) is a synthetic hexapeptide identified as a potent agonist of FPRs. FPRs are widely expressed on the cell membrane of immune cells. Therefore, WKYMVm participates in the regulation of immune cells by activating FPRs, and plays a therapeutic role in infections, tumors, autoimmune diseases and so on. WKYMVm can promote the chemotactic migration, increase the bactericidal activity of neutrophils and monocytes. WKYMVm also regulates the number and polarization of macrophages, affects the maturation of DCs and the differentiation of T cells, and promotes the activation and chemotaxis of NK cells. These functions make WKYMVm a candidate drug for immunotherapy. In this paper, we summarize the regulatory effects and underlying mechanisms of WKYMVm on six immune cells (neutrophils, monocytes, macrophages, DCs, T cells and NK cells) to increase comprehensive understanding and promote further research on WKYMVm. [ABSTRACT FROM AUTHOR]

Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR‐T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR‐T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR‐T cell therapy, and considers future outlooks for research development. Significance statement: The necessity and importance of chimeric antigen receptor (CAR) T cells and their therapeutic efficiency in treating diseases other than cancer, mainly cardiovascular diseases, have emerged in recent years. However, there is still room for advancement in the current models of CAR‐T cell therapy. This paper highlights the evolution and roadblocks of CAR‐T technology at different levels, from technical concerns to clinical outcomes, in an attempt to improve the therapeutic efficiency of CAR‐T cell therapy in this area. [ABSTRACT FROM AUTHOR]

Metabolic heterogeneity is one of the characteristics of tumour cells. In order to adapt to the tumour microenvironment of hypoxia, acidity and nutritional deficiency, tumour cells have undergone extensive metabolic reprogramming. Metabolites involved in tumour cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumour microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumour cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumour cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarised, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumour metabolites caused by tumour metabolic remodelling not only changes the energy and material supply of tumour, but also participates in the regulation of tumour-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumour cells. Regulating the availability of local metabolites is a new aspect that affects tumour progress. (The graphical abstract is by Figdraw). Metabolic heterogeneity is one of the important characteristics of tumour cells, and the metabolites of tumour cells are very different from those of normal cells. Lactate, fatty acids, glutamine, arginine, tryptophan and adenosine are all important metabolites in tumour metabolism. Nano-medicines are used to regulate tumour metabolites, affecting the energy and material supply of tumour cells, thus achieving therapeutic effects. [ABSTRACT FROM AUTHOR]

The use of extracellular vesicle (EV)-based vaccines is a strategically promising way to prevent cancer metastasis. The effective roles of immune cell-derived EVs have been well understood in the literature. In the present paper, we focus on cancer cell-derived EVs to enforce, more thoroughly, the use of EV-based vaccines against unexpected malignant cells that might appear in poor prognostic patients. As a model of such a cancer cell with high malignancy, Nanog-overexpressing melanoma cell lines were developed. As expected, Nanog overexpression enhanced the metastatic potential of melanomas. Against our expectations, a fantastic finding was obtained that determined that EVs derived from Nanog-overexpressing melanomas exhibited a metastasis-suppressive effect. This is considered to be a novel role for Nanog in regulating the property of cancer cell-derived EVs. Stimulated by this result, the review of Nanog's roles in various cancer cells and their EVs has been updated once again. Although there was no other case presenting a similar contribution by Nanog, only one case suggested that NANOG and SOX might be better prognosis markers in head and neck squamous cell carcinomas. This review clarifies the varieties of Nanog-dependent phenomena and the relevant signaling factors. The information summarized in this study is, thus, suggestive enough to generate novel ideas for the construction of an EV-based versatile vaccine platform against cancer metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a high degree of immune tolerance. Galectins induce induction of immune evasion behavior in tumor cells. Galectins each play a role in promoting PDAC progression during PDAC immune evasion by coordinating the function and number of immune cells, especially galectin-1. In this paper. we review the involvement of galectins in the construction of PDAC privileged zones by regulating relevant immune cells, establishing fibrotic barriers, and promoting cellular metabolism. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is highly immune tolerant. Although there is immune cell infiltration in PDAC tissues, most of the immune cells do not function properly and, therefore, the prognosis of PDAC is very poor. Galectins are carbohydrate-binding proteins that are intimately involved in the proliferation and metastasis of tumor cells and, in particular, play a crucial role in the immune evasion of tumor cells. Galectins induce abnormal functions and reduce numbers of tumor-associated macrophages (TAM), natural killer cells (NK), T cells and B cells. It further promotes fibrosis of tissues surrounding PDAC, enhances local cellular metabolism, and ultimately constructs tumor immune privileged areas to induce immune evasion behavior of tumor cells. Here, we summarize the respective mechanisms of action played by different Galectins in the process of immune escape from PDAC, focusing on the mechanism of action of Galectin-1. Galectins cause imbalance between tumor immunity and anti-tumor immunity by coordinating the function and number of immune cells, which leads to the development and progression of PDAC. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a global health problem with increasing prevalence and association with an enormous medical and socioeconomic burden. New recognition of immune cells such as type 2 innate lymphocytes (ILC2s), T helper (Th2) 2 cells, follicular helper T cells, follicular regulatory T cells, regulatory T cells, B cells, dendritic cells, and epithelial cells in AR pathogenesis has been updated in this review paper. An in‐depth understanding of the mechanisms underlying AR will aid the identification of biomarkers associated with disease and ultimately provide valuable parameters critical to guide personalized targeted therapy. As the only etiological treatment option for AR, allergen‐specific immunotherapy (AIT) has attracted increasing attention, with evidence for effectiveness of AIT recently demonstrated in several randomized controlled trials and long‐term real‐life studies. The exploration of biologics as therapeutic options has only involved anti‐IgE and anti‐type 2 inflammatory agents; however, the cost‐effectiveness of these agents remains to be elucidated precisely. In the midst of the currently on‐going COVID‐19 pandemic, a global life‐threatening disease, although some studies have indicated that AR is not a risk factor for severity and mortality of COVID‐19, this needs to be confirmed in multi‐centre, real‐life studies of AR patients from different parts of the world. [ABSTRACT FROM AUTHOR]

The prevalence of obesity has increased alarmingly both worldwide and in Korea. This has also dramatically increased the prevalence of chronic obesity-associated diseases, including type 2 diabetes (T2D). Extensive studies on the molecular etiology of T2D have revealed several potential mechanisms by which obesity induces the development of insulin resistance and T2D. One of these is low-grade chronic inflammation. Studies hinting at the existence of this phenomenon were first published about 30 years ago. Ten years later, several seminal papers confirmed its existence, which then led to a rapid and massive escalation of research in this field. Today, the notion that obesity-induced inflammation mediates T2D is now well-accepted. This paper will review the key developments in this field, including the discovery that obesity-induced inflammation and insulin resistance is mainly regulated by adipose tissue-resident immune cells, particularly those in visceral adipose tissue. This review further details the research areas, including (1) the obesity-related factors that induce adipose tissue macrophage (ATM) inflammation, (2) the precise effector functions by which adipose tissue immune cells promote insulin resistance, (3) whether there are early immunological events that have an outsize effect on later events and could be targeted to arrest the development of insulin resistance, (4) the roles played by nonimmunological functions of ATMs and other immune cells, and (5) whether there are noncanonical immune responses to obesity (i.e., immune responses that are unique to obesity and cannot be detected by following the discoveries in the classical immunity field). [ABSTRACT FROM AUTHOR]

In this paper, we will investigate the effect of diffusion, which is ubiquitous in nature, on the immune system using a reaction-diffusion model in order to understand the dynamical behavior of complex patterns and control the dynamics of different patterns. Through control theory and linear stability analysis of local equilibrium, we obtain the optimal condition under which the system loses stability and a Turing pattern occurs. By combining mathematical analysis and numerical simulation, we show the possible patterns and how these patterns evolve. In addition, we establish a bridge between the complex patterns and the biological mechanism using the results from a previous study in Nature Cell Biology. The results in this paper can help us better understand the biological significance of the immune system. [ABSTRACT FROM AUTHOR]

Sepsis is an unsolved clinical condition with a substantial mortality rate in the hospital. Despite decades of research, no effective treatments for sepsis exists. The role of adenosine in the pathogenesis of sepsis is discussed in this paper. Adenosine is an essential endogenous molecule that activates the A1, A2a, A2b, and A3 adenosine receptors to regulate tissue function. These receptors are found on a wide range of immune cells and bind adenosine, which helps to control the immune response to inflammation. The adenosine receptors have many regulatory activities that determine the onset and progression of the disease, which have been discovered via the use of animal models. A greater understanding of the role of adenosine in modulating the immune system has sparked hope that an adenosine receptor-targeted treatment may be used one day to treat sepsis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the third most common malignant neoplasm of the hematological system. It often develops from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precursor states. In this process, the immune microenvironment interacts with the MM cells to exert yin and yang effects, promoting tumor progression on the one hand and inhibiting it on the other. Despite significant therapeutic advances, MM remains incurable, and the main reason for this may be related to the complex and variable immune microenvironment. Therefore, it is crucial to investigate the dynamic relationship between the immune microenvironment and tumors, to elucidate the molecular mechanisms of different factors in the microenvironment, and to develop novel therapeutic agents targeting the immune microenvironment of MM. In this paper, we review the latest research progress and describe the dual influences of the immune microenvironment on the development and progression of MM from the perspective of immune cells and molecules. [ABSTRACT FROM AUTHOR]

Current treatments for hepatocellular carcinoma (HCC) are less effective and prone to recurrence after surgery, so it's needed to seek new ideas for its therapy. Tumour immune microenvironment (TME) is crucial for the pathogenesis, development and metastasis of HCC. Interactions between immune cells and tumour cells significantly impact responses to immunotherapies and patient prognosis. In recent years, immunotherapies for HCC have shown promising potential, but the response rate is still unsatisfactory. Understanding their cross‐talks is helpful for selecting potential therapeutic targets, predicting immunotherapy responses, determining immunotherapy efficacy, identifying prognostic markers and selecting individualized treatment options. In this paper, we reviewed the research advances on the roles of immune cells and multi‐omic research associated with HCC pathogenesis and therapy, and future perspectives on TME. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction caused by the host's malfunctioning response to infection. Due to its high mortality rate and medical cost, sepsis remains one of the world's most intractable diseases. In the early stage of sepsis, the over-activated immune system and a cascade of inflammation are usually accompanied by immunosuppression. The core pathogenesis of sepsis is the maladjustment of the host's innate and adaptive immune response. Many immune cells are involved in this process, including neutrophils, mononuclear/macrophages and lymphocytes. The immune cells recognize pathogens, devour pathogens and release cytokines to recruit or activate other cells in direct or indirect manner. Pyroptosis, immune cell-extracellular traps formation and autophagy are several novel forms of cell death that are different from apoptosis, which play essential roles in the progress of sepsis. Immune cells can initiate "self-sacrifice" through the above three forms of cell death to protect or kill pathogens. However, the exact roles and mechanisms of the self-sacrifice in the immune cells in sepsis are not fully elucidated. This paper mainly analyzes the self-sacrifice of several representative immune cells in the forms of pyroptosis, immune cell-extracellular traps formation and autophagy to reveal the specific roles they play in the occurrence and progression of sepsis, also to provide inspiration and references for further investigation of the roles and mechanisms of self-sacrifice of immune cells in the sepsis in the future, meanwhile, through this work, we hope to bring inspiration to clinical work. [ABSTRACT FROM AUTHOR]

Pattern formation is very broad in nature, and understanding the causes of its generation has greatly advanced over the past decades. In this paper, we investigate Turing pattern formation in a cancer-immune cells interaction which is spatially distributed. We derived conditions under which Turing patterns emerged due to diffusion-driven instability. Numerical results revealed the formation of isolated groups such as spotted and stripe-like patterns due to the cells interaction. Furthermore, the results have shown that the model exhibited patterns due to cross-diffusion. [ABSTRACT FROM AUTHOR]

This paper focuses on the analysis of the activity of immune cells for supporting medical workers. Recognition frequency space selects a region including neighboring multiple cells as a single cell is one of the major issues in activity analysis of immune cells. This study focuses on the locality of immune cell features and uses a high-velocity weighting method for the analysis while the Gaussian distribution is used in the literature. The analysis was conducted for a few well-known methods such as final feature maps, class activation mapping (CAM), gradient weighted class activation mapping (Grad-CAM), Grad-CAM++, and Eigen-CAM. The results show that the densely inhabited immune cells are correctly selected by CAM, Grad-CAM, Grad-CAM++, and Eigen-CAM. These algorithms also show stability with respect to the threshold used to select tracking targets. In addition, the higher threshold makes the selection robust, and the lower one is useful for analyzing tends of multiple cells in a whole frame efficiently. [ABSTRACT FROM AUTHOR]

Compared with the traditional forms of cell death—apoptosis, necrosis and autophagy, ferroptosis is a novel form of iron-dependent programmed cell death forms which is different from the above traditional forms of cell death. Brent R Stockwell, a Professor of Columbia University, firstly proposed that this from of cell death was named ferroptosis in 2012. The main characteristics of ferroptosis is increasing iron loading and driving a lot of lipid peroxide generated and ultimately lead to cell death. In this paper, the mechanism of ferroptosis, relationship between ferroptosis and common diseases and immune state of body are reviewed, and the inhibitors and inducers related to ferroptosis that have been found are summarized to provide medicine exploration targeted of ferroptosis and reference for the research in the future. [ABSTRACT FROM AUTHOR]

This paper deals with the modeling of the immune system response to cancer cells. A mathematical model is proposed for a large system of interacting cells, by means of the mathematical methods of the kinetic theory for active particles. The first part of the paper deals with the assessment of the mathematical framework suitable for the derivation of specific models. Then a qualitative analysis is carried out to prove the existence of the solutions of the Cauchy problem related to the model. Some simulations visualize the applicability of the model to the description of biological events characterizing the immune competition. [ABSTRACT FROM AUTHOR]

In epidemiology, gerontology, human development and the social sciences, age-period-cohort (APC) models are used to study the variability in trajectories of change over time. A well-known issue exists in simultaneously identifying age, period and birth cohort effects, namely that the three characteristics comprise a perfectly collinear system. That is, since age = period−cohort, only two of these effects are estimable at a time. In this paper, we introduce an alternative framework for considering effects relating to age, period and birth cohort. In particular, instead of directly modeling age in the presence of period and cohort effects, we propose a risk modeling approach to characterize age-related risk (i.e., a hybrid of multiple biological and sociological influences to evaluate phenomena associated with growing older). The properties of this approach, termed risk-period-cohort (RPC), are described in this paper and studied by simulations. We show that, except for pathological circumstances where risk is uniquely determined by age, using such risk indices obviates the problem of collinearity. We also show that the size of the chronological age effect in the risk prediction model associates with the correlation between a risk index and chronological age and that the RPC approach can satisfactorily recover cohort and period effects in most cases. We illustrate the advantages of RPC compared to traditional APC analysis on 27496 individuals from NHANES survey data (2005–2016) to study the longitudinal variability in depression screening over time. Our RPC method has broad implications for examining processes of change over time in longitudinal studies. [ABSTRACT FROM AUTHOR]

Established cell lines are widely used in research, however an appealing question is the comparability of the cells between various laboratories, their characteristics and stability in time. Problematic is also the cell line misidentification, genetic and phenotypic shift or Mycoplasma contamination which are often forgotten in research papers. The monocyte/macrophage-like cell line RAW 264.7 has been one of the most commonly used myeloid cell line for more than 40 years. Despite its phenotypic and functional stability is often discussed in literature or at various scientific discussion panels, their stability during the consecutive passages has not been confirmed in any solid study. So far, only a few functional features of these cells have been studied, for example their ability to differentiate into osteoclasts. Therefore, in the present paper we have investigated the phenotype and functional stability of the RAW 264.7 cell line from passage no. 5 till passage no. 50. We found out that the phenotype (expression of particular macrophage-characteristic genes and surface markers) and functional characteristics (phagocytosis and NO production) of RAW 264.7 cell line remains stable through passages: from passage no. 10 up to passage no. 30. Overall, our results indicated that the RAW 264.7 cell line should not be used after the passage no. 30 otherwise it may influence the data reliability. [ABSTRACT FROM AUTHOR]

Kaempferol (kae) and its glycosides are widely distributed in nature and show multiple bioactivities, yet few reports have compared them. In this paper, we report the antitumor, antioxidant and anti-inflammatory activity differences of kae, kae-7-O-glucoside (kae-7-O-glu), kae-3-O-rhamnoside (kae-3-O-rha) and kae-3-O-rutinoside (kae-3-O-rut). Kae showed the highest antiproliferation effect on the human hepatoma cell line HepG2, mouse colon cancer cell line CT26 and mouse melanoma cell line B16F1. Kae also significantly inhibited AKT phosphorylation and cleaved caspase-9, caspase-7, caspase-3 and PARP in HepG2 cells. A kae-induced increase in DPPH and ABTS radical scavenging activity, inhibition of concanavalin A (Con A)-induced activation of T cell proliferation and NO or ROS production in LPS-induced RAW 264.7 macrophage cells were also seen. Kae glycosides were used to produce kae via environment-friendly enzymatic hydrolysis. Kae-7-O-glu and kae-3-O-rut were hydrolyzed to kae by β-glucosidase and/or α-L-rhamnosidase. This paper demonstrates the application of enzymatic catalysis to obtain highly biologically active kae. This work provides a novel and efficient preparation of high-value flavone-related products. [ABSTRACT FROM AUTHOR]

Stroke is a multiphasic process, and the initial ischemic phase of neuronal damage is followed by secondary innate and adaptive responses that unfold over days after stroke, offer a longer time frame of intervention, and represent a novel therapeutic target. Therefore, revealing the distinct functions of immune cells in both brain and periphery is important for identification of immunotherapeutic targets for stroke to extend the treatment time window. In this paper an examination of the cellular dynamics of the immune response in the central nervous system (CNS) and periphery provoked by cerebral ischemia is provided. New data is presented for the number of immune cells in brain and spleen of mice during the 7 days following middle cerebral artery occlusion (MCAO). A novel analysis of the correlation among various cell types in the brain and spleen following stroke is presented. It is found that the infiltrated macrophages in the ischemic hemisphere positively correlate with neutrophils which implies their synergic effect in migrating into the brain after stroke onset. It is noted that during infiltration of adaptive immune cells, the number of neutrophils correlate positively with T cells, which suggests neutrophils contribute to T cell infiltration in the stroked brain. Furthermore, the correlation among neurological deficit and various immune cells suggests that microglia and splenic adaptive immune cells (T and B cells) are protective while infiltrating peripheral myeloid cells (macrophage and neutrophils) worsen stroke outcome. Comprehension of such immune responses post cerebral ischemia is crucial for differentiating the drivers of outcomes and also predicting the stroke outcome. [ABSTRACT FROM AUTHOR]

The cornea is a special interface between the internal ocular tissue and the external environment that provides a powerful chemical, physical, and biological barrier against the invasion of harmful substances and pathogenic microbes. This protective effect is determined by the unique anatomical structure and cellular composition of the cornea, especially its locally resident innate immune cells, such as Langerhans cells (LCs), mast cells (MCs), macrophages, γδ T lymphocytes, and innate lymphoid cells. Recent studies have demonstrated the importance of these immune cells in terms of producing different cytokines and other growth factors in corneal homeostasis and its pathologic conditions. This review paper briefly describes the latest information on these resident immune cells by specifically analyzing research from our laboratory. [ABSTRACT FROM AUTHOR]

In this paper, we establish and examine a mathematical model that combines the effects of vitamins intervention on strengthening the immune system and its role in suppressing and delaying the growth and division of tumour cells. In order to accomplish this, we propose a tumour–immune–vitamins model (TIVM) governed by ordinary differential equations and comprised of two populations, namely tumour and immune cells. It is presumed that the source of vitamins in TIVM originates from organic foods and beverages, based on the food pyramid. The simulation of TIVM employs the fourth order Runge–Kutta method. It is found from the analysis and simulation results that one of the side effects of weakening the immune system is the possibility of transforming immune cells into immune cancer cells to prevent or delay the growth and division of tumour cells. Evidently, for regular intakes of vitamins, which is projected at 55% of vitamins per day, the immune system is strengthened, preventing the production of tumour cells. [ABSTRACT FROM AUTHOR]

Immunosenescence, also known as immune aging, refers to the degeneration, compensation, and reconstruction of the immune system with aging. Immune aging is an important factor in the increased susceptibility of the elderly to infectious diseases, malignant tumors, and a variety of chronic diseases and has long been a hotspot in geriatrics and immunology research. In this paper, the characteristics and progression of immune aging are briefly reviewed for clinicians' reference. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study. [ABSTRACT FROM AUTHOR]

This document is a comment letter published in the Journal of Virology. It discusses the presence of HSV-1 LAT (latency-associated transcript) in non-neuronal ganglionic cells of mice and humans. The authors respond to a reanalysis of their data that claimed no LAT in non-neuronal cells, highlighting concerns about the reanalysis methodology. They argue that their study and a repeated scRNA-seq experiment provide ample evidence for the presence of LAT in non-neuronal cells. The authors recommend readers review both papers and draw their own conclusions. [Extracted from the article]

The current review paper highlights the complicacies associated with communities relying on wheat as their dietary staple. Although, wheat is an important source of nutrients but is also linked with allergenic responses in genetically susceptible subjects. The wheat proteins especially α-amylase inhibitors, ω-5 gliadins, prolamins, nonprolamin, glucoprotein, and profilins are of significance importance. The allergenic responses are further categorized into IgE-mediated and non-IgE-mediated reactions. Conjugation and degranulation of the IgEs with the allergens results in release of several mediators. In contrary, non-IgE-mediated wheat allergy depends on immune complexes formed by food and food antibodies and cell-mediated immunity. As results, different diseases tend to occur on the completion of these reactions, i.e., celiac disease, baker's asthma, diarrhea, atopic dermatitis, and urticaria. This instant paper highlighted the concept of food allergy with special reference to wheat. The models are developed that are included in this paper showing the wheat allergen, their possible routes, impact on human health, and indeed possible remedies. The paper would provide the basic information for the researchers, common man, and allied stakeholders to cater the issue in details. However, the issue needs the attention of the researchers as there is a need to clarify the issues of wheat allergy and wheat intolerance. [ABSTRACT FROM PUBLISHER]

Our study investigated the causal relationship between immune cells, metabolites, and epilepsy using two-sample Mendelian Randomization (MR) and mediation MR analysis of 731 immune cell traits and 1400 metabolites. Our core methodology centered on inverse-variance weighted MR, supplemented by other methods. This approach was crucial in clarifying the potential intermediary functions of metabolites in the genetic links between traits of immune cells and epilepsy. We found a causal relationship between immune cells and epilepsy. Specifically, the genetically predicted levels of CD64 on CD14-CD16- are positively correlated with the risk of epilepsy (p < 0.001, OR = 1.0826, 95% CI 1.0361–1.1312). Similarly, metabolites also exhibit a causal relationship with both immune cells (OR = 1.0438, 95% CI 1.0087–1.0801, p = 0.0140) and epilepsy (p = 0.0334, OR = 1.0897, 95% CI 1.0068–1.1795), and sensitivity analysis was conducted to further validate these relationships. Importantly, our intermediate MR results suggest that the metabolite Paraxanthine to linoleate (18:2n6) ratio may mediate the causal relationship between immune cell CD64 on CD14-CD16- and epilepsy, with a mediation effect of 5.05%. The results suggest the importance of specific immune cell levels and metabolites in understanding epilepsy's pathogenesis, which is significant for its prevention and treatment. [ABSTRACT FROM AUTHOR]