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Purpose: Chronic inflammation is one of the key mechanisms of depression. Wenyang-Tianjin-Jie Decoction (WTJD) is an effective antidepressant found in the course of diagnosis and treatment, but the mechanism of therapeutic effect is not clear. The study aimed to evaluate the efficacy of WTJD in the kidney yang deficiency (KYD) type of depression rats and reveal its mechanisms. Materials and Methods: We selected forty 6-week-old male Sprague-Dawley rats for the study. We established a KYD [Phellodendron amurense Rupr (Huangbai) solution oral gavage and 4°C environments; 8 weeks] type of depression (chronic unpredictable mild stimulus; 6 weeks) rat model first. After successful modeling, we used WTJD or fluoxetine on rats for 3 weeks. Then we evaluated the depression and KYD behavior. Finally, we observed the expression of key inflammatory factors and proteins in peripheral blood and hippocampus, and further investigated the immune balance of Th17/Treg and Th1/Th2 cells and the activity of their main regulatory pathways JAK2/STAT3 and TLR4/TRAF6/NF-κB. Results: The imbalance of Th17/Treg and Th1/Th2 cells in rats were related to KYD and depressive symptoms. Through this study, we found that WTJD can inhibit the activity of JAK2/STAT3 and TLR4/TRAF6/NF-κB pathways, balance Th17/Treg and Th1/Th2 cell homeostasis, regulate the levels of inflammatory factors in the hippocampus and peripheral blood, and reverse KYD and depression. Conclusion: This study confirmed that WTJD had a reliable effect on depression rats with KYD, and its mechanism was to regulate the immune homeostasis of hippocampal T cells and related inflammatory factors to improve KYD and depression symptoms in rats. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advancements in cancer research have proven immunotherapies to be a promising strategy for the treatment of hematological malignancies. The bispecific antibody (BsAb) format was developed to overcome the issues of monoclonal antibody-based therapies. T-cell engagers (TCEs) are BsAbs, which directly activate T-cells and their anti-tumor features, ultimately resulting in the lysis of the targeted tumor cells. In 2014, the FDA approved blinatumomab for treatment of acute lymphoblastic leukemia. As of November 2023, seven clinically approved TCE therapies are on the market. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3+ T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by the formation of a hyperplastic pannus, as well as cartilage and bone damage. The pathogenesis of RA is complex and involves broad interactions between various cells present in the inflamed synovium, including fibroblast-like synoviocytes (FLSs), macrophages, and T cells, among others. Under inflammatory conditions, these cells are activated, further enhancing inflammatory responses and angiogenesis and promoting bone and cartilage degradation. Novel treatment methods for RA are greatly needed, and mesenchymal stromal cells (MSCs) have been suggested as a promising new regenerative and immunomodulatory treatment. In this paper, we present the interactions between MSCs and RA-FLSs, and macrophages and T cells, and summarise studies examining the use of MSCs in preclinical and clinical RA studies. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR‐T cell therapy, many factors were found to be associated with the efficacy of CAR‐T therapy. This paper reviews the factors affecting the effect of CAR‐T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR‐T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies. [ABSTRACT FROM AUTHOR]

Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git. [ABSTRACT FROM AUTHOR]

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]

Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs. [ABSTRACT FROM AUTHOR]

Objective: Multiple myeloma (MM) is a bone marrow cancer that profoundly affects plasma cells involved in the immune response. Myeloma cells alter the average production of cells in the bone marrow. Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy allows genetic modifications of an individual's T-cells to increase the expression of CARs used to identify and attach BCMA proteins to the malignant cells. Our main objective is to perform a systematic review and meta-analysis to explore the efficacy and safety of anti-BCMA CAR T-cell therapy for MM. Material and Methods: We searched five databases, PubMed, CNKI, EMBASE, Cochrane, Web of Science, and CNKI, for studies published on anti-BCMA,CAR-T-cell treatment for MM. Inclusion criteria involved prospective single-arm studies either single or multi-center, in various MM phases and studies that reported anti-BCMA,CAR-T-cell treatment for MM. We excluded non-English publications and conference papers. All statistical analyses were performed in R software and Review Manager 5.4.1. Results: Thirteen articles were included in the analysis. We found that the overall response survival complete response increase was statistically significant. Similarly, the reduction in cytokine release syndrome grades 3 and 4 and neurotoxicity after follow-up was statistically significant. However, the reduction in minimal residual disease negativity (MRDN) was not statistically significant. Conclusion: Using anti-BCMA CAR T-cell therapy in MM was highly efficacious and safe in lowering the adverse outcomes and improving the survival outcomes, complete response, and overall response. [ABSTRACT FROM AUTHOR]

Background: HBV-specific T lymphocytes are pivotal in eliminating the hepatitis B virus (HBV) and regulating intrahepatic inflammatory reactions. Effective T cell responses curtail HBV infection; however, compromised immunity can result in persistent infection. Beyond the acute phase, the continued presence of antigens and inflammation leads to the increased expression of various inhibitory receptors, such as PD-1, CTLA-4, Tim-3, LAG3, 2B4, CD160, BTLA, and TIGIT. This escalates the dysfunction of and diminishes the immune and proliferative abilities of T cells. Methods: In this study, we reviewed English-language literature from PubMed, Web of Science, and Scopus up to 9 July 2023. This paper aims to elucidate the inhibitory effects of these receptors on HBV-specific T lymphocytes and how immune function can be rejuvenated by obstructing the inhibitory receptor signaling pathway in chronic HBV patients. We also summarize the latest insights into related anti-HBV immunotherapy. Result: From 66 reviewed reports, we deduced that immunotherapy targeting inhibitory receptors on T cells is a reliable method to rejuvenate T cell immune responses in chronic HBV patients. However, comprehensive combination therapy strategies are essential for a functional cure. Conclusions: Targeting T cell suppressor receptors and combining immunotherapy with antiviral treatments may offer a promising approach towards achieving a functional cure, urging future research to prioritize effective combination therapeutic strategies for chronic HBV infection. [ABSTRACT FROM AUTHOR]

The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures. [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]

Tumor immune escape refers to the inability of the immune system to clear tumor cells, which is one of the major obstacles in designing effective treatment schemes for cancer diseases. Although clinical studies have led to promising treatment outcomes, it is imperative to design theoretical models to investigate the long-term treatment effects. In this paper, we develop a mathematical model to study the interactions among tumor cells, immune escape tumor cells, and T lymphocyte. The chimeric antigen receptor (CAR) T-cell therapy is also described by the mathematical model. Bifurcation analysis shows that there exists backward bifurcation and saddle-node bifurcation when the immune intensity is used as the bifurcation parameter. The proposed model also exhibits bistability when its parameters are located between the saddle-node threshold and backward bifurcation threshold. Sensitivity analysis is performed to illustrate the effects of different mechanisms on the backward bifurcation threshold and basic immune reproduction number. Simulation studies confirm the bifurcation analysis results and predict various types of treatment outcomes using different CAR T-cell therapy strengths. Analysis and simulation results show that the immune intensity can be used to control the tumor size, but it has no effect on the control of the immune escape tumor size. The introduction of the CAR T-cell therapy will reduce the immune escape tumor size and the treatment effect depends on the CAR T-cell therapy strength. [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]

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]

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumour. Despite advancements in surgery, radiotherapy and chemotherapy, which have improved the prognosis of most patients, a subset of patients with poor prognoses still exist due to loss of surgical opportunities, postoperative recurrence, and metastasis, among other reasons. The tumour microenvironment (TME) is a complex organization composed of tumour, stromal, and endothelial cells. Communication and interaction between tumours and immune cells within the TME are increasingly being recognized as pivotal in inhibiting or promoting tumour development. Previous studies on T cells in the TME of HNSCC have yielded novel therapeutic possibilities. However, the function of B cells, another adaptive immune cell type, in the TME of HNSCC patients has yet to be determined. Recent studies have revealed various distinct subtypes of B cells and tertiary lymphoid structures (TLSs) in the TME of HNSCC patients, which are believed to impact the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this paper focuses on B cells in the TME to explore potential directions for future immunotherapy for HNSCC. [ABSTRACT FROM AUTHOR]

Tumor cells primarily employ the PD-1/PD-L1 pathway to thwart the anti-tumor capabilities of T lymphocytes, inducing immunosuppression. This occurs through the direct interaction of PD-L1 with PD-1 on T lymphocyte surfaces. Recent research focusing on the tumor microenvironment has illuminated the pivotal role of immune cells, particularly tumor-associated macrophages (TAMs), in facilitating PD-L1-mediated immunosuppression. Exosomes, characterized by their ability to convey information and be engulfed by cells, significantly contribute to promoting TAM involvement in establishing PD-L1-mediated immunosuppression within the tumor microenvironment. Exosomes, characterized by their ability to convey information and be engulfed by cells, significantly contribute to promoting TAM involvement in establishing PD-L1-mediated immunosuppression within the tumor microenvironment. In addition to receiving signals from tumor-derived exosomes that promote PD-L1 expression, TAMs also exert control over PD-L1 expression in tumor cells through the release of exosomes. This paper aims to summarize the mechanisms by which exosomes participate in this process, identify crucial factors that influence these mechanisms, and explore innovative strategies for inhibiting or reversing the tumor-promoting effects of TAMs by targeting exosomes. [ABSTRACT FROM AUTHOR]

Nanoencapsulation of living cells within artificial shells is a powerful approach for augmenting the inherent capacity of cells and enabling the acquisition of extrinsic functions. However, the current state of the field requires the development of nanoshells that can dynamically sense and adapt to environmental changes by undergoing transformations in form and composition. This paper reports the compositional transformation of an enzyme‐embedded nanoshell of Fe3+‐trimesic acid complex to an iron phosphate shell in phosphate‐containing media. The cytocompatible transformation allows the nanoshells to release functional molecules without loss of activities and biorecognition, while preserving the initial shell properties, such as cytoprotection. Demonstrations include the lysis and killing of Escherichia coli by lysozyme, and the secretion of interleukin‐2 by Jurkat T cells in response to paracrine stimulation by antibodies. This work on micrometric Transformers will benefit the creation of cell‐in‐shell nanobiohybrids that can interact with their surroundings in active and adaptive ways. [ABSTRACT FROM AUTHOR]

Background: It has been reported that programmed death‐ligand 1 (PD‐L1) is highly expressed in cells during viral infection, which helps the virus escape host immunity. However, the relationship between human papillomavirus (HPV) and PD‐L1 in condyloma acuminatum and whether they participate in immunosuppression have not been reported. In this paper, we aimed to explore the expression and significance of PD‐L1 in condyloma acuminatum. Methods: The expression of PD‐L1 in the wart of condyloma acuminatum patients and the foreskin of healthy individuals was evaluated. Lentivirus transfection was used to introduce the HPV11‐E7 gene into HaCaT cells to investigate whether HPV infection could affect the expression of PD‐L1. The successfully constructed HPV11‐E7 HaCaT cells were cocultured with Jurkat cells, and Jurkat cell apoptosis and proliferation as well as the Jurkat cell cycle were evaluated by flow cytometry and cell counting kit‐8 (CCK‐8) assays. Results: PD‐L1 was highly expressed in keratinocytes of genital warts. Through the construction of a cell model, we found that HPV11‐E7 could upregulate the expression of PD‐L1 in HaCaT cells. Furthermore, HPV11‐E7 HaCaT cells can promote the apoptosis of Jurkat cells, inhibit the proliferation of Jurkat cells and mediate the cell cycle arrest of Jurkat cells through the PD‐1/PD‐L1 signalling pathway. Conclusions: HPV infection may upregulate PD‐L1 expression in the keratinocytes of genital warts and participate in the inhibition of local T‐cell function. [ABSTRACT FROM AUTHOR]

Objective: This paper aimed to investigate the PI3K/Akt/mTOR signal-pathway regulator factor-related lncRNA signatures (PAM-SRFLncSigs), associated with regulators of the indicated signaling pathway in patients with lung adenocarcinoma (LUAD) undergoing immunotherapy. Materials and Methods: In this retrospective study, we employed univariate Cox, multivariate Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses to identify prognostically relevant long non-coding RNAs (lncRNAs), construct prognostic models, and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Subsequently, immunoassay and chemotherapy drug screening were conducted. Finally, the prognostic model was validated using the Imvigor210 cohort, and tumor stem cells were analyzed. Results: We identified seven prognosis-related lncRNAs (AC084757.3, AC010999.2, LINC02802, AC026979.2, AC024896.1, LINC00941 and LINC01312). We also developed prognostic models to predict survival in patients with LUAD. KEGG enrichment analysis confirmed association of LUAD with the PI3K/Akt/mTOR signaling pathway. In the analysis of immune function pathways, we discovered three good prognostic pathways (Cytolytic_activity, Inflammation-promoting, T_cell_co-inhibition) in LUAD. Additionally, we screened 73 oncology chemotherapy drugs using the "pRRophetic" algorithm. Conclusion: Identification of seven lncRNAs linked to regulators of the PI3K/Akt/mTOR signaling pathway provided valuable insights into predicting the prognosis of LUAD, understanding the immune microenvironment and optimizing immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Helminths are multicellular parasites that are a substantial problem for both human and veterinary medicine. According to estimates, 1.5 billion people suffer from their infection, resulting in decreased life quality and burdens for healthcare systems. On the other hand, these infections may alleviate autoimmune diseases and allergy symptoms. The immune system is programmed to combat infections; nevertheless, its effector mechanisms may result in immunopathologies and exacerbate clinical symptoms. This review summarizes the role of the immune response against worms, with an emphasis on the Th2 response, which is a hallmark of helminth infections. We characterize non-immune cells (enteric tuft cells—ETCs) responsible for detecting parasites, as well as the role of hematopoietic-derived cells (macrophages, basophils, eosinophils, neutrophils, innate lymphoid cells group 2—ILC2s, mast cells, T cells, and B cells) in initiating and sustaining the immune response, as well as the functions they play in granulomas. The aim of this paper is to review the existing knowledge regarding the immune response against helminths, to attempt to decipher the interactions between cells engaged in the response, and to indicate the gaps in the current knowledge. [ABSTRACT FROM AUTHOR]

The major histocompatibility complexes of vertebrates play a key role in the immune response. Antigen-presenting cells are loaded on MHC I molecules, which mainly present endogenous antigens; when MHC I presents exogenous antigens, this is called cross-presentation. The discovery of cross-presentation provides an important theoretical basis for the study of exogenous antigens. Cross-presentation is a complex process in which MHC I molecules present antigens to the cell surface to activate CD8+ T lymphocytes. The process of cross-representation includes many components, and this article briefly outlines the origins and development of MHC molecules, gene structures, functions, and their classical presentation pathways. The cross-presentation pathways of MHC I molecules, the cell lines that support cross-presentation, and the mechanisms of MHC I molecular transporting are all reviewed. After more than 40 years of research, the specific mechanism of cross-presentation is still unclear. In this paper, we summarize cross-presentation and anticipate the research and development prospects for cross-presentation. [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]

Persistent host inflammatory and immune responses to biofilm play a critical role in the mechanisms that govern soft and hard tissue destruction in periodontal disease. Among the less explored facets of these mechanisms are chemokines, including CCL5 (C-C motif chemokine ligand 5), also known as RANTES (regulated on activation, normal T cell expressed and secreted), a proinflammatory CC subfamily chemokine synthesized by T lymphocytes. Despite its importance, there is currently no comprehensive review of the role of CCL5 in periodontitis in the literature. Therefore, this paper aims to fill this gap by summarizing the existing knowledge on the involvement of CCL5 in the onset and progression of periodontitis. In addition, we aim to stimulate interest in this relatively overlooked factor among periodontitis researchers, potentially accelerating the development of drugs targeting CCL5 or its receptors. The review examines the association of CCL5 with periodontitis risk factors, including aging, cigarette smoking, diabetes, and obesity. It discusses the involvement of CCL5 in pathological processes during periodontitis, such as connective tissue and bone destruction. The data show that CCL5 expression is observed in affected gums and gingival crevicular fluid of periodontitis patients, with bacterial activity contributing significantly to this increase, but the reviewed studies of the association between CCL5 expression and periodontal disease have yielded inconclusive results. Although CCL5 has been implicated in the pathomechanism of periodontitis, a comprehensive understanding of its molecular mechanisms and significance remains elusive, hindering the development of drugs targeting this chemokine or its receptors. [ABSTRACT FROM AUTHOR]

Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology is a novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review the latest developments in CAR-T in cancer treatment. We present the structure of the different generations and variants of CAR-T cells including TRUCK (T cells redirected for universal cytokine killing. We explain the approaches of the CAR-T cells manufactured ex vivo and in vivo. Moreover, we describe the limitations and areas of opportunity for this immunotherapy and the current challenges of treating hematological and solid cancer using CAR-T technology as well as its constraints and engineering approaches. We summarize other immune cells that have been using CAR technology, such as natural killer (NK), macrophages (M), and dendritic cells (DC). We conclude that CAR-T cells have the potential to treat not only cancer but other chronic diseases. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability. [ABSTRACT FROM AUTHOR]

Simple Summary: This article addresses the topic of primary immunodeficiencies, with particular emphasis on antibody deficiencies with near-normal immunoglobulin levels or hyperimmunoglobulinemia. This paper goes beyond genetics and emphasizes the importance of the immune system and particularly immune checkpoints and Epstein–Barr virus (EBV) reactivation in the context of these disorders. The article delves into the immune dysregulations occurring in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical picture of patients and, in the future, may contribute to the development of cancer, especially those related to hematological malignancies. Disturbances observed in the immunopathogenesis of the presented diseases go beyond the accepted scheme, with the development of PID largely associated only with genetic disorders, and the article emphasizes that the regulation of immunity and virus reactivation also contributes to the progression of PID. This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein–Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies. [ABSTRACT FROM AUTHOR]

Mutations and the glycosylation of epitopes can convert immunogenic epitopes into non-immunogenic ones via natural selection or evolutionary pressure, thereby decreasing their sensitivity to neutralizing antibodies. Based on Thomas Francis's theory, memory B and T cells induced during primary infections or vaccination will freeze the new mutated epitopes specific to naïve B and T cells from the repertoire. On this basis, some researchers argue that the current vaccines derived from the previous strains of the SARS-CoV-2 virus do not increase immunity and may also prevent the immune response against new epitopes. However, evidence shows that even if the binding affinity is reduced, the previous antibodies or T cell receptors (TCRs) can still bind to this new epitope of the Beta, Gamma, and Delta variant if their concentration is high enough (from a booster injection) and neutralize the virus. This paper presents some convincing immunological reasons that may challenge this theory and argue for the continuation of universal vaccination to prevent further mutations of the SARS-CoV-2 virus. Simultaneously, the information presented can be used to develop vaccines that target novel epitopes or create new recombinant drugs that do not lose their effectiveness when the virus mutates. [ABSTRACT FROM AUTHOR]

This paper presents and analyzes two mathematical models for the human immunodeficiency virus type-1 (HIV-1) infection with Cytotoxic T Lymphocyte cell (CTL) immune impairment. These models describe the interactions between healthy CD 4 + T cells, latently and actively infected cells, HIV-1 particles, and CTLs. The healthy CD 4 + T cells might be infected when they make contact with: (i) HIV-1 particles due to virus-to-cell (VTC) contact; (ii) latently infected cells due to latent cell-to-cell (CTC) contact; and (iii) actively infected cells due to active CTC contact. Distributed time delays are considered in the second model. We show the nonnegativity and boundedness of the solutions of the systems. Further, we derive basic reproduction numbers ℜ 0 and ℜ ˜ 0 , that determine the existence and stability of equilibria of our proposed systems. We establish the global asymptotic stability of all equilibria by using the Lyapunov method together with LaSalle's invariance principle. We confirm the theoretical results by numerical simulations. The effect of immune impairment, time delay and CTC transmission on the HIV-1 dynamics are discussed. It is found that weak immunity contributes significantly to the development of the disease. Further, we have established that the presence of time delay can significantly decrease the basic reproduction number and then suppress the HIV-1 replication. On the other hand, the presence of latent CTC spread increases the basic reproduction number and then enhances the viral progression. Thus, neglecting the latent CTC spread in the HIV-1 infection model will lead to an underestimation of the basic reproduction number. Consequently, the designed drug therapies will not be accurate or sufficient to eradicate the viruses from the body. These findings may help to improve the understanding of the dynamics of HIV-1 within a host. [ABSTRACT FROM AUTHOR]

Astragaloside IV (AS-IV) is one of the main active components extracted from the Chinese medicinal herb Astragali and serves as a marker for assessing the herb's quality. AS-IV is a tetracyclic triterpenoid saponin in the form of lanolin ester alcohol and exhibits various biological activities. This review article summarizes the chemical structure of AS-IV, its pharmacological effects, mechanism of action, applications, future prospects, potential weaknesses, and other unexplored biological activities, aiming at an overall analysis. Papers were retrieved from online electronic databases, such as PubMed, Web of Science, and CNKI, and data from studies conducted over the last 10 years on the pharmacological effects of AS—IV as well as its impact were collated. This review focuses on the pharmacological action of AS-IV, such as its anti-inflammatory effect, including suppressing inflammatory factors, increasing T and B lymphocyte proliferation, and inhibiting neutrophil adhesion-associated molecules; antioxidative stress, including scavenging reactive oxygen species, cellular scorching, and regulating mitochondrial gene mutations; neuroprotective effects, antifibrotic effects, and antitumor effects. [ABSTRACT FROM AUTHOR]

Background: In the global effort to discover biomarkers for cancer prognosis, prediction tools have become essential resources. TCR (T cell receptor) repertoires contain important features that differentiate healthy controls from cancer patients or differentiate outcomes for patients being treated with different drugs. Considering, tools that can easily and quickly generate and identify important features out of TCR repertoire data and build accurate classifiers to predict future outcomes are essential. Results: This paper introduces GENTLE (GENerator of T cell receptor repertoire features for machine LEarning): an open-source, user-friendly web-application tool that allows TCR repertoire researchers to discover important features; to create classifier models and evaluate them with metrics; and to quickly generate visualizations for data interpretations. We performed a case study with repertoires of TRegs (regulatory T cells) and TConvs (conventional T cells) from healthy controls versus patients with breast cancer. We showed that diversity features were able to distinguish between the groups. Moreover, the classifiers built with these features could correctly classify samples ('Healthy' or 'Breast Cancer')from the TRegs repertoire when trained with the TConvs repertoire, and from the TConvs repertoire when trained with the TRegs repertoire. Conclusion: The paper walks through installing and using GENTLE and presents a case study and results to demonstrate the application's utility. GENTLE is geared towards any researcher working with TCR repertoire data and aims to discover predictive features from these data and build accurate classifiers. GENTLE is available on https://github.com/dhiego22/gentle and https://share.streamlit.io/dhiego22/gentle/main/gentle.py. [ABSTRACT FROM AUTHOR]

The aim of this research is to use bibliometric analysis to investigate the status and patterns of the 100 most frequently cited publications regarding the cytotoxic T-lymphocyte-associated protein (CTLA-4) research for cancer. The articles published on the topic were retrieved from the core collection database of Web of Science and PubMed using the Medical Subject Heading (MeSH) of "CTLA-4" from 1986 to December 6, 2020. The selected articles were examined and the bibliometric data compiled based on the number of citations, the author's name, journal, publication year, institution, country, and co-occurrence keywords. 4,874 eligible papers were returned from the Web of Science Core Collection Database and PubMed. The citation frequency ranged from 2372 to 205, with a median of 460, and the top cited paper had 2372 citations. The journals with the most papers were Cell (n = 8, 3541 citations, Impact Factor (IF) = 41.577) and Journal of Experimental Medicine (n = 7, 2716 citations, IF = 10.790). Most of the published papers were from the United States of America (USA) (41.8%). A total of 485 institutes and 29 countries were involved in these 100 articles. There were 1192 authors and the author with the highest number of papers was the Nobel Prize winner, Professor James P. Allison (17 papers; 8700 citations). CTLA-4 blockade was the most frequent keyword (42.1%), followed by metastatic melanoma (4.26%). This work presents an important bibliographic source and can be saved as a reference for future medical health research on the function of CTLA-4 in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy targeting immune checkpoints and stromal cells in the tumor microenvironment is currently one of the most promising directions for tumor therapy. Ongoing studies suggest that CD73 plays an important role in the tumor immune process in certain tumors, however, the exact mechanism is unknown. We aim to fully reveal the prognostic value of CD73 in pan-cancer and its role in tumor immunity through large-scale single-cell and bulk sequencing analysis. We found that high CD73 expression was significantly associated with poor prognosis in many tumors. It is also strongly associated with immune scores, stromal cell infiltration, and immune-related pathways. CD73 can regulate the biological behavior of immune cells in the tumor microenvironment, especially macrophages and T cells. Immunotherapy targeting CD73 has obvious effects, and CD73 may shine as a new immune checkpoint in future tumor immunotherapy. CD73 is essential in promoting tumor growth by prohibiting anti-tumor immunity in many cancer types. While the mechanism remains largely unknown, our paper comprehensively confirmed the onco-immunological characteristics of CD73 in the tumor microenvironment (TME) of pan-cancer. This paper explored the expression pattern, mutational profile, prognostic value, tumor immune infiltration, and response to immunotherapy of CD73 in a continuous cohort of cancers through various computational tools. The co-expression of CD73 on cancer cells, immune cells, and stromal cells in the TME was also detected. Especially, we examined the correlation between CD73 and CD8+ (a marker of T cell), CD68+ (a marker of macrophage), and CD163+ (a marker of M2 macrophage) cells using multiplex immunofluorescence staining of tissue microarrays. CD73 expression is significantly associated with a patient's prognosis and could be a promising predictor of these cancers. High CD73 levels are strongly linked to immune infiltrations, neoantigens, and immune checkpoint expression in the TME. In particular, enrichment signaling pathway analysis demonstrated that CD73 was obviously related to activation pathways of immune cells, including T cells, macrophages, and cancer-associated fibroblasts (CAFs). Meanwhile, single-cell sequencing algorithms found that CD73 is predominantly co-expressed on cancer cells, CAFs, M2 macrophages, and T cells in several cancers. In addition, we explored the cellular communication among 14 cell types in glioblastoma (GBM) based on CD73 expression. Based on the expression of CD73 as well as macrophage and T cell markers, we predicted the methylation and enrichment pathways of these markers in pan-cancer. Furthermore, a lot of therapeutic molecules sensitive to these markers were predicted. Finally, potential anticancer inhibitors, immunotherapies, and gene therapy responses targeting CD73 were identified from a series of immunotherapy cohorts. CD73 is closely linked to clinical prognosis and immune infiltration in many cancers. Targeting CD73-dependent signaling pathways may be a promising therapeutic strategy for future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Much is known about the natural history of syphilis; however, less is known about the immune response against it, and even less is known about people living with HIV (PLWH). Due to the lack of an animal model to study host-pathogen interactions, it remains unclear how the host eliminates the bacteria. Here, we attempt to elucidate the immune response against infection by summarizing all the reported data in a systematic review. We found that only seven papers included PLWH, and they did not accurately describe the immune response against Treponema pallidum since only lymphopenia was reported upon coinfection. On the other hand, at least sixteen papers described the host-pathogen interaction in individual cell populations. Using this information, we established the kinetics of the immune response against syphilis and hypothesized how CD4+ T cells, such as Th17 and T rex cells, worsen the progression of the disease in PLWH through their hallmark cytokines, IL-10 and IL-17, and how these two cytokines may play important roles as biomarkers. [ABSTRACT FROM AUTHOR]

With the great stride forward of socialist progress, various medical treatment measures have also made a leap forward in development, providing a deeper guarantee for people's life safety. At the same time, the research field of nanotechnology has gradually developed in the medical field, which plays an important role in the development of medicine, and massage exercise rehabilitation training also provides convenience for patients' recuperation. The purpose of this study is to study the application of composite NanoBone transplantation in patients with limb replantation and the application of massage exercise rehabilitation training in patients with limb replantation. The methods used in this paper are: consulting the literature to understand the composite NanoBone transplantation technology and massage exercise rehabilitation training methods, interviewing the patients and attending doctors, and asking about the selection method of experiment and questionnaire used in the paper, so as to carry out the questionnaire survey. The treatment group and the control group were set up to analyze the results. The results showed that there were no significant differences in T lymphocyte subsets, serum complement, and circulating immune complex in the replantation of amputated limbs. Combined with the clinical manifestations and pathological results, early rejection occurred, and the body temperature of the patients increased after clinical treatment; The characteristics of massage are not practical, the course of treatment is short, the effect is fast, the clinical operation is simple, easy to grasp, and has high clinical application and promotion value. The final test results showed that: comparing the two groups of patients before treatment, the VAS scores were 23% and 21%, respectively, and the treatment group scores were 23% and 21%, respectively. After treatment, the VAS scores of the test group and the control group were 29 % and 27%, respectively. The treatment group scored 2% higher than the control group. From this, it can be concluded that massage is better than traditional massage, and massage exercise has great application prospects in clinical practice. [ABSTRACT FROM AUTHOR]

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244 , P = 0.025 , P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785 , P = 0.005 , P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising modality for anti-cancer treatment. Its efficacy is quite remarkable in hematological tumors. Owing to their excellent clinical results, gene- modified cell therapies, including T cells, natural killer (NK) cells, and macrophages, are being actively studied in both academia and industry. However, the protocol to make CAR immune cells is too complicated, so it is still unclear how to efficiently produce the potent CAR immune cells. To manufacture effective CAR immune cells, we need to be aware of not only how to obtain highly infective viral particles, but also how to transduce CAR genes into immune cells. In this paper, we provide detailed information on spinoculation, which is one of the best known protocols to transduce genes into immune cells, in a methodological view. Our data indicate that gene transduction is significantly dependent on speed and duration of centrifugation, concentration and number of viral particles, the concentration of polybrene, and number of infected immune cells. In addition, we investigated on the optimal polyethylene glycol (PEG) solution to concentrate the viral supernatant and the optimized DNA ratios transfected into 293T cells to produce high titer of viral particles. This study provides useful information for practical production of the gene-modified immune cells using viral vectors. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell therapy approaches, including adoptive cell therapy with engineered T cells remains challenging in the clinical setting of solid tumors. Clinical results have not been encouraging so far, with a general lack of significant therapeutic response and presence of on-target off-tumor toxicity. For this reason, novel cell therapy programs are currently exploring (i) advanced therapy medicinal products capable of increasing T cell affinity or avidity; and (ii) cell therapy in combination with other therapeutic agents. Our review will focus on the current clinical research in this setting, which will likely play a role in improving cancer treatment outcomes in the near future. In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) data has been widely used for cell trajectory inference, with the assumption that cells with similar expression profiles share the same differentiation state. However, the inferred trajectory may not reveal clonal differentiation heterogeneity among T cell clones. Single-cell T cell receptor sequencing (scTCR-seq) data provides invaluable insights into the clonal relationship among cells, yet it lacks functional characteristics. Therefore, scRNA-seq and scTCR-seq data complement each other in improving trajectory inference, where a reliable computational tool is still missing. We developed LRT, a computational framework for the integrative analysis of scTCR-seq and scRNA-seq data to explore clonal differentiation trajectory heterogeneity. Specifically, LRT uses the transcriptomics information from scRNA-seq data to construct overall cell trajectories and then utilizes both the TCR sequence information and phenotype information to identify clonotype clusters with distinct differentiation biasedness. LRT provides a comprehensive analysis workflow, including preprocessing, cell trajectory inference, clonotype clustering, trajectory biasedness evaluation, and clonotype cluster characterization. We illustrated its utility using scRNA-seq and scTCR-seq data of CD8+ T cells and CD4+ T cells with acute lymphocytic choriomeningitis virus infection. These analyses identified several clonotype clusters with distinct skewed distribution along the differentiation path, which cannot be revealed solely based on scRNA-seq data. Clones from different clonotype clusters exhibited diverse expansion capability, V-J gene usage pattern and CDR3 motifs. The LRT framework was implemented as an R package 'LRT', and it is now publicly accessible at https://github.com/JuanXie19/LRT. In addition, it provides two Shiny apps 'shinyClone' and 'shinyClust' that allow users to interactively explore distributions of clonotypes, conduct repertoire analysis, implement clustering of clonotypes, trajectory biasedness evaluation, and clonotype cluster characterization. Author summary: Understanding the dynamic changes behind biological processes is important for determining molecular mechanisms underlying normal tissue formulation, developmental disorders and pathologies. Usually, a biological process can be characterized by identifying a trajectory, a path that goes through the various cellular states associated with the process. Since cells in different states may express different sets of genes, researchers often infer cell trajectory via capturing transcriptomics changes. Dozens of methods have been developed for cell trajectory inference, and scRNA-seq data is predominantly utilized. However, cells from different clones may exist distinct differentiation patterns, while methods based only on scRNA-seq data cannot capture this heterogeneity. T cells play a key role in the immune system, and their high antigen recognition specificity is largely determined by their TCR sequences. Thanks to the advent of scTCR-seq technology, we can now identify the group of cells coming from the same clone. This paper describes our novel computational framework, namely LRT, and demonstrates that by complementing scRNA-seq data with the clonal information from scTCR-seq data using LRT, we are able to examine the clonal differentiation heterogeneity that cannot be revealed solely based on scRNA-seq data. [ABSTRACT FROM AUTHOR]

The ability to identify and track T-cell receptor (TCR) sequences from patient samples is becoming central to the field of cancer research and immunotherapy. Tracking genetically engineered T cells expressing TCRs that target specific tumor antigens is important to determine the persistence of these cells and quantify tumor responses. The available high-throughput method to profile TCR repertoires is generally referred to as TCR sequencing (TCR-Seq). However, the available TCR-Seq data are limited compared with RNA sequencing (RNA-Seq). In this paper, we have benchmarked the ability of RNA-Seq-based methods to profile TCR repertoires by examining 19 bulk RNA-Seq samples across 4 cancer cohorts including both T-cell-rich and T-cell-poor tissue types. We have performed a comprehensive evaluation of the existing RNA-Seq-based repertoire profiling methods using targeted TCR-Seq as the gold standard. We also highlighted scenarios under which the RNA-Seq approach is suitable and can provide comparable accuracy to the TCR-Seq approach. Our results show that RNA-Seq-based methods are able to effectively capture the clonotypes and estimate the diversity of TCR repertoires, as well as provide relative frequencies of clonotypes in T-cell-rich tissues and low-diversity repertoires. However, RNA-Seq-based TCR profiling methods have limited power in T-cell-poor tissues, especially in highly diverse repertoires of T-cell-poor tissues. The results of our benchmarking provide an additional appealing argument to incorporate RNA-Seq into the immune repertoire screening of cancer patients as it offers broader knowledge into the transcriptomic changes that exceed the limited information provided by TCR-Seq. [ABSTRACT FROM AUTHOR]

Simple Summary: As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, extracellular matrix (ECM), and soluble molecules forming the widely recognized tumor microenvironment. The main components of the tumor microenvironment include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), ECM, and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). The tumor microenvironment has been suggested to play a central role in tumor progression and treatment resistance. Accumulated evidence indicates that tumor maintenance, progression, and treatment resistance are determined by components of the microenvironment. Thus, targeting the components of the tumor microenvironment may have a therapeutic impact on melanoma treatment. The main topic of this paper deals with the main components of the tumor microenvironment and their impact as therapeutic targets in melanoma treatment. The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies. [ABSTRACT FROM AUTHOR]

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy. [ABSTRACT FROM AUTHOR]

This paper proposes a modified Schmitt-trigger (ST)-based single-ended 11 T (MST11T) SRAM cell. The proposed cell is best suited to ultra-low voltage applications. Two ST-based cross-coupled inverters comprise the storage cell of the proposed MST11T bit cell. In comparison with conventional inverters, ST-based inverters have sharp voltage transfer characteristics. As a result, the proposed bit cell's stability performance increases. The proposed SRAM cell's leakage power consumption is reduced because of the use of stacked N-type transistors. For the read operation of the proposed bit cell, the read decoupled technique is used. As a result, the read static noise margin (RSNM) has greatly improved. The proposed bit cell's write static noise margin (WSNM) is increased by adopting feedback-cutting methodology. The performance of the proposed bit cell is compared with that of conventional 6 T, conventional 8 T, Schmitt-trigger 10 T (known as ST2), modified PMOS-PMOS-NMOS-based cell core 10 T (MPPN10T), feedback-cutting 11 T (FC11T), Schmitt-trigger 11 T (ST11), and Schmitt-trigger 12 T (ST12T) cells. According to the simulation results, the proposed MST11T SRAM cell has RSNM of 2.42, 1.18, 1.71, 1.30, and 1.80 times higher when compared to 6 T, FC11T, ST2, MPPN10T, and ST12T, respectively. The WSNM of the proposed bit cell has been increased by 1.56, 2.44, 1.28, 1.71, 1.35, 1.52, and 1.02 times, respectively, over 6 T, 8 T, ST2, MPPN10T, FC11T, ST11T, and ST12T. Furthermore, the suggested cell has a read delay that is 1.32, 1.79, and 1.53 times lower than ST11T, FC11T, and ST12T, respectively. The proposed bit cell has a write delay that is 1.14 and 1.63 times lower than FC11T and ST11T, respectively. The proposed MST11T bit-cell consumes 3.74, 1.56, 4.59, 5.38, and 4.83 times less leakage power than the 8 T, ST2, MPPN10T, FC11T, and ST12 bit-cells, respectively. When compared to 8 T/ST2/MPPN10T/ST12T at 0.2 V supply voltage, the enhanced facts incur a 4.87/3.79/3.78/1.97 penalty in write delay. The figure of merit (FOM) is derived as a result of this extensive access to the revolutionary SRAM cell performance, i.e., offering greater values at a 0.2 V DC supply voltage. In addition, the paper examines the impact of manufacturing process and temperature changes on MST11T cell enactment, as well as the circuit robustness using HSPICE with 7-nm FinFET technology. [ABSTRACT FROM AUTHOR]

The AIDS is a chronic disease and the researchers still exert their high efforts to reach the cure of HIV infection. The most common treatment is the antiretroviral therapy (cART) and the virus can be more effected if the patients stop using cART. The other problem is that the CD8+ T cells might be exhausted by persistent immune activation by cART. This paper introduces fractional-order into a mathematical model of HIV infection combining with stem cell therapy and control the infection by the immune system cells (CD8+ T cells). The paper introduced the numerical solutions for the mathematical model. The results show that the stem cell therapy with the activation of immune system cells might causes the cure for a HIV patient. This results are consistent with medical studies. Also, we proposed the effect of the fractional order (α) on the figures of the components. [ABSTRACT FROM AUTHOR]

The cells of acute myeloid leukemia are defined by clonal growth and heterogenous immunophenotypes. Chimeric antigen receptors (CARs) commonly recognize molecular targets by single-chain antibody fragments (scFvs) specific to a tumor-associated antigen. However, ScFvs may form aggregates, thus stimulating tonic CAR T-cell activation and reducing CAR T-cell functioning in vivo. Harnessing natural ligands as recognition parts of CARs, specific targeting of membrane receptors can be achieved. Previously, we presented ligand-based Flt3-CAR T-cells targeting the Flt3 receptor. The extracellular part of Flt3-CAR consisted of full-size Flt3Lg. Meanwhile, upon recognition, Flt3-CAR may potentially activate Flt3, triggering proliferative signaling in blast cells. Moreover, the long-lasting presence of Flt3Lg may lead to Flt3 downregulation. In this paper, we present mutated Flt3Lg-based Flt3m-CAR ('m'—for 'mutant') T-cells targeting Flt3. The extracellular part of Flt3m-CAR consists of full-length Flt3Lg-L27P. We have determined that ED50 for recombinant Flt3Lg-L27P produced in CHO cells is at least 10-fold higher than for the wild-type Flt3Lg. We show that the mutation in the recognizing domain of Flt3m-CAR did not affect the specificity of Flt3m-CAR T-cells when compared to Flt3-CAR T-cells. Flt3m-CAR T-cells combine the specificity of ligand–receptor recognition with reduced Flt3Lg-L27P bioactivity, leading to potentially safer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most prevalent cerebral cancer in adults without proven therapy. Chimeric antigen receptor T cell treatment has demonstrated good clinical success in hematologic cancers. The application of chimeric antigen receptor T cell therapy to solid tumors, such as glioblastoma, is currently the subject of scientific investigation. The creation of chimeric antigen receptor T cells and its iterations are briefly described in this article. Specifically, this study addresses the obstacles and hurdles faced and glioblastoma targets studied in recent years. This review provides the reader with a comprehensive understanding of the current state of chimeric antigen receptor T cell therapy for glioblastoma and a clear understanding of each therapeutic target. Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. [ABSTRACT FROM AUTHOR]