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Natural killer (NK) cells are immune cells that defend against viral infections and cancer and are used in cancer immunotherapies. Subpopulations of NK cells include CD56dim and CD56bright which either produce cytokines or cytotoxically kill cells directly. The absolute number and proportion of these cells in peripheral blood are tied to proper immune function. Current methods of cytokine detection and proportion of NK cell subpopulations require fluorescent dyes and highly specialized equipment, e.g., flow cytometry, thus rapid cell quantification and subpopulation analysis are needed in the clinical setting. Here, a smartphone-based device and a two-component paper microfluidic chip were used towards identifying NK cell subpopulation and inflammatory markers. One unit measured flow velocity via smartphone-captured video, determining cytokine (IL-2) and total NK cell concentrations in undiluted buffy coat blood samples. The other, single flow lane unit performs spatial separation of CD56dim and CD56bright and cells over its length using differential binding of anti-CD56 nanoparticles. A smartphone microscope combined with cloud-based machine learning predictive modeling (utilizing a random forest classification algorithm) analyzed both flow data and NK cell subpopulation differentiation. Limits of detection for cytokine and cell concentrations were 98 IU/mL and 68 cells/mL, respectively, and cell subpopulation analysis showed 89% accuracy. • First smartphone-based paper microfluidic cell chromatography that can identify cell subpopulation. • Machine learning predictive modeling for NK cell subpopulation differentiation. • Integration of both cell chromatography and flow rate analysis on a single platform. • Potential application to many other cytokines and cell subpopulation analyses. [ABSTRACT FROM AUTHOR]

Podocalyxin-like protein (PCLP) is a sialomucin-type membrane protein structurally related to CD34 and endoglycan. It was first described in glomerular podocytes and endothelial cells. In mice, PCLP is present in haemangioblasts, and in both chicken and mice it is a marker of early haematopoietic stem cells and lineage-restricted haematopoietic progenitors. Its expression decreases during differentiation of haematopoietic cells. Of mature blood cells, only chicken and rat thrombocytes express PCLP protein. PCLP expression in human haematopoietic cells has not been studied. Here we demonstrate PCLP mRNA in human CD34+ cells, in lineage committed erythroid, megakaryocyte and myeloid progenitors, in K562 leukaemia cells, and in peripheral blood leucocytes. The mRNA expression level was higher in developing cells than in mature leucocytes. By Northern blotting and cDNA sequencing, the haematopoietic and renal PCLP mRNAs were identical. Of the mobilized CD34+ cells, 28% (mean; range 14–61%) expressed PCLP protein and the majority of PCLP+ cells were CD117+. Almost all of the K562 cells expressed PCLP protein. Surprisingly, PCLP protein was not detected in any mature blood cells. These results suggest that human PCLP may be a valuable marker for a subset of haematopoietic stem cells. [ABSTRACT FROM AUTHOR]

We have established a culture system for the development of eosinophils from murine embryonic stem (ES) cells. After transferring ES cells from embryonic fibroblast cells onto macrophage colony-stimulating factor-deficient stromal cells, OP9, ES cells were cultured in the presence of interleukin (IL)-5 with either IL-3 or granulocyte–macrophage colony stimulating factor (GM-CSF) for 20 d to obtain approximately 50% eosinophils. Electron microscopy confirmed the presence of crystallized major basic protein (MBP) in the granules of some of these cells. Neither IL-5, IL-3, GM-CSF nor eotaxin alone could induce eosinophils as efficiently as the conditions described above. Eotaxin induced eosinophil development in combination with either IL-3 or IL-5. Levels of GATA-1, Friend of GATA (FOG)-1, PU.1, CCAAT/enhancer binding protein (C/EBP) α, C/EBP β, IL-3 receptor α (IL-3R α), GM-CSF receptor α (GM-CSFR α), and MBP mRNAs were increased in ES cells 10 d after transfer onto OP9 cells. In contrast, C/EBP ℇ, IL-5R α, and eosinophil peroxidase mRNAs were induced in response to IL-3 and IL-5 after transfer onto OP9 cells. Eosinophils that developed in this system expressed Gr-1, F4/80, B220, CCR3, IL-3R α, IL-5R α, and DX5. Finally, eosinophils developed from ES cells produced reactive oxygen species in response to Leishmania as do peripheral blood eosinophils. [ABSTRACT FROM AUTHOR]

Reduced natural killer (NK) cell cytotoxicity is the most consistent immune finding in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Meta-analysis of the published literature determined the effect size of the decrement in ME/CFS. Databases were screened for papers comparing NK cell cytotoxicity in ME/CFS and healthy controls. A total of 28 papers and 55 effector: target cell ratio (E:T) data points were collected. Cytotoxicity in ME/CFS was significantly reduced to about half of healthy control levels, with an overall Hedges’ g of 0.96 (0.75–1.18). Heterogeneity was high but was explained by the range of E:T ratios, different methods, and potential outliers. The outcomes confirm reproducible NK cell dysfunction in ME/CFS and will guide studies using the NK cell model system for pathomechanistic investigations [ABSTRACT FROM AUTHOR]

Objectives: As emerging adoptive immunotherapy after CAR-T cell therapy, CAR-NK cell therapy has been developing rapidly in recent years. Presently, the research on CAR-NK cells has become a hotspot in the field of tumor immunotherapy. Methods: In this descriptive study, CtieSpace and VOSviewer were used to perform the bibliometric and scientific knowledge-map analysis of articles and reviews related to CAR-NK cells. Results: 5371 authors from 715 institutions in 65 countries published 1028 papers about CAR-NK cells in 346 journals. The number of publications related to CAR-NK cells was increasing overall, especially from 2018 to 2021. The United States was in a leading position. The most active institution was Univ Texas, MD Anderson Cancer Center (USA). The journal with the most publications was Frontiers in immunology, and the most co-cited journal was Blood. The researcher with the most published papers was Winfried S. Wels, while the most co-cited researcher was Shannon L Maude. The research of CAR-NK cells in hematological malignancies and solid tumors (especially the selection of targets and the evaluation of efficacy and safety) was a research hotspot in this field. The emerging topics mainly included three aspects. First, further improve the proliferation and persistence of NK cells in vivo. Secondly, optimizing and improving the CAR structure for NK cells to improve the antitumor ability of CAR-NK cells. Thirdly, the related research of CRISPR/Cas9 gene-editing technology in constructing engineered immune cells. Conclusion: In this study, a bibliometric and scientific knowledge-map study provided a unique and objective perspective for the CAR-NK cell field. This information would provide a helpful reference for researchers interested in this field. [ABSTRACT FROM AUTHOR]

To accelerate the development of Advanced Therapy Medicinal Products (ATMPs) for patients suffering from life-threatening cancer with limited therapeutic options, regulatory approaches need to be constantly reviewed, evaluated and adjusted, as necessary. This includes utilizing science and riskbased approaches to mitigate and balance potential risks associated with early clinical research and a more flexible manufacturing paradigm. In this paper, T2EVOLVE an Innovative Medicine Initiative (IMI) consortium explores opportunities to expedite the development of CAR and TCR engineered T cell therapies in the EU by leveraging tools within the existing EU regulatory framework to facilitate an iterative and adaptive learning approach across different product versions with similar design elements or based on the same platform technology. As understanding of the linkage between product quality attributes, manufacturing processes, clinical efficacy and safety evolves through development and post licensure, opportunities are emerging to streamline regulatory submissions, optimize clinical studies and extrapolate data across product versions reducing the need to perform duplicative studies. It is worth noting that this paper is focusing on CAR- and TCR-engineered T cell therapies but the concepts may be applied more broadly to engineered cell therapy products (e.g., CAR NK cell therapy products). [ABSTRACT FROM AUTHOR]

In the field of breast cancer treatment, the immunotherapy involving natural killer (NK) cells is increasingly highlighting its distinct potential and significance. Members of the interleukin (IL) family play pivotal regulatory roles in the growth, differentiation, survival, and apoptosis of NK cells, and are central to their anti-tumor activity. These cytokines enhance the ability of NK cells to recognize and eliminate tumor cells by binding to specific receptors and activating downstream signaling pathways. Furthermore, interleukins do not function in isolation; the synergistic or antagonistic interactions between different interleukins can drive NK cells toward various functional pathways, ultimately leading to diverse outcomes for breast cancer patients. This paper reviews the intricate relationship between NK cells and interleukins, particularly within the breast cancer tumor microenvironment. Additionally, we summarize the latest clinical studies and advancements in NK cell therapy for breast cancer, along with the potential applications of interleukin signaling in these therapies. In conclusion, this article underscores the critical role of NK cells and interleukin signaling in breast cancer treatment, providing valuable insights and a significant reference for future research and clinical practice. [ABSTRACT FROM AUTHOR]

The article highlights the top papers on reproduction research in 2004-2008. According to the author, the top two papers include J. Hanna's paper on the role of decidual NK cells in regulating key developmental processes at the human fetal-maternal inteface and M. Xu's paper on tissue-engineered follicles, which produce live, fertile offspring. Other papers that have seen important advances include the immunology of reproduction and the effect of environmental toxins on reproduction.

The tumor microenvironment (TME) constitutes a complex microenvironment comprising a diverse array of immune cells and stromal components. Within this intricate context, tumor-associated macrophages (TAMs) exhibit notable spatial heterogeneity. This heterogeneity contributes to various facets of tumor behavior, including immune response modulation, angiogenesis, tissue remodeling, and metastatic potential. This review summarizes the spatial distribution of macrophages in both the physiological environment and the TME. Moreover, this paper explores the intricate interactions between TAMs and diverse immune cell populations (T cells, dendritic cells, neutrophils, natural killer cells, and other immune cells) within the TME. These bidirectional exchanges form a complex network of immune interactions that influence tumor immune surveillance and evasion strategies. Investigating TAM heterogeneity and its intricate interactions with different immune cell populations offers potential avenues for therapeutic interventions. Additionally, this paper discusses therapeutic strategies targeting macrophages, aiming to uncover novel approaches for immunotherapy. EjPgUqH7NocL1u9xj7Aojm Video Abstract [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells, as innate lymphocytes, possess cytotoxic capabilities and engage target cells through a repertoire of activating and inhibitory receptors. Particularly, natural killer group 2, member D (NKG2D) receptor on NK cells recognizes stress‐induced ligands—the MHC class I chain‐related molecules A and B (MICA/B) presented on tumor cells and is key to trigger the cytolytic response of NK cells. However, tumors have developed sophisticated strategies to evade NK cell surveillance, which lead to failure of tumor immunotherapy. In this paper, we summarized these immune escaping strategies, including the downregulation of ligands for activating receptors, upregulation of ligands for inhibitory receptors, secretion of immunosuppressive compounds, and the development of apoptosis resistance. Then, we focus on recent advancements in NK cell immune therapies, which include engaging activating NK cell receptors, upregulating NKG2D ligand MICA/B expression, blocking inhibitory NK cell receptors, adoptive NK cell therapy, chimeric antigen receptor (CAR)‐engineered NK cells (CAR‐NK), and NKG2D CAR‐T cells, especially several vaccines targeting MICA/B. This review will inspire the research in NK cell biology in tumor and provide significant hope for improving cancer treatment outcomes by harnessing the potent cytotoxic activity of NK cells. [ABSTRACT FROM AUTHOR]

The negative effects of continuous exposure to electromagnetic waves know a continuous growth on the last years because of new developments in electronics and mobile communication applications in different fields (medical, smart devices for IoT applications). There are some researches concluding that exposure to electromagnetic fields could affect the cells (PMBCs, T lymphocytes, B lymphocytes, NK cells and macrophages) of the immune system including cell proportion, cell cycle, apoptosis, destruction activity and cytokine content. Considering the negative effect of electromagnetic inference, it is necessary to develop advanced materials to attenuate electromagnetic waves to protect electronic equipment and humans. In this context, this paper presents an experimental plan based on completely randomized blocks (RCBD) for obtaining adequate textile coating for electromagnetic shielding applications taking into account the design of electromagnetic shielding devices should include the modelling of the attenuation phenomenon of electromagnetic waves using Schelkunoff and Calculation theories. The proposed experimental plan consists of experiments distributed in blocks, each block corresponding to the technology used. For each experimental block, the factors specific to the technology used (independent variables such as the metals used (Ni, Cu, graphite, Fe3O4, Ag, Zn), mass (M), air permeability (Pa), thickness (d)) that could influence the response variable (electrical resistance (Rs)) have been taken into consideration. [ABSTRACT FROM AUTHOR]

Background: Both psoriasis and metabolic dysfunction-associated steatotic liver disease (MASLD) are immune-mediated chronic inflammatory diseases. Psoriasis manifests itself mainly as skin damage, while MASLD mainly involves the liver promoting liver fibrosis, which has a significant impact on patient health and quality of life. Some clinical studies have shown that there are mutually reinforcing mechanisms between these two diseases, but they are not clearly defined, and this paper aims to further explore their common pathogenesis. Methods: Gene expression profiling datasets (GSE30999, GSE48452) and single cell datasets (GSE151177, GSE186328) for psoriasis and MASLD were downloaded from the Gene Expression Omnibus (GEO) database. Common differential gene sets were obtained by gene differential analysis, and then functional enrichment of differential genes was performed to find associated transcription factors and PPI protein network analysis. Single-cell datasets were validated for gene expression and explored for cellular communication, gene set differential analysis and immune infiltration analysis. Results: We identified seven common differential genes, all of which were upregulated.The IL-17 pathway, tumor necrosis factor (TNF-α) pathway were shown in strong association with both diseases, and five transcription factors regulating the differential genes were predicted. Two key genes (MMP9, CXCL10) and three key transcription factors (TF) (IRF1, STAT1, NFKB1) were obtained by PPI protein network analysis. Single cell dataset verified the expression of key genes, and combined with gene set differential analysis, immune infiltration revealed that CD4+ T cells, NK cells and macrophages were heavily infiltrated in both diseases. IL-17, IL-1 and cGAS-STING pathways were highly expressed in both diseases, and both diseases share a similar immune microenvironment. Conclusions: Our study reveals the common pathogenesis of psoriasis and MASLD from gene expression to immune cell similarities and differences, identifies key genes and regulatory pathways common to both, and elucidates the similarities in the immune microenvironment of both diseases, providing new ideas for subsequent studies on targeted therapy. [ABSTRACT FROM AUTHOR]

Background: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s). Methods: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-κB phosphorylation, and they have been silenced with specific small interfering RNAs. Results: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals. Conclusions: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects. [ABSTRACT FROM AUTHOR]

Natural killer cells (NKCs) are non-specific immune lymphocytes with diverse morphologies. Their broad killing effect on cancer cells has led to increased attention towards activating NKCs for anticancer immunotherapy. Consequently, understanding the motion characteristics of NKCs under different morphologies and modeling their collective dynamics under cancer cells has become crucial. However, tracking small NKCs in complex backgrounds poses significant challenges, and conventional industrial tracking algorithms often perform poorly on NKC tracking datasets. There remains a scarcity of research on NKC dynamics. In this paper, we utilize deep learning techniques to analyze the morphology of NKCs and their key points. After analyzing the shortcomings of common industrial multi-object tracking algorithms like DeepSORT in tracking natural killer cells, we propose Distance Cascade Matching and the Re-Search method to improve upon existing algorithms, yielding promising results. Through processing and tracking over 5000 frames of images, encompassing approximately 300,000 cells, we preliminarily explore the impact of NKCs' cell morphology, temperature, and cancer cell environment on NKCs' motion, along with conducting basic modeling. The main conclusions of this study are as follows: polarized cells are more likely to move along their polarization direction and exhibit stronger activity, and the maintenance of polarization makes them more likely to approach cancer cells; under equilibrium, NK cells display a Boltzmann distribution on the cancer cell surface. [ABSTRACT FROM AUTHOR]

The article presents abstracts on medical topics including acute pancreatitis as a symptom in severe preeclampsia, the relationship of increase uterine natural killer cells in first trimester miscarriages with cytogenetic karyotypic abnormalities and the effect of vitamin D supplementation on hemodialysis patients.

Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy. [ABSTRACT FROM AUTHOR]

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Simple Summary: Cell therapy is emerging as a promising modality to treat cancers such as hematological malignancies and solid tumors; hence there is a need to develop processes to manufacture and maintain functional and lasting cells. The use of cytokines, as well as transcription and growth factors, is critical to ensure effective cell therapeutics. This is especially important for allogeneic cell therapies that employ induced pluripotent stem cells (iPSC). The use of iPSC offers the potential to treat a large number of patients with consistent material without relying on limited donor cells and the delay associated with processing immediately before treatment. This paper demonstrates the importance and use of cytokines and growth factors in driving the iPSC-to-effector differentiation and expansion process, which leads to the generation of functional and persistent immune-effector cells such as natural killer cells or T cells. Cytokines and other growth factors are essential for cell expansion, health, function, and immune stimulation. Stem cells have the additional reliance on these factors to direct differentiation to the appropriate terminal cell type. Successful manufacturing of allogeneic cell therapies from induced pluripotent stem cells (iPSCs) requires close attention to the selection and control of cytokines and factors used throughout the manufacturing process, as well as after administration to the patient. This paper employs iPSC-derived natural killer cell/T cell therapeutics to illustrate the use of cytokines, growth factors, and transcription factors at different stages of the manufacturing process, ranging from the generation of iPSCs to controlling of iPSC differentiation into immune-effector cells through the support of cell therapy after patient administration. [ABSTRACT FROM AUTHOR]

With the deepening of people's understanding of lung cancer, the research of lung cancer immunotherapy has gradually become the focus of attention. As we all know, the treatment of many diseases relies on the rich sources, complex and varied compositions and wide range of unique biological properties of natural products. Studies have shown that natural products can exert anticancer effects by inducing tumor cell death, inhibiting tumor cell proliferation, and enhancing tumor cell autophagy. More notably, natural products can adjust and strengthen the body's immune response, which includes enhancing the function of NK cells and promoting the differentiation and proliferation of T lymphocytes. In addition, these natural products may enhance their anticancer effects by affecting inhibitory factors in the immune system, hormone levels, enzymes involved in biotransformation, and modulating other factors in the tumor microenvironment. The importance of natural products in lung cancer immunotherapy should not be underestimated. However, the specific links and correlations between natural products and lung cancer immunity are not clear enough, and further studies are urgently needed to clarify the relationship between the two. In this paper, we will focus on the correlation between natural products and lung cancer immune responses, with a view to providing new research perspectives for immunotherapy of lung cancer. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have recently shown renewed promise as therapeutic cells for use in treating hematologic cancer indications. Despite this promise, NK cell manufacturing workflows remain largely manual, open, and disconnected, and depend on feeders, as well as outdated unit operations or processes, often utilizing research-grade reagents. Successful scale-up of NK cells critically depends on the availability and performance of nutrient-rich expansion media and cryopreservation conditions that are conducive to high cell viability and recovery post-thaw. In this paper we used Cytiva hardware and media to expand the NK92 cell line in a model process that is suitable for GMP and clinical manufacturing of NK cells. We tested a range of cryopreservation factors including cooling rate, a range of DMSO-containing and DMSO-free cryoprotectants, ice nucleation, and cell density. Higher post-thaw recovery was seen in cryobags over cryovials cooled in identical conditions, and cooling rates of 1°C/min or 2°C/min optimal for cryopreservation in DMSO-containing and DMSO-free cryoprotectants respectively. Higher cell densities of 5x107 cells/ml gave higher post-thaw viability than those cryopreserved at either 1x106 or 5x106 cells/ml. This enabled us to automate, close and connect unit operations within the workflow while demonstrating superior expansion and cryopreservation of NK92 cells. Cellular outputs and performance were conducive to clinical dosing regimens, serving as a proof-of-concept for future clinical and commercial manufacturing. [ABSTRACT FROM AUTHOR]

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The "inflammatory storm" formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms. [ABSTRACT FROM AUTHOR]

Our previous studies have introduced osteoclasts (OCs) as major activators of NK cells. It was found that OCs exhibit the capabilities of inducing cell expansion as well as increasing the cytotoxic activity of NK cells by granule release and increasing the secretion of TNF-α and TRAIL, leading to increased lysis of tumors in short-term as well as long-term periods, respectively. OC- induced expanded NK cells were named supercharged NK cells (sNK) due to their significantly high functional activity as well as their significantly higher cell expansion rate. It is, however, unclear whether the OC-mediated effect in NK cells is specific or whether other cytotoxic immune cells can also be expanded and activated by OCs. We chose to focus on γδ T cells and pan T cells, which also include CD8+ T cells. In this paper, we report that OCs are capable of expanding and functionally activating both γδ T cells and pan T cells. Expanded γδ T and pan T cells were capable of secreting high levels of INF-γ, albeit with different dynamics to those of NK cells, and, moreover, they are unable to kill NK-specific targets. Since we used humanized-BLT (hu-BLT) mice as a model of human disease, we next determined whether NK and T cell activation through OCs is also evident in cells obtained from hu-BLT mice. Similar to humans, OCs were capable of increasing the cell expansion and secretion of IFN-γ in the culture of either NK or T cells from hu-BLT mice, providing yet further evidence that these mice are appropriate models to study human disease. Therefore, these studies indicated that CD3+ T or γδ T cells can proliferate and be supercharged by OCs similar to the NK cells; thus, they can be used individually or in combination in the cell therapy of cancers. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

Histological terminology of the female genital organs is currently a part of the internationally accepted nomenclature Terminologia Histologica (TH), the latest edition of which dates back to 2008. Many new discoveries have been documented within 16 years since then, and many discrepancies have been found. This paper aims to revise the terminology from clinical and educational perspectives comprehensively. The authors thoroughly searched the current edition of "Terminologia Histologica: International Terms for Human Cytology and Histology," focusing on missing and controversial terms in the chapter Female genital system. The authors identified six controversial and ambiguous terms and four missing important histological terms. The authors also discussed the addition of less used eponymic terms in the histological description of female genital organs like Hamperl cells, Popescu cells, Kroemer lacunae, Balbiani bodies, Call–Exner bodies, membrane of Slavianski, nabothian cysts, or anogenital sweat glands of van der Putte. We expect the second and revised edition of the TH to be published soon and hope that the Federative International Program on Anatomical Terminology will approve and incorporate all these propositions and suggestions. We also strongly recommend using the official internationally accepted Latin and English histological nomenclature—the TH, either in oral or written form, both in theoretical and clinical medicine. [ABSTRACT FROM AUTHOR]

In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural killer cells are a part of the native immune response to cancer. NK cell-based immunotherapies are an emerging strategy to kill tumor cells. This paper reviews the role of NK cells, their mechanism of action for killing tumor cells, and the receptors which could serve as potential targets for signaling. In this review, the role of nanoparticles in NK cell activation and increased cytotoxicity of NK cells against cancer are highlighted. Natural killer (NK) cells are one of the first lines of defense against infections and malignancies. NK cell-based immunotherapies are emerging as an alternative to T cell-based immunotherapies. Preclinical and clinical studies of NK cell-based immunotherapies have given promising results in the past few decades for hematologic malignancies. Despite these achievements, NK cell-based immunotherapies have limitations, such as limited performance/low therapeutic efficiency in solid tumors, the short lifespan of NK cells, limited specificity of adoptive transfer and genetic modification, NK cell rejection by the patient's immune system, insignificant infiltration of NK cells into the tumor microenvironment (TME), and the expensive nature of the treatment. Nanotechnology could potentially assist with the activation, proliferation, near-real time imaging, and enhancement of NK cell cytotoxic activity by guiding their function, analyzing their performance in near-real time, and improving immunotherapeutic efficiency. This paper reviews the role of NK cells, their mechanism of action in killing tumor cells, and the receptors which could serve as potential targets for signaling. Specifically, we have reviewed five different areas of nanotechnology that could enhance immunotherapy efficiency: nanoparticle-assisted immunomodulation to enhance NK cell activity, nanoparticles enhancing homing of NK cells, nanoparticle delivery of RNAi to enhance NK cell activity, genetic modulation of NK cells based on nanoparticles, and nanoparticle activation of NKG2D, which is the master regulator of all NK cell responses. [ABSTRACT FROM AUTHOR]

Objectives: Chronic graft-versus-host disease (cGvHD) is the most frequent cause of late non-relapse mortality after allogeneic haematopoietic stem cell transplantation (alloHCT). Nevertheless, established biomarkers of cGvHD are still missing. The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGvHD provided recommendations for biomarker research. We evaluated to which extent studies on cellular and soluble biomarkers in cGvHD published in the last 10 years complied with these recommendations. Also, we highlight the most promising biomarker candidates, verified in independent cohorts and/or repeatedly identified by separate studies. Methods: We searched Medline and EMBASE for “cGvHD”, “biomarkers”, “soluble” and “cells” as MeSH terms or emtree subject headings, and their variations on July 28th, 2021, limited to human subjects, English language and last ten years. Reviews, case reports, conference abstracts and single nucleotide polymorphism studies were excluded. Criteria based on the set of recommendations from the NIH group for biomarker research in cGvHD were used for scoring and ranking the references. Results: A total of 91 references encompassing 15,089 participants were included, 54 prospective, 17 retrospective, 18 cross-sectional, and 2 studies included both prospective and retrospective cohorts. Thirty-five papers included time-matched controls without cGvHD and 20 studies did not have any control subjects. Only 9 studies were randomized, and 8 were multicentric. Test and verification cohorts were included in 11 studies. Predominantly, diagnostic biomarkers were explored (n=54). Assigned scores ranged from 5-34. None of the studies fulfilled all 24 criteria (48 points). Nevertheless, the scores improved during the last years. Three cell subsets (CXCR³+CD56bright NK cells, CD19+CD21low and BAFF/CD19+ B cells) and several soluble factors (BAFF, IL 15, CD163, DKK3, CXCL10 and the panel of ST2, CXCL9, MMP3 and OPN) had the highest potential as diagnostic and/or prognostic biomarkers in cGvHD. Conclusion: Despite several limitations of this review (limited applicability for paediatric population, definition of verification, missing data on comorbidities), we identified promising candidate biomarkers for further evaluation in multicentre collaborative studies. This review confirms the importance of the NIH consensus group criteria for improving the quality and reproducibility of cGvHD biomarker research. [ABSTRACT FROM AUTHOR]

This paper addresses the controversy of Granzyme B (GzmB) expression by murine Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous immature myeloid population that are generated in chronic inflammatory pathologies for the purpose to suppress inflammatory responses. MDSCs express a multitude of factors to induce suppressive function such as PD-L1, reactive oxygen species (ROS), nitric oxide synthase (iNOS), and Arginase-1. Recently, Dufait et al. sought to demonstrate GzmB as an additional mechanism for suppression by MDSCs. They reported that murine MDSCs not only significantly express GzmB as well as Perforin (Prf1), but this expression is functionally important for tumor growth in vivo as well as tumor migration in vitro. We conducted experiments to address the same question but made confounding observations: MDSCs under stringent developmental process do not express GzmB. Our results show that not only GzmB protein is not produced at functional level, but the mRNA transcript is not detectable either. In fact, the GzmB protein found in the media of MDSC culture was due to T cells or natural killer cells contained in bone marrow and cultured alongside MDSCs. We strengthen this finding by genetically deleting GzmB from the myeloid lineage and measuring tumor burden compared to WT counterpart. Our results show no significant difference in tumor burden, suggesting that even if there is minor expression of GzmB, it is not produced at a functional amount to affect tumor growth. Therefore, this paper proposes alternative theories that align with the known understanding of GzmB expression and secretion. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a major challenge for current therapies. CAR-T cells have shown promising results in blood cancers, however, their effectiveness against solid tumors remains a hurdle. Recently, CD44v6-directed CAR-T cells demonstrated efficacy in controlling tumor growth in multiple myeloma and solid tumors such as HNSCC, lung and ovarian adenocarcinomas. Apart from CAR-T cells, CAR-NK cells offer a safe and allogenic alternative to autologous CAR-T cell therapy. In this paper, we investigated the capacity of CAR-NK cells redirected against CD44v6 to execute cytotoxicity against HNSCC. Anti-CD44v6 CAR-NK cells were generated from healthy donor peripheral blood-derived NK cells using gamma retroviral vectors (gRVs). The NK cell transduction was optimized by exploring virus envelope proteins derived from the baboon endogenous virus envelope (BaEV), feline leukemia virus (FeLV, termed RD114-TR) and gibbon ape leukemia virus (GaLV), respectively. BaEV pseudotyped gRVs induced the highest transduction rate compared to RD114-TR and GaLV envelopes as measured by EGFP and surface CAR expression of transduced NK cells. CAR-NK cells showed a two- to threefold increase in killing efficacy against various HNSCC cell lines compared to unmodified, cytokine-expanded primary NK cells. Anti-CD44v6 CAR-NK cells were effective in eliminating tumor cell lines with high and low CD44v6 expression levels. Overall, the improved cytotoxicity of CAR-NK cells holds promise for a therapeutic option for the treatment of HNSCC. However, further preclinical trials are necessary to test in vivo efficacy and safety, as well to optimize the treatment regimen of anti-CD44v6 CAR-NK cells against solid tumors. [ABSTRACT FROM AUTHOR]

Immunotherapy utilizing checkpoint inhibitors has shown remarkable success in the treatment of cancers. In addition to immune checkpoint inhibitors, immune co-stimulation has the potential to enhance immune activation and destabilize the immunosuppressive tumor microenvironment. CD137, also known as 4-1BB, is one of the potent immune costimulatory receptors that could be targeted for effective immune co-stimulation. The interaction of the 4-1BB receptor with its natural ligand (4-1BBL) generates a strong costimulatory signal for T cell proliferation and survival. 4-1BBL lacks costimulatory activity in soluble form. To obtain co-stimulatory activity in soluble form, a recombinant 4-1BBL protein was generated by fusing the extracellular domains of murine 4-1BBL to a modified version of streptavidin (SA-4-1BBL). Treatment with SA-4-1BBL inhibited the development of lung tumors in A/J mice induced by weekly injections of the tobacco carcinogen NNK for eight weeks. The inhibition was dependent on the presence of T cells and NK cells; depletion of these cells diminished the SA-4-1BBL antitumor protective effect. The number of lung tumor nodules was significantly reduced by the administration of SA-4-1BBL to mice during ongoing exposure to NNK. The data presented in this paper suggest that utilizing an immune checkpoint stimulator as a single agent generate a protective immune response against lung cancer in the presence of a carcinogen. More broadly, this study suggests that immune checkpoint stimulation can be extended to a number of other cancer types, including breast and prostate cancers, for which improved diagnostics can detect disease at the preneoplastic stage. [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 development of pre-eclampsia is associated with immunological interactions between the foreign maternal and fetal tissues, which are characterized by a predominance of the influence of type 1 T-helper cells, leading to increased production of highly aggressive pro-inflammatory cytokines. However, the mechanism of cellular-humoral immune and cytokine changes leading to the manifestation of pre-eclampsia is not fully understood and no corrective measures have been developed. Purpose. To investigate the changes in the cellular-humoral immunity and cytokine profile in a cervical mucus of pregnant women at high risk for developing PE and to find out the effectiveness of the proposed secondary prevention of PE in the normalization of these indicators. Method and Materials. The main group (MG) consisted of 91 pregnant women with risk factors for pre-eclampsia who had impaired blood flow in the uterine spiral arteries at 18-20 weeks of pregnancy. Among them, 59 patients (MG-II) received secondary prevention of pre-eclampsia from 18-20 weeks until delivery using metformin, vitamin D3, and corvitin, while the remaining 32 patients (MG-I) declined preventive measures. The control group (CG) consisted of 30 healthy pregnant women. The research was regulated by the rules of humane treatment of patients in accordance with the requirements of the Tokyo Declaration of the World Medical Association, the international recommendations of the Helsinki Declaration on Human Rights, the Convention of the Council of Europe on Human Rights and Biomedicine, and the laws of Ukraine. TNF-α, INFγ and IL-10 levels were determined in cervical mucus by enzyme-linked immunosorbent assay (ELISA); peripheral blood lymphocyte CD3+, CD4+, CD8+, CD16+, CD22+ levels were assessed by indirect immunofluorescence. The CD4/CD8 ratio was calculated as an immunoregulatory index. Blood serum immunoglobulin (Ig) levels were determined by competitive enzyme-linked immunosorbent assay (A, M, and G). The concentration of circulating immune complexes (CIC) in blood serum was measured by the immunoturbidimetric assay. The data were analyzed by mathematical-statistical methods, calculating the mean (M), variance (σ), and standard error (m), applying Student's t-test, and performing correlation analysis using the statistical program «STATISTICA» (StatSoft Inc., USA). The paper is an excerpt from the initiative scientific research project of the Department of Obstetrics and Gynecology № 2 of the Poltava State Medical University entitled «Optimization of approaches to management of pregnancy in women at high risk of obstetric and perinatal pathology» (state registration number 0122U201228, duration: 10.2022-09.2027). Results. In women at high risk of developing pre-eclampsia (MG-I), a significant decrease in the concentration of T helper cells (CD4+), an increase in T suppressor/killer cells (CD8+), a decrease in the immunoregulatory index, a decrease in B cells (CD22+) and an increase in CIC were observed. In addition, CIC greater than 100 IU/ml strongly correlated with the development of pre-eclampsia. IgM levels were significantly elevated in women with pre-eclampsia, indicating possible trophoblastic stimulation of their immune system, while IgG levels were significantly reduced. Women with pre-eclampsia had a significant predominance of pro-inflammatory cytokines and a deficiency of anti-inflammatory cytokines. In women of the MG-II group who received the proposed complex of secondary prevention of pre-eclampsia, the content of T-helper cells (CD4+) and T-suppressor/killer cells (CD8+) was normalized. The immunoregulatory index increased significantly, and the number of CD22+ cells was about the level observed in healthy pregnant women. The concentrations of IgA and IgG increased to the levels observed in the control group, while the level of IgM decreased. The level of CIC decreased in pregnant women with MG-II, in contrast to the levels observed in women with MG-I. The levels of pro-inflammatory cytokines INF-γ and TNF-α decreased after preventive treatment. However, the levels of the antiinflammatory cytokine IL-10 increased significantly in MG-II, leading to a significant reduction in the TNF-α/IL-10 ratio (p<0.001). Conclusions. Pregnant wo men with a history of increased risk factors for PE and a decrease in the intensity of blood flow in the spiral arteries of the uterus at 18-20 weeks of gestation have a pronounced imbalance of the T-cell subpopulation, which is accompanied by a decrease in the production of T-helpers (CD4+) and an increase in the synthesis of T-suppressors/killers (CD8+), which causes a decrease in the immunoregulatory index. This is accompanied by the development of a cytokine imbalance with a predominance of pro-inflammatory cytokines and a deficiency of anti-inflammatory cytokines, and is also associated with a significant decrease in the concentration of IgG and a decrease in the number of B cells. Such changes are a consequence of the exhaustion of the reactivity of the humoral link of the general immunity, creating the conditions for the frequent manifestation of PE, which occurs in almost half of such women. The application of our proposed improved method of secondary prevention of pulmonary embolism in pregnant women with a high risk of developing this disease leads to significant positive changes in the work of the immune system and a corresponding improvement in clinical results. It makes it possible to reduce the frequency of PE development by 1.4 times and to prevent the occurrence of its severe forms by 2.6 times. [ABSTRACT FROM AUTHOR]

An automaton is k-visit-bounded if during any computation its work tape head visits each tape cell at most k times. In this paper we consider stack automata which are k-visit-bounded for some integer k. This restriction resets the visits when popping (unlike similarly defined Turing machine restrictions) which we show allows the model to accept a proper superset of context-free languages and also a proper superset of languages of visit-bounded Turing machines. We study two variants of visit-bounded stack automata: one where only instructions that move the stack head downwards increase the number of visits of the destination cell, and another where any transition increases the number of visits. We prove that the two types of automata recognize the same languages. We then show that all languages recognized by visit-bounded stack automata are effectively semilinear, and hence are letter-equivalent to regular languages, which can be used to show other properties. [ABSTRACT FROM AUTHOR]

Aptamers are artificial oligonucleotides with excellent molecule-targeting ability. Compared with monoclonal antibodies, aptamers have the advantages of low cost, no batch effect, and negligible immunogenicity, making them promising candidates for cancer immunotherapy. To date, a series of aptamer agonists/antagonists have been discovered and directly used to activate immune response, such as immune checkpoint blockade, immune costimulation, and cytokine regulation. By incorporating both tumor- and immune cell-targeting aptamers, multivalent bispecific aptamers were designed to pursue high tumor affinity and enhanced immune efficacy. More importantly, benefiting from feasible chemical modification and programmability, aptamers can be engineered with diverse nanomaterials (e.g., liposomes, hydrogels) and even living immune cells (e.g., NK cells, T cells). These aptamer-based assemblies exhibit powerful capabilities in targeted cargo delivery, regulation of cell–cell interactions, tumor immunogenicity activation, tumor microenvironment remodeling, etc., holding huge potential in boosting immunotherapeutic efficacy. In this review, we focus on the recent advances in aptamer-based immune drug systems (AptIDCs) and highlight their advantages in cancer immunotherapy. The current challenges and future prospects of this field are also pointed out in this paper. [ABSTRACT FROM AUTHOR]

The Special Issue "Proteases: Role and Function in Cancer" aimed to focus on basic and translational research to highlight the role of peptidases in tumor development and to assess their potential in cancer diagnosis and therapy. In this issue, the papers are focused on two peptidase groups: metallo peptidases and cysteine peptidases. It is predominantly expressed in immune cells and shown as an important regulator of the granzyme/perforin mediated cytotoxicity of natural killer (NK) and CD8+ T cells, the most important cytotoxic effector cells in antitumor immune response. ADAM8 was suggested to be involved in cell-cell communication as its expression has been observed in tumor and immune cells. [Extracted from the article]

Dysregulation of the immune response plays an important role in the progression of SARS-CoV-2 infection. A "cytokine storm", which is a phenomenon associated with uncontrolled production of large amounts of cytokines, very often affects patients with COVID-19. Elevated activity of chemotactic cytokines, called chemokines, can lead to serious consequences. CXCL10 has an ability to activate its receptor CXCR3, predominantly expressed on macrophages, T lymphocytes, dendritic cells, natural killer cells, and B cells. So, it has been suggested that the chemokine CXCL10, through CXCR3, is associated with inflammatory diseases and may be involved in the development of COVID-19. Therefore, in this review paper, we focus on the role of CXCL10 overactivity in the pathogenesis of COVID-19. We performed an extensive literature search for our investigation using the MEDLINE/PubMed database. Increased concentrations of CXCL10 were observed in COVID-19. Elevated levels of CXCL10 were reported to be associated with a severe course and disease progression. Published studies revealed that CXCL10 may be a very good predictive biomarker of patient outcome in COVID-19, and that markedly elevated CXCL10 levels are connected with ARDS and neurological complications. It has been observed that an effective treatment for SARS-CoV-2 leads to inhibition of "cytokine storm", as well as reduction of CXCL10 concentrations. It seems that modulation of the CXCL10–CXCR3 axis may be an effective therapeutic target of COVID-19. This review describes the potential role of CXCL10 in the pathogenesis of COVID-19, as well as its potential immune–therapeutic significance. However, future studies should aim to confirm the prognostic, clinical, and therapeutic role of CXCL10 in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Immunotherapy has become the cornerstone of current malignant tumor treatment. However, the response of different patients to immunotherapy is highly heterogeneous, and not all patients can benefit from it. There is an urgent need to find biomarkers that can effectively predict the efficacy of immunotherapy. C-C chemokine ligand 4 (CCL4) is a cytokine, belonging to the inflammatory CCL subfamily. It is mainly secreted by immune cells and tumor cells and shows low or no expression in normal tissues but abnormally high expression in various malignant tumor tissues. After binding to CCL4 and its receptor C-C chemokine receptor type 5 (CCR5), it can recruit and mediate immune cell migration, destroy the stability of the tumor microenvironment (TME), participate in carcinogenesis and promote the development of tumors. In the tumor immune microenvironment, CCL4 can mediate and recruit the directed migration of key immune cells such as monocytes, macrophages, natural killer (NK) cells, and T cells, which makes it a potentially important element affecting the efficacy of immunotherapy and has specific value. This paper reviews the research progresses of CCL4's effects on immune escape in TME, in order to provide clues and references for basic research and clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Benign natural killer cell enteropathy (NKCE) was first identified in the gastrointestinal (GI) tract. Notably, instances of NKCE have previously been observed at various sites other than the GI tract, including the gallbladder, lymph nodes, esophagus, and female genital tract. Typical NKCE manifests as an NK‐cell immunohistological phenotype, with or without TCR rearrangement, and is characterized by the absence of Epstein–Barr virus (EBV) infection and protracted clinical progression. The misdiagnosis of NKT‐cell lymphoma has resulted in some patients receiving chemotherapy, while in other instances, the patients' conditions resolved without treatment and showed no evidence of disease recurrence or progression during follow‐up examinations. In this paper, we describe a unique case of EBV‐negative NKCE occurring in the oral cavity, the first time such a case has been documented. The tumor completely resolved after an excisional biopsy, and subsequent follow‐up did not reveal any signs of disease recurrence. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays an important role in the development of tumors. Immunoregulatory cells and cytokines facilitate cancer cells to avoid immune surveillance. Overexpression of immune checkpoint molecules such as CTLA-4 and PD-1/PD-L1 inhibits immune function and enables cancer cells to avoid clearance by the immune system. Thus, minimizing tumor immunosuppression could be an important strategy for cancer therapy. Currently, many immune checkpoint-targeted drugs, such as PD-1/PD-L1 inhibitors, have been approved for marketing and have shown unique advantages in the clinical treatment of cancers. The concept of "strengthening resistance to eliminate pathogenic factors" in traditional Chinese medicine (TCM) is consistent with the immunotherapy of cancer. According to previous studies, the role of TCM in tumor immunotherapy is mainly associated with the positive regulation of natural killer cells, CD8/CD4 T cells, dendritic cells, M2 macrophages, interleukin-2, tumor necrosis factor- α , and IFN- γ , as well as with the negative regulation of Tregs, myeloid-derived suppressor cells, cancer-associated fibroblasts, PD-1/PD-L1, transforming growth factor- β , and tumor necrosis factor- β. This paper summarizes the current research on the effect of TCM targeting the TME, and further introduces the research progress on studying the effects of TCM on immune checkpoints. Modern pharmacological studies have demonstrated that TCM can directly or indirectly affect the TME by inhibiting the overexpression of immune checkpoint molecules and enhancing the efficacy of tumor immunotherapy. TCM with immunomodulatory stimulation could be the key factor to achieve benefits from immunotherapy for patients with non-inflammatory, or "cold", tumors. [ABSTRACT FROM AUTHOR]

Immunotherapy is revolutionizing cancer therapy. The rapid development of new immunotherapeutic strategies to treat solid tumors is posing new challenges for preclinical research, demanding novel in vitro methods to test treatments. Such methods should meet specific requirements, such as enabling the evaluation of immune cell responses like cytotoxicity or cytokine release, and infiltration into the tumor microenvironment using cancer models representative of the original disease. They should allow high-throughput and high-content analysis, to evaluate the efficacy of treatments and understand immune-evasion processes to facilitate development of new therapeutic targets. Ideally, they should be suitable for personalized immunotherapy testing, providing information for patient stratification. Consequently, the application of in vitro 3-dimensional (3D) cell culture models, such as tumor spheroids and organoids, is rapidly expanding in the immunotherapeutic field, coupled with the development of novel imaging-based techniques and -omic analysis. In this paper, we review the recent advances in the development of in vitro 3D platforms applied to natural killer (NK) cell-based cancer immunotherapy studies, highlighting the benefits and limitations of the current methods, and discuss new concepts and future directions of the field. [ABSTRACT FROM AUTHOR]

This paper investigates the intricate interplay of fetal human leukocyte antigen (HLA) and maternal killer cell immunoglobulin-like receptor (KIR) interactions, focusing on their implications for pregnancy outcomes. The study explores the impact of HLA mismatches, particularly in the context of the HY immunity system, on the maternal immune response. The presence of HLA antibodies is assessed, with consideration given to the correlation with total immunoglobulin levels, aiming to discern associations with potential pregnancy complications. Complement activity is examined, adding a layer of understanding to the dynamics of fetal HLA and maternal KIR interactions. Furthermore, the paper delves into the delicate balance between Th1 and Th2 helper T cells, crucial components of the immune system, and their potential influence on maternal-fetal immune tolerance. Natural Killer Cell Cytotoxic Activity (NKa) is investigated, providing insights into the cytotoxicity of these immune cells and their role in the context of maternal-fetal interactions. The findings presented contribute to a nuanced comprehension of the immunological factors shaping pregnancy outcomes and may inform future research and clinical approaches aimed at optimizing maternal and fetal health. [ABSTRACT FROM AUTHOR]

The Major Histocompatibility Complex (MHC) binds to the derived peptides from pathogens to present them to killer T cells on the cell surface. Developing computational methods for accurate, fast, and explainable peptide-MHC binding prediction can facilitate immunotherapies and vaccine development. Various deep learning-based methods rely on separate feature extraction from the peptide and MHC sequences and ignore their pairwise binding information. This paper develops a capsule neural network-based method to efficiently capture the peptide-MHC complex features to predict the peptide-MHC class I binding. Various evaluations confirmed our method outperformance over the alternative methods, while it can provide accurate prediction over less available data. Moreover, for providing precise insights into the results, we explored the essential features that contributed to the prediction. Since the simulation results demonstrated consistency with the experimental studies, we concluded that our method can be utilized for the accurate, rapid, and interpretable peptide-MHC binding prediction to assist biological therapies. A capsule neural network-based method captures pairwise information to accurately predict MHC-I and peptide binding. The comprehensive test of the model indicated both its superiority in performance and interpretability. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are members of a rapidly expanding family of innate lymphoid cells (ILCs). NK cells play roles in the spleen, periphery, and in many tissues, such as the liver, uterine, lung, adipose, and so on. While the immunological functions of NK cells are well established in these organs, comparatively little is known about NK cells in the kidney. Our understanding of NK cells is rapidly rising, with more and more studies highlighting the functional significance of NK cells in different types of kidney diseases. Recent progress has been made in translating these findings to clinical diseases that occur in the kidney, with indications of subset-specific roles of NK cells in the kidney. For the development of targeted therapeutics to delay kidney disease progression, a better understanding of the NK cell with respect to the mechanisms of kidney diseases is necessary. In order to promote the targeted treatment ability of NK cells in clinical diseases, in this paper we demonstrate the roles that NK cells play in different organs, especially the functions of NK cells in the kidney. [ABSTRACT FROM AUTHOR]

Background. The pathogenesis of ankylosing spondylitis (AS) is still not clear, and immune-related genes have not been systematically explored in AS. The purpose of this paper was to identify the potential early biomarkers most related to immunity in AS and develop a predictive disease risk model with bioinformatic methods and the Gene Expression Omnibus database (GEO) to improve diagnostic and therapeutic efficiency. Methods. To identify differentially expressed genes and create a gene coexpression network between AS and healthy samples, we downloaded the AS-related datasets GSE25101 and GSE73754 from the GEO database and employed weighted gene coexpression network analysis (WGCNA). We used the GSVA, GSEABase, limma, ggpubr, and reshape2 packages to score immune data and investigated the links between immune cells and immunological functions by using single-sample gene set enrichment analysis (ssGSEA). The value of the core gene set and constructed model for early AS diagnosis was investigated by using receiver operating characteristic (ROC) curve analysis. Results. Biological function and immune score analyses identified central genes related to immunity, key immune cells, key related pathways, gene modules, and the coexpression network in AS. Granulysin (GNLY), Granulysin (GZMK), CX3CR1, IL2RB, dysferlin (DYSF), and S100A12 may participate in AS development through NK cells, CD8+ T cells, Th1 cells, and other immune cells and represent potential biomarkers for the early diagnosis of AS occurrence and progression. Furthermore, the T cell coinhibitory pathway may be involved in AS pathogenesis. Conclusion. The AS disease risk model constructed based on immune-related genes can guide clinical diagnosis and treatment and may help in the development of personalized immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein–Barr virus is a highly prevalent virus associated with a multitude of diseases, including autoimmune conditions such as multiple sclerosis and many types of cancer. As such, it is imperative to have a foundational understanding of this virus. This review discusses the contribution of the Epstein–Barr virus to key hematologic malignancies with a focus on the roles of latent proteins, including diffuse large B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, NK/T-cell lymphoma, and primary CNS lymphoma. It then provides a brief overview of treatment for each of these diseases. The clinical significance of Epstein–Barr virus (EBV) cannot be understated. Not only does it infect approximately 90% of the world's population, but it is also associated with numerous pathologies. Diseases linked to this virus include hematologic malignancies such as diffuse large B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, primary CNS lymphoma, and NK/T-cell lymphoma, epithelial malignancies such as nasopharyngeal carcinoma and gastric cancer, autoimmune diseases such as multiple sclerosis, Graves' disease, and lupus. While treatment for these disease states is ever evolving, much work remains to more fully elucidate the relationship between EBV, its associated disease states, and their treatments. This paper begins with an overview of EBV latency and latency-associated proteins. It will then review EBV's contributions to select hematologic malignancies with a focus on the contribution of latent proteins as well as their associated management. [ABSTRACT FROM AUTHOR]

The biological processes underlying NK cell alloreactivity in haematopoietic stem cell transplantation (HSCT) remain unclear. Many different models to predict NK alloreactivity through KIR and MHC genotyping exist, raising ambiguities in its utility and application for clinicians. We assessed 27 predictive models, broadly divided into six categories of alloreactivity prediction: ligand-ligand, receptor-ligand, educational, KIR haplotype-based, KIR matching and KIR allelic polymorphism. The models were applied to 78 NGS-typed donor/recipient pairs undergoing allogeneic HSCT in genoidentical (n=43) or haploidentical (n=35) matchings. Correlations between different predictive models differed widely, suggesting that the choice of the model in predicting NK alloreactivity matters. For example, two broadly used models, educational and receptor-ligand, led to opposing predictions especially in the genoidentical cohort. Correlations also depended on the matching fashion, suggesting that this parameter should also be taken into account in the choice of the scoring strategy. The number of centromeric B-motifs was the only model strongly correlated with the incidence of acute graft-versushost disease in our set of patients in both the genoidentical and the haploidentical cohorts, suggesting that KIR-based alloreactivity, not MHC mismatches, are responsible for it. To our best knowledge, this paper is the first to experimentally compare NK alloreactivity prediction models within a cohort of genoidentical and haploidentical donor-recipient pairs. This study helps to resolve current discrepancies in KIR-based alloreactivity predictions and highlights the need for deeper consideration of the models used in clinical studies as well as in medical practice. [ABSTRACT FROM AUTHOR]

Introduction: Globally, breast cancer constitutes 12.5% of new cancer cases each year. Amygdalin, a cyanogenic glycoside found in fruit kernels like bitter almonds and apricots, is valued for its therapeutic attributes, including antioxidative and antibacterial properties. Recent studies emphasize its anti- tumor effects, involving processes such as apoptosis, toxin release targeting cancer cells, and immunomodulation. However, debates surrounding its efficacy in cancer treatment arise due to concerns about human toxicity. The presence of unverified data emphasizes the importance of investigating amygdalin as a potential avenue for advancing breast cancer treatment. This review examines amygdalin's anticancer and immunomodulatory effects, and potential toxicity in the context of breast cancer. Methods: A search was conducted across electronic databases such as Fortune Journals, PubMed, ScienceDirect, and Google Scholar to identify studies on amygdalin's anticancer effects and toxicity in breast cancer treatment. A thorough review was conducted, analyzing a total of about 20 research papers. Results: Amygdalin can be broken down through enzymatic and acid hydrolysis and converted to hydrocyanic acid - an essential element required to induce apoptosis by down-regulating BcL-2 protein and up-regulating Bax protein thus inhibiting the proliferation of breast cancer cells. It also induces cell cycle arrest by down regulating MAPK/P53 and nitric oxide, and up regulating the reactive oxygen species. Furthermore, it acts as an immunomodulator by suppressing the expression of many tumor growth signaling molecules and CD4, while up regulating natural killer cells and CD8 expression. However, amygdalin metabolism also produces cyanide ion, which contributes to its toxic effects by causing even noncancerous cells to undergo hypoxia and lactic acidosis. Conclusion: Despite its potential side effects, amygdalin holds significant promise as a candidate for breast cancer treatment. More investigation is needed to establish the most effective dosage levels, potential combinations with other treatments, and strategies for amplifying its cancer-fighting properties while managing potential drawbacks. Further research is required to better understand the impact of amygdalin, aiming to enhance its potential as a viable therapeutic agent. [ABSTRACT FROM AUTHOR]

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings. [ABSTRACT FROM AUTHOR]