Challenges and strategies in relation to effective CAR-T cell immunotherapy for solid tumors.

Chimeric Antigen Receptor T cell (CAR-T) therapy has revolutionized cancer treatment, but its application to solid tumors is limited. CAR-T cells have poor incapability of entering, surviving, proliferating, and finally exerting function in the tumor microenvironment. This review summarizes the main strategies related to enhancing the infiltration, efficacy, antigen recognition, and production of CAR-T in solid tumors. Additional applications of CAR-γδ T and macrophages are also discussed. We believe CAR-T will be a milestone in treating solid tumors once these problems are solved.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Single-cell transcriptome analyses reveal disturbed decidual homoeostasis in obstetric antiphospholipid syndrome.

OBJECTIVES: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies in circulation and pathological pregnancy. However, the pathogenesis of OAPS remains unknown. We aimed to reveal cellular compositions and molecular features of decidual cells involved in the development of OAPS using single-cell RNA sequencing (scRNA-seq). METHODS: We performed unbiased scRNA-seq analysis on the first-trimester decidua from five OAPS patients and five healthy controls (HCs), followed by validations with flow cytometry, immunohistochemical staining and immunofluorescence in a larger cohort. Serum chemokines and cytokines were measured by using ELISA. RESULTS: A higher ratio of macrophages but a lower ratio of decidual natural killer (dNK) cells was found in decidua from OAPS compared with HCs. Vascular endothelial cells shrinked in OAPS decidua while having upregulated chemokine expression and conspicuous responses to IFN-γ and TNF-α. Macrophages in OAPS had stronger phagocytosis function, complement activation signals and relied more on glycolysis. dNK cells were more activated in OAPS and had enhanced cytotoxicity and IFN-γ production. Downregulation of granules in OAPS dNK cells could be associated with suppressed glycolysis. Moreover, stromal cells had a prosenescent state with weakened immune surveillance for senescent cells in OAPS. In addition, the cellular interactions between decidual immune cells and those of immune cells with non-immune cells under disease state were altered, especially through chemokines, IFN-γ and TNF-α. CONCLUSION: This study provided a comprehensive decidual cell landscape and identified aberrant decidual microenvironment in OAPS, providing some potential therapeutic targets for this disease.

Effects of different gonadotropin preparations in GnRH antagonist protocol for patients with polycystic ovary syndrome during IVF/ICSI: a retrospective cohort study.

Purpose: To compare the effects of recombinant FSH alfa (rFSH-alfa), rFSH-beta, highly purified human menopausal gonadotropin (HP-hMG) and urinary FSH (uFSH) in women with polycystic ovarian syndrome who have undertaken the GnRH antagonist protocol during IVF/ICSI treatment. Method: A single-center retrospective cohort study including women with PCOS who received the GnRH antagonist protocol from January 2019 to July 2022 was conducted. Patients were divided into rFSH-alfa group, HP-hMG group, uFSH group, and rFSH-beta group, and the number of oocytes retrieved, clinical pregnancy rate of the fresh cycle (primary outcomes), embryo quality, and severe OHSS rate (secondary outcomes) were compared. Results: No statistical differences were found among the four groups in fresh cycle clinical pregnancy rate (p=0.426), nor in the subgroup analyses. The HP-hMG group had a smaller number of oocytes retrieved and a higher high-quality D3 embryo rate than the three FSH groups (p<0.05). No statistical differences were found among the four groups in the severe OHSS rate (p=0.083). Conclusion: For women with PCOS undergoing the GnRH antagonist protocol, the clinical pregnancy rates of fresh IVF/ICSI-ET cycle are similar for all four types of Gn. With a lower risk of OHSS and a similar number of high-quality and available embryos, HP-hMG may have an advantage in the PCOS population.

CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.

γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges.

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

Cluster analysis reveals a homogeneous subgroup of PCOS women with metabolic disturbance associated with adverse reproductive outcomes.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a heterogeneous and complex reproductive endocrinological disease that could lead to infertility. There were many attempts to classify PCOS but it remains unclear whether there is a specific subgroup of PCOS that is associated with the best or worst reproductive outcomes of assisted reproductive techniques (ART). METHODS: Infertile PCOS patients who underwent their first cycle of in vitro fertilization (IVF) in West China Second University Hospital, Sichuan University from January 2019 to December 2021 were included. Basic clinical and laboratory information of each individual were extracted. Unsupervised cluster analysis was performed. Controlled ovarian stimulation parameters and reproductive outcomes were collected and compared between the different clusters of PCOS. RESULTS: Our analysis clustered women with PCOS into "reproductive", "metabolic", and "balanced" clusters based on nine traits. Reproductive group was characterized by high levels of testosterone (T), sex hormone-binding globulin (SHBG), follicular stimulation hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Metabolic group was characterized by high levels of body mass index (BMI), fasting insulin, and fasting glucose. Balanced group was characterized by low levels of the aforementioned reproductive and metabolic parameters, except for SHBG. Compared with PCOS patients in reproductive and balanced clusters, those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst formation. Moreover, PCOS patients in the reproductive cluster had greater fresh embryo transfer (ET) cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.77-6.44, and OR = 6.19, 95% CI: 1.58-24.24, respectively). And compared with PCOS of metabolic cluster, PCOS of balanced cluster also had higher chance for fresh ET cancelation (OR = 2.83, 95% CI: 1.26-6.35). CONCLUSION: Our study suggested that PCOS patients in metabolic cluster may be associated with adverse reproductive outcomes and might need individualized treatment and careful monitoring before and during ART.

A correlation analysis on the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus.

Objective: The aim of this study is to discuss the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus (GDM) to provide a clinical basis for better early identification and intervention of adverse mood. Methods: Convenient sampling method was adopted to investigate 205 pregnant women as the observation group and 201 normal healthy pregnant women in the same period as the control group. The self-rating anxiety scale (SAS) was used to investigate and observe the respondents, evaluate the postpartum anxiety status of patients with GDM, and analyze the related influencing factors. Statistical analysis of the data was performed using SAS 3.0 software. A proposed P < 0.05 was considered as statistically significant. Results: Patients with GDM had a higher risk than normal maternal anxiety, related to years of education, triglycerides, 1-h postprandial blood glucose, and a history of induced abortion. Conclusion: GDM can lead to the occurrence of postpartum anxiety, and the poor psychological state is not conducive to the maternal and infant health. Early identification and early intervention can reduce the harm caused by anxiety and promote the progress of maternal and infant health and clinical research.

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.

CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.

The robust and stable expression of CD38 in T-cell acute lymphoblastic leukemia (T-ALL) blasts makes CD38 chimeric antigen receptor (CAR)-T/natural killer (NK) a potential therapy for T-ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR-T/NK cells. Here a "2-in-1" gene editing strategy is developed to generate fratricide-resistant locus-specific CAR-T/NK cells. CD38-specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI ) or exogenous EF1α promoter (CD38KO/KI EF1α). CD38 knockout reduces fratricide and allows the expansion of CAR-T cells. Meanwhile, CD38KO/KI EF1α results in higher CAR expression than CD38KO/KI in both CAR-T and CAR-NK cells. In a mouse T-ALL model, CD38KO/KI EF1α CAR-T cells eradicate tumors better than CD38KO/KI CAR-T cells. Surprisingly, CD38KO/KI CAR-NK cells show superior tumor control than CD38KO/KI EF1α CAR-NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR-T and CAR-NK cells differently. Therefore, these results support the efficacy of CD38 CAR-T/NK against T-ALL and demonstrate that the "2-in-1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation.

Single-cell analysis reveals HBV-specific PD-1+CD8+ TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients.

Immune checkpoint blockade (ICB) treatment of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection may activate viral-specific T cells to attack HBV infected hepatocytes and thus induce immune-related liver injury. Therefore, it is important to deeply understand the impacts of HBV infection on HCC immune microenvironment in order to better design effective immunotherapies for HBV+ (HBV infected) HCC patients. Here, We performed cytometry by time-of-flight (CyTOF) analyses to characterize the distinct immune compositions of HCC tumors, tumor borders, and their associations with HCC/HBV related clinical characteristics. We identified 31 distinct immune clusters and found significant associations between immune signatures with clinicopathological features of HCC. We further revealed the HBV infection had more effects on shaping immune compositions in tumor borders than in tumors, with the significant enrichment of HBV-specific PD-1+CD8+ tissue-resident memory T (TRM) cells in tumor borders of HBV+ patients. We confirmed this subset with a more exhausted phenotype and respond more actively under anti-PD-L1 treatment, suggesting its involvement in immune-related liver injury induced by ICB treatment to HBV+ HCC patients. Our study shows it may be necessary to consider antiviral prophylaxis for HBV+ HCC patients receiving ICB treatment.

Triple and double twin interfaces in magnesium-the role of disconnections and facets.

Twin boundaries have been shown to deviate from the twinning planes in hcp metals, and facets have often been observed in twin interfaces. This study presents a twinning disconnection-based model for faceting in single, double and triple twin boundaries in magnesium. Primary twinning disconnections predicted via symmetry arguments are shown to produce commensurate facets in single twin boundaries, which are then transformed into commensurate facets in double twin boundaries via the action of secondary twinning disconnections. In contrast, it is shown that for triple twin boundaries with tension-compression-tension twinning sequence, no commensurate facets can be produced by the action of tertiary twinning disconnections. The effect of facets on the macroscopic orientation of twin interfaces is discussed. Theoretical findings are validated by a transmission electron microscopy study of a hot rolled Mg-1.18wt%Al-1.77wt%Nd alloy. Single and double twins are observed, as well as rare triple twins, and the interface between the matrix and a triple twin is captured for the first time. Facets consistent with theoretical predictions are imaged via high-resolution TEM and macroscopic deviations of the boundaries from the primary twinning planes are measured.

The function of γδ T cells in humoral immune responses.

PURPOSE: The purpose of this review is to discuss the role of γδ T cells played in humoral immune responses. BACKGROUND: The γδ T cell receptor (γδ TCR) recognizes antigens, including haptens and proteins, in an MHC-independent manner. The recognition of these antigens by γδ TCRs crosses antigen recognition by the B cell receptors (BCRs), suggesting that γδ T cells may be involved in the process of antigen recognition and activation of B cells. However, the role of γδ T cells in humoral immune responses is still less clear. METHODS: The kinds of literature about the γδ T cell-B cell interaction were searched on PubMed with search terms, such as γδ T cells, antibody, B cell responses, antigen recognition, and infection. RESULTS: Accumulating evidence indicates that γδ T cells, independent of αß T cells, participate in multiple steps of humoral immunity, including B cell maturation, activation and differentiation, antibody production and class switching. Mechanically, γδ T cells affect B cell function by directly interacting with B cells, secreting cytokines, or modulating αß T cells. CONCLUSION: In this review, we summarize current knowledge on how γδ T cells take part in the humoral immune response, which may assist future vaccine design.

Deformation Mechanisms of Magnesium Alloys with Rare-Earth and Zinc Additions under Plane Strain Compression.

The introduction of rare-earth (RE) elements into magnesium (Mg) alloys can significantly improve their ductility, thereby extending the applications of Mg products. However, the impacts of their chemical composition, temperature and processing methods on the mechanical properties of Mg products are highly debatable. In this work, we systematically investigate the deformation behaviors of Mg-Nd and Mg-Zn-Nd alloys using electron backscattered diffraction (EBSD) characterization. The samples were deformed to different stress levels to study the microstructure and texture development during channel die compression. The results reveal that the room temperature formability of the Mg-Nd alloy can be enhanced with the addition of Zn. This is attributed to the higher activities of prismatic slip and tensile twinning in the Mg-Zn-Nd alloy as compared to the binary counterpart, facilitating strain accommodation. When the strain increases, the growing and merging of the same twin variant rapidly consumes the parent grain, which is responsible for the texture modification from the transverse to the basal direction. At elevated temperatures, the twinning is suppressed in both alloys due to the decreased critical resolved shear stress of the non-basal slip systems. Additionally, an obvious sigmoidal yielding phenomenon is observed due to the multiple activation of the different deformation modes. These findings offer valuable insights into the evolution of the microstructure and texture during plane strain compression, elucidating the connections between material chemical composition, processing and mechanical properties, which are important for the advancement of Mg alloy application.

The relationship between pregnancy stress and mental health of the pregnant women: the bidirectional chain mediation roles of mindfulness and peace of mind.

Objective: This study aimed to investigate the relationship between pregnancy stress and mental health of the pregnant women, employing a positive psychology perspective. Specifically, the study sought to explore how the two positive psychological qualities of mindfulness and peace of mind may serve as potential mediators in the association between pregnancy stress and mental health of the pregnant women. Methods: Seven hundreds and thirteen pregnant women seeking care at the First Affiliated Hospital of Sun Yat-Sen University were included in this study. The participants completed a self-report demographic questionnaire, as well as several validated scales including the Pregnancy Pressure Scale (PPS), Mindful Attention Awareness Scale (MAAS), Peace of Mind Scale (PoMS), and Chinese Health Questionnaire (CHQ). The Amos 23.0 system was utilized to construct structural equation models. Results: A total of 713 participants had an average age of 29.46 ± 4.81 years and an average gestational age of 24.26 ± 22.66 weeks. Out of the pregnant women, 163 (22.9%) experienced moderate or higher levels of pregnancy stress (PPS > 1), while 212 (29.7%) exhibited mental distress (CHQ > 3). Pregnancy stress exhibited a positive association with mental distress, while displaying negative associations with mindfulness and peace of mind. Mindfulness and peace of mind were negatively associated with mental distress. By employing structural equation modeling, the analysis revealed that mindfulness and peace of mind acted as partial mediators in the relationship between pregnancy stress and mental health. Furthermore, the identified models exhibited bidirectional sequential mediating pathways, suggesting that the pathways of mindfulness ↔ peace of mind mitigated the harmful influence of pregnancy stress on the mental health of pregnant women. Conclusion: This study adds to the current body of knowledge by investigating the relationships among mindfulness, peace of mind, pregnancy stress, and mental health in pregnant women. From a positive psychology framework, it provides valuable understanding of the intricate dynamics between pregnancy stress and protective factors of mental health. Consequently, interventions aimed at bolstering positive psychological qualities in pregnant women should prioritize the cultivation of mindfulness to foster peace of mind, or alternatively, the cultivation of peace of mind to enhance mindfulness, ultimately leading to improved mental health outcomes.

Assessment of the status quo of social responsibility performance of inclusive kindergartens: Evidence from China.

China is determined to accomplish universal preschool education by asking the kindergartens to participate in social responsibility programs. This study intends to assess the level of participation of inclusive kindergartens in social responsibility programs. This study uses the Delphi expert method, integrated ISO26000 International Standard Guidelines for Social Responsibility, CSR (Corporate Social Responsibility) Scale, and the characteristics of the preschool education industry to construct a social responsibility evaluation model for inclusive kindergartens. It includes five dimensions (responsibility management, customer responsibility, employee responsibility, social service, and organizational responsibility) to show the social responsibility status of kindergartens. Data was collected from 832 respondents from 27 provinces, cities, and regions in China. This study reveals that the overall performance of social responsibility of inclusive kindergarten (3.67) is better, while organization responsibility (3.91) shows the highest performance. In comparison, customer (3.63) and staff responsibility (3.63) deliver average performance, and responsibility management (3.56) offers lower performance. The statistical analysis shows that the nature of kindergartens, whether inclusive or not, the number of classes, years of establishment, the distribution area, and performance are different. Kindergartens should have certain social values, including specific behaviors and participating in social activities in the spirit of social service. They should ensure preschool teacher's professional and vocational development through multiple subjects' synergetic governance. In addition to fulfilling the teachers' social responsibility and professional development, the findings can put forward the cooperation with the government, social organizations, and kindergartens to improve teachers' professional quality and social responsibility.

Prediction of tumor recurrence by distinct immunoprofiles in liver transplant patients based on mass cytometry.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is a marker of poor prognosis. However, the reliable biomarkers of post-LT HCC recurrence remain to be identified. In this study, serial peripheral blood samples from the LT recipients with and without HCC recurrence were collected at five time points. Single-cell mass cytomertry (CyTOF) was utilized for the in-depth analysis of peripheral blood monocellular cells (PBMCs). CyTOF analysis showed that at 3 weeks post-LT, the activated immune cell population was increased, while the fraction of immune cells with suppressive functions (myeloid-derived suppressive cells) was reduced. The post-LT immune composition in patients with LT for HCC was enormously different from that in patients with LT for causes other than HCC. Furthermore, at 3 weeks after LT, compared with patients without recurrence, the patients with HCC recurrences were high in two subsets of T cells: CD57+ HLA-DR+ CD8+ and CD28+γδ. The CD57+ HLA-DR+ CD8+ T cells presented high levels of perforin, granzyme B, and Ki-67 and displayed a highly cytotoxic and proliferative phenotype, while the CD28+γδ T cells had reduced levels of IFN-γ and, hence, were less activated compared to CD28- cells. Based on these findings, we concluded that analyzing the PBMCs of LT recipients by CyTOF can predict the post-LT HCC recurrence. The distinct immune features can stratify patients with the risk of HCC recurrence at 3 weeks after LT, which will help clinician in further management plan and improve the prognosis of patients.

Immune-infiltrating signature-based classification reveals CD103+CD39+ T cells associate with colorectal cancer prognosis and response to immunotherapy.

Background: Current stratification systems for tumor prognostic prediction and immunotherapeutic efficacy evaluation are less satisfying in colorectal cancer (CRC). As infiltrating immune cells in tumor microenvironment (TME) played a key role in tumor progression and responses to immune checkpoint blockade (ICB) therapy, we want to construct an immune-related scoring system with detailed immune profiles to stratify CRC patients. Methods: We developed a scoring system based on immune-related signatures and validated its ability to predict prognosis and immunotherapeutic outcomes in CRC. CD45+ cells from CRC patients were sorted to investigate detailed immune profiles of the stratification system using mass cytometry. A single-cell RNA sequencing dataset was used to analyze transcriptomic profiles. Results: We constructed an immune-related signature score (IRScore) based on 54 recurrence-free survival (RFS)-related immune signatures to stratify CRC patients. We revealed that IRScore was positively correlated with RFS and favorable outcomes in ICB treatment. Moreover, we depicted a detailed immune profile in TME using mass cytometry and identified that CD103+CD39+ T cells, characterized by an exhaustive, cytotoxic and proliferative phenotype, were enriched in CRC patients with high IRScore. As a beneficial immune signature, CD103+CD39+ T cells could predict prognosis and responses to ICB therapy in CRC. Conclusions: All the analyses above revealed that IRScore could be a valuable tool for predicting prognosis and facilitating the development of new therapeutic strategies in CRC, and CD103+CD39+ T cells were one of defined immune signatures in IRScore, which might be a key factor for antitumor immunity.

The role of adenosine A1 receptor on immune cells.

BACKGROUND: Adenosine, acting as a regulator by mediating the activation of G protein-coupled adenosine receptor families (A1, A2A, A2B, and A3), plays an important role under physiological and pathological conditions. As the receptor with the highest affinity for adenosine, the role of adenosine A1 receptor (A1R)-mediated adenosine signaling pathway in the central nervous system has been well addressed. However, functions of A1R on immune cells are less summarized. Considering that some immune cells express multiple types of adenosine receptors with distinct effects and varied density, exogenous adenosine of different concentrations may induce divergent immune cell functions. MATERIALS AND METHODS: The literatures about the expression of A1R and its regulation on immune cells and how it regulates the function of immune cells were searched on PubMed and Google Scholar. CONCLUSION: In this review, we discussed the effects of A1R on immune cells, including monocytes, macrophages, neutrophils, dendritic cells, and microglia, and focused on the role of A1R in regulating immune cells in diseases, which may facilitate our understanding of the mechanisms by which adenosine affects immune cells through A1R.

The Essential Role of Body Weight in Adjusting Gn Dosage to Prevent High Ovarian Response for Women With PCOS During IVF: A Retrospective Study.

Polycystic ovarian syndrome (PCOS) is the major cause of anovulatory infertility. Since women with PCOS are often accompanied by increased body weight and hyper response to controlled ovarian stimulation, individualized gonadotropin (Gn) dose is required to achieve a therapeutic effect while minimizing the risk of ovarian hyperstimulation simultaneously. We aimed to investigate the essential role of body weight in optimizing initial Gn dosage for PCOS patients during in vitro fertilization (IVF). We retrospectively included 409 infertile PCOS patients who used gonadotropin-releasing hormone (GnRH)-antagonist fixed protocol and underwent their first cycle of IVF in West China Second University Hospital from January 2019 to June 2021. Baseline characteristics controlled ovarian stimulation parameters, and reproductive outcomes were compared between patients with different body weights and different ovarian responses. Multivariable linear regression analyses were adopted to investigate the relationship between body weight and initial Gn dosage. Receiver operating characteristic (ROC) curves were drawn to find the optimal cut-off value of body weight in predicting the starting Gn dosage so as to prevent high ovarian response (HOR). We found that luteinizing hormone (LH) level and Anti-Mullerian hormone (AMH) level were lowest in the group with body weight over 70 kg and was highest in the group with body weight less than 50 kg. Increased body weight was significantly correlated to the rise of initial Gn dosage (Beta = 0.399, t = 8.921, p < 0.001). Normal ovarian response (NOR) patients had significantly less fresh cycle cancel rate and ovarian hyperstimulation syndrome (OHSS) rate which outweighed the fewer embryos compared with HOR patients. Using ROC curves, 53.25 kg (sensitivity, 84.2%; specificity, 53.8%) and 70.5 kg (sensitivity, 58.8%; specificity, 93.0%) were identified as the optimal cut-off values to predict the initial Gn dosage of no more than 150 IU and 225 IU, respectively. In conclusion, adjusting the initial Gn dosage based on body weight is crucial to preventing ovarian hyperstimulation while not influencing reproductive outcomes for PCOS patients during IVF.