Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.

BACKGROUND: Programmed death-1 (PD-1) blockade promotes combination therapy in advanced non-small cell lung cancer (NSCLC), hypofractionated radiotherapy (HFRT) and chemotherapy combined with immunotherapy improves the outcome of prognosis in advanced NSCLC, while effective biomarkers to follow prognostic efficacy are still to be found. METHODS: We enrolled 44 NSCLC patients with HFRT combined with PD-1 blockade, 13 patients with chemotherapy combined with immunotherapy, additionally collected tissue samples from 8 patients with earlystage NSCLC without therapy, and peripheral whole blood from 16 healthy donors, detected the expression differences of cytokines Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Interleukin 17A (IL-17A) in the peripheral plasma and tissues by flow cytometry, immunofluorescence, and real-time fluorescence quantitative PCR. Cultured peripheral blood mononuclear cell (PBMC) and tumor-infiltrating T cells with recombinant human IL-8 in vitro to observe the changes of immune memory T cell subtypes and apoptosis. RESULTS: Our results show that IL-6, IL-8, and IL-17A are highly expressed in advanced NSCLC, high levels of IL-8 are significantly associated with poor prognosis in advanced NSCLC patients treated with HFRT + PD1 blockade, high circulating IL-8 in NSCLC increased apoptosis of effector memory RA (TemRA; CD45RA+CCR7-) T cell subsets and CD8+ T cell subsets in tissues, resulting in decreased peripheral TemRA and stem cell-like memory T cells (TSCM: CD45RA +CCR7 + CD95 +) in tissue. CONCLUSION: We suggest that IL-8 can impair immune memory function in NSCLC. It is a useful biomarker to evaluate the efficacy of HFRT + PD1 blockade in advanced NSCLC. Further exploration of easily available plasma biomarkers for personalized treatment of NSCLC is required.

Steering interface effect of H-ZSM-5 zeolites with tailored surface barriers to improve their catalytic performances.

An efficient zeolite interface with optimized surface barriers was tailored by passivating the hydroxyl-group defects at surfaces or near pore mouths. The surface permeability of the modified zeolite was almost 90% greater than that of the pristine one, leading to remarkable improvements in C=2-3 selectivity and an anti-inactivation rate of 75% for the catalytic cracking reaction.

Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer.

In response to prolonged stimulation by tumour antigens, T cells gradually become exhausted. There is growing evidence that exhausted T cells not only lose their potent effector functions but also express multiple inhibitory receptors. Checkpoint blockade (CPB) therapy can improve cancer by reactivating exhausted effector cell function, leading to durable clinical responses, but further improvements are needed given the limited number of patients who benefit from treatment, even with autoimmune complications. Here, we suggest, based on recent advances that tumour antigens are the primary culprits of exhaustion, followed by some immune cells and cytokines that also play an accomplice role in the exhaustion process, and we also propose that chronic stress-induced hypoxia and hormones also play an important role in promoting T-cell exhaustion. Understanding the classification of exhausted CD8+ T-cell subpopulations and their functions is important for the effectiveness of immune checkpoint blockade therapies. We mapped the differentiation of T-cell exhausted subpopulations by changes in transcription factors, indicating that T-cell exhaustion is a dynamic developmental process. Finally, we summarized the novel immune checkpoints associated with depletion in recent years and combined them with bioinformatics to construct a web of exhaustion-related immune checkpoints with the aim of finding novel therapeutic targets associated with T-cell exhaustion in malignant tumours, aiming to revive the killing ability of exhausted T cells and restore anti-tumour immunity through combined targeted immunotherapy.

Effect of the m6ARNA gene on the prognosis of thyroid cancer, immune infiltration, and promising immunotherapy.

Background: Accumulating evidence suggests that N6-methyladenosine (m6A) RNA methylation plays an important role in tumor proliferation and growth. However, its effect on the clinical prognosis, immune infiltration, and immunotherapy response of thyroid cancer patients has not been investigated in detail. Methods: Clinical data and RNA expression profiles of thyroid cancer were extracted from the Cancer Genome Atlas-thyroid carcinoma (TCGA-THCA) and preprocessed for consensus clustering. The risk model was constructed based on differentially expressed genes (DEGs) using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. The associations between risk score and clinical traits, immune infiltration, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), immune infiltration, and immunotherapy were assessed. Immunohistochemistry was used to substantiate the clinical traits of our samples. Results: Gene expression analysis showed that 17 genes, except YHTDF2, had significant differences (vs healthy control, P<0.001). Consensus clustering yielded 2 clusters according to their clinical features and estimated a poorer prognosis for Cluster 1 (P=0.03). The heatmap between the 2 clusters showed differences in T (P<0.01), N (P<0.001) and stage (P<0.01). Based on univariate Cox and LASSO regression, a risk model consisting of three high-risk genes (KIAA1429, RBM15, FTO) was established, and the expression difference between normal and tumor tissues of three genes was confirmed by immunohistochemical results of our clinical tissues. KEGG and GSEA analyses showed that the risk DEGs were related mainly to proteolysis, immune response, and cancer pathways. The levels of immune infiltration in the high- and low-risk groups were different mainly in iDCs (P<0.05), NK cells (P<0.05), and type-INF-II (P<0.001). Immunotherapy analysis yielded 30 drugs associated with the expression of each gene and 20 drugs associated with the risk score. Conclusions: Our risk model can act as an independent marker for thyroid cancer and provides promising immunotherapy targets for its treatment.

Systematic Pan-Cancer Analysis Identifies CDK1 as an Immunological and Prognostic Biomarker.

Cyclin-dependent kinase 1 (CDK1) plays an important role in cancer development, progression, and the overall process of tumorigenesis. However, no pan-cancer analysis has been reported for CDK1, and the predictive role of CDK1 in immune checkpoint inhibitors (ICIs) therapy response remains unexplored. Thus, in this study, we first investigated the potential oncogenic role of CDK1 in 33 tumors by multidimensional bioinformatics analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Bioinformatic analysis and immunohistochemical experiments confirmed that CDK1 is significantly upregulated in most common cancers and is strongly associated with prognosis. Further analysis indicated that CDK1 may influence tumor immunity mainly by mediating the degree of tumor infiltration of immune-associated cells, and the effect of CDK1 on immunity is diverse across tumor types in tumor microenvironment. CDK1 was also positively correlated with tumor mutational burden (TMB) and microsatellite instability (MSI) in certain cancer types, linking its expression to the assessment of possible treatment response. The results of the pan-cancer analysis study showed that the CDK1 gene was positively associated with the expression of three classes of RNA methylation regulatory proteins, and affects RNA function through multiple mechanisms of action and plays an important role in the posttranscriptional regulation of the tumor microenvironment. These findings shed light on the role of the CDK1 gene in cancer progression and provide information to further study the CDK1 gene as a potential target for pan-cancer.

EphA2 recognizes Dermatophagoidespteronyssinus to mediate airway inflammation in asthma.

Most of the asthma with low Th2 is severe steroid-resistant asthma, the exact pathogenesis of which has not yet been fully elucidated. We found that IL-6 and IL-8 were highly expressed in the sputum supernatant of severe asthma and ephrin type-A receptor 2 (EphA2) was highly expressed on bronchial epithelial cells. So, is there a connection between these two phenomena? To clarify this issue, we stimulated bronchial epithelial cells 16HBE with Dermatophagoides pteronyssinus and its compontents LPS, respectively, and detected the activation of EphA2, activation of downstream pathways and secretion of inflammatory cytokines. A mouse asthma model was established, and the therapeutic effects of inhibiting or blocking EphA2 on mouse asthma were investigated. The results showed that D. pteronyssinus and its component LPS phosphorylated EphA2 on 16HBE, activated downstream signaling pathways STAT3 and p38 MAPK, and promoted the secretion of IL-6 and IL-8. After knockout of EphA2 on 16HBE, the activation of inflammatory pathways was attenuated and the secretion of IL-6 and IL-8 was significantly reduced. Inhibition or blockade of EphA2 on mouse airways resulted in a significant reduction in airway hyperresponsiveness and airway inflammation, and a significant decrease in the expression levels of IL-6, IL-17F, IL-1α, IL-1ß and TNF in bronchoalveolar lavage fluid and lung tissue. Our study uncovers a novel role for EphA2 expressed on airway epithelial cells in the pathogenesis of asthma; EphA2 recognizes D. pteronyssinus or its component LPS and promotes the secretion of IL-6 and IL-8 by airway epithelial cell, thereby mediating airway inflammation. Thus, it is possible to provide a new molecular therapy for severe asthma.

A novel fully human recombinant antibody neutralizing α-hemolysin of Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to almost all ß-lactam antibiotics. Hence, new ways to control MRSA infection, such as antibacterial antibodies, need to be explored. α-hemolysin is the most important virulence factor widely expressed in S. aureus. This study aimed to develop a new fully human antibody against α-hemolysin of S. aureus and research its neutralizing effect. The single-chain antibody fragments (scFvs) against S. aureus were screened from a fully human scFv library using phage display technology. The selected scFvs had good binding affinities to α-hemolysin and S. aureus. The IgG-like scFv-Fc inserted into the pcDNA3.1 or pMH3 vector was expressed in HEK293F suspension cells to extend the half-life and restore Fc function. The size of purified scFv-Fc was about 55 kDa. The functions of expressed scFv-Fcs against α-hemolysin were validated. The cytotoxicity assays showed that scFv555-Fc had better protective effects on A549 cells than other scFv-Fcs. The results of anti-rabbit erythrocyte lysis and A549 cell apoptosis assay confirmed that scFv555-Fc had a significant neutralizing effect on α-hemolysin. The scFv555-Fc was used to construct the docking model of antigen-antibody complexes using Discovery Studio software. It predicted that the key binding sites of α-hemolysin were TYR28, LYS37, PHE39, ARG56, and LYS58, which might be the key toxic sites of α-hemolysin. A novel fully human scFv-Fc antibody neutralizing the α-hemolysin toxin of S. aureus was successfully developed. The findings might provide a new theoretical basis and treatment method for preventing MRSA infection.

The Predictive Value of Serum Calcium on Heart Rate Variability and Cardiac Function in Type 2 Diabetes Patients.

Background: Cardiovascular autonomic neuropathy (CAN) is common in patients with type 2 diabetes mellitus (T2DM), mainly presented as decreased heart rate variability (HRV) which often leads to cardiac death. However, HRV measurement is not convenient in most clinics. Therefore, identifying high-risk patients for CAN in diabetes with easier measurements is crucial for the early intervention and prevention of catastrophic consequences. Methods: In this cross-sectional study, 675 T2DM patients with normocalcemia were selected. Of these, they were divided into two groups: normal HRV group (n = 425, 100 ms≤ SDNN ≤180 ms) vs. declined HRV group (n = 250, SDNN <100 ms). All patients' clinical data were collected and the correlation of clinical variables with HRV were analyzed by correlation and logistic regression analysis. The area below the ROC curve was used to evaluate the predictive performance of serum calcium on HRV. Results: In this study, declines in HRV were present in 37.0% of T2DM patients. Significant differences in albumin-adjusted serum calcium levels (CaA) (8.86 ± 0.27 vs. 9.13 ± 0.39 mg/dl, p <0.001) and E/A (0.78 ± 0.22 vs. 0.83 ± 0.26, p = 0.029) were observed between declined HRV and normal HRV groups. Bivariate linear correlation analysis showed that CaA and E/A were positively correlated with HRV parameters including SDNN (p < 0.001), SDNN index (p < 0.001), and Triangle index (p < 0.05). The AUC in the ROC curve for the prediction of CaA on HRV was 0.730 (95% CI (0.750-0.815), p < 0.001). The cutoff value of CaA was 8.87 mg/dl (sensitivity 0.644, specificity 0.814). The T2DM patients with CaA <8.87 mg/dl had significantly lower HRV parameters (SDNN, SDNN index, rMSSD, and triangle index) than those with CaA ≥8.87 mg/dl (p < 0.01, respectively). Multivariate logistic regression analysis showed a significantly increased risk of declined HRV in subjects with CaA level <8.87 mg/dl [OR (95% CI), 0.049 (0.024-0.099), p < 0.001]. Conclusions: Declined HRV is associated with a lower CaA level and worse cardiac function. The serum calcium level can be used for risk evaluation of declined HRV in T2DM patients even within the normocalcemic range.

Changes in the phenotype and function of mucosal-associated invariant T cells in neutrophilic asthma.

Asthma is a chronic heterogeneous inflammatory disease. Most neutrophilic asthma (NA) cases are severe asthma involving many inflammatory cells and mediators, although the specific pathogenesis is not clear. Mucosal-associated invariant T (MAIT) cells as innate-like T lymphocytes play an important role in the immune response in asthma by producing cytokines. In this study, we evaluated the phenotype and function of circulating MAIT cells in patients with NA and inflammatory-related cytokines in plasma and induced sputum supernatants using flow cytometry. The results showed that the frequency of circulating MAIT cells in asthma patients, particularly NA patients, decreased significantly, and CD8+ MAIT and MAIT Temra cells also decreased significantly. Increased expression of CD69 and PD-1 on MAIT cells indicated excessive activation and depletion, leading to the decrease in MAIT cells. Levels of IL-17A and TNF-α secreted by MAIT cells of NA patients increased, whereas IFN-γ levels decreased, indicating that MAIT cells in NA are biased to the Th17 subtype. MAIT cells were also negatively correlated with clinical parameters, indicating that these cells are related to asthma severity. Pro-inflammatory cytokines in plasma and sputum supernatant increased to varying degrees, whereas IL-10 declined, corresponding with asthma severity. We speculate that increased IL-17A and TNF-α synergistically stimulated respiratory epithelial cells to secrete IL-6 and IL-8, thereby recruiting neutrophils to inflammatory sites and aggravating asthma symptoms. Therefore, MAIT cells could serve as a potential therapeutic target in NA immunity, thus providing a new strategy for the treatment of asthma.

The onset, development and pathogenesis of severe neutrophilic asthma.

Bronchial asthma is divided into Th2 high, Th2 low and mixed types. The Th2 high type is dominated by eosinophils while the Th2 low type is divided into neutrophilic and paucigranulocytic types. Eosinophilic asthma has gained increased attention recently, and its pathogenesis and treatment are well understood. However, severe neutrophilic asthma requires more in-depth research because its pathogenesis is not well understood, and no effective treatment exists. This review looks at the advances made in asthma research, the pathogenesis of neutrophilic asthma, the mechanisms of progression to severe asthma, risk factors for asthma exacerbations, and biomarkers and treatment of neutrophilic asthma. The pathogenesis of neutrophilic asthma is further discussed from four aspects: Th17-type inflammatory response, inflammasomes, exosomes and microRNAs. This review provides direction for the mechanistic study, diagnosis and treatment of neutrophilic asthma. The treatment of neutrophilic asthma remains a significant challenge for clinical therapists and is an important area of future clinical research.

The Emerging Roles of T Helper Cell Subsets and Cytokines in Severe Neutrophilic Asthma.

Neutrophilic asthma (NA) is a severe type of steroid resistant asthma, and so far the immune mechanisms underlying NA are not clear. In this article, we performed a comprehensive assessment of Th-cell subsets and cytokines in severe NA patients. A total of 13 healthy individuals and 31 severe asthma patients were enrolled in this study. Refractory asthma patients were defined as those with eosinophilic asthma (EA, accounted for 32% of asthmatic patients) or NA (68%) according to sputum neutrophil/eosinophil counts or blood eosinophils. Th-cell subsets in peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry, and cytokines were detected by cytometric bead array (CBA). The results showed significant differences were observed in Th-cell phenotypes, where the number of Th1 cells were reduced and the numbers of Th2 cells were increased in NA and EA groups, respectively, when compared with healthy controls. Th17 cells were not strongly associated with severe neutrophilic asthma. The frequencies of mucosal-associated invariant T (MAIT) cells were strikingly reduced in severe asthma patients, especially in the NA group. This NA group also showed increased levels of IL-17A, IL-17F, TNF-α, and IL-6 in serum and increased levels of IL-17A, IL-17F, IFN-γ, TNF-α, IL-1ß, IL-5, IL-6, and IL-8 in sputum. In addition, sputum IL-6 was positively correlated with TNF-α, IFN-γ, IL-17A, and IL-8. Our results uncovered a controversial role for Th17 cells, which were reduced in severe asthma patients. Severe neutrophilic asthma was associated with a striking deficiency of MAIT cells and high pro-inflammatory cytokine levels.

[Preparation and functional identification of human single chain recombinant antibody targeting α-hemolysin of Staphylococcus aureus].

Objective To prepare a new fully human antibody against α-hemolysin of Staphylococcus aureus (S. aureus) and to investiagete its neutralizing effect. Methods The IgG-like scFv-Fc inserted into the pcDNA3.1 vector by homologous recombination was expressed in HEK293F suspension cells and purified. ELISA was used to detect the purified scFv538-Fc's binding activity and specificity to S. aureus. The cell proliferation & toxicity assay and rabbit erythrocyte hemolysis assay were used to identify the scFv538-Fc against α-hemolysin of S. aureus. Results A new fully human recombinant antibody scFv-Fc against S. aureus. α-hemolysin was successfully prepared. The mass of the purified scFv-Fc was about 55 kDa. The purified antibody had binding activity to scFv538-Fc, and the antibody bound to Staphylococcus aureus specifically. The results of A549 cytotoxicity assays showed that scFv538-Fc had protective effects on A549 cells. The result of anti-rabbit erythrocyte hemolysis assay confirmed that scFv538-Fc had a significant neutralizing effect on toxins. Conclusion A novel fully human scFv-Fc antibody neutralizing the α-hemolysin toxin of S. aureus is successfully prepared.

Fully human recombinant antibodies against EphA2 from a multi-tumor patient immune library suitable for tumor-targeted therapy.

Enhanced EphA2 expression is observed in a variety of epithelial-derived malignancies and is an important target for anti-tumor therapy. Currently, Therapeutic monoclonal antibodies against immune checkpoints have shown good efficacy for tumor treatment. In this study, we constructed an immune single-chain fragment variable (scFv) library using peripheral blood mononuclear cells (PBMCs) from 200 patients with a variety of malignant tumors. High affinity scFvs against EphA2 can be easily screened from the immune library using phage display technology. Anti-EphA2 scFvs can be modified into any form of recombinant antibody, including scFv-Fc and full-length IgG1 antibodies, and the recombinant antibody affinity was improved following modification. Among the modified anti-EphA2 antibodies the affinity of 77-IgG1 was significantly increased, reaching a pmol affinity level (10-12). We further demonstrated the binding activity of recombinant antibodies to the EphA2 protein, tumor cells, and tumor tissues using macromolecular interaction techniques, flow cytometry and immunohistochemistry. Most importantly, both the constructed scFvs-Fc, as well as the IgG1 antibodies against EphA2 were able to inhibit the growth of tumor cells to some extent. These results suggest that the immune libraries from patients with malignant tumors are more likely to screen for antibodies with high affinity and therapeutic effect. The constructed fully human scFv immune library has broad application prospects for specific antibody screening. The screened scFv-Fc and IgG1 antibodies against EphA2 can be used for the further study of tumor immunotherapy.

PERK-Dependent Activation of the JAK2/STAT3 Pathway Contributes to High Glucose-Induced Extracellular Matrix Deposition in Renal Tubular Epithelial Cells.

BACKGROUND: Although the deposition of extracellular matrix (ECM) is critical leading to tubular damage in diabetic kidney disease (DKD), the mechanism still remains unclear. The purpose of this study was to demonstrate a role for protein kinase R-like endoplasmic reticulum kinase (PERK) (a protein located in the endoplasmic reticulum membrane) in this pathologic process. METHODS: NRK-52E cells were grown in the media containing different concentrations of glucose or thapsigargin for different durations. Cells were subsequently incubated with or without AG490, a selective inhibitor of Janus kinase 2 (JAK2) or GSK2606414 (a selective PERK inhibitor). We evaluated the production of TGF-ß1, fibronectin, and collagen I proteins by ELISA. The levels of 78 kD-glucose-regulated protein (GRP78) and PERK, as well as the phosphorylation statues of PERK and JAK2/signal transducer and activator of transcription (STAT3), were determined by western blotting analysis. RESULTS: We showed that the increased phosphorylation of JAK2 and STAT3 was accompanied by overexpression of TGF-ß1 and ECM deposition in high glucose medium. Disruption of the JAK2/STAT3 pathway with AG490 significantly prevents the high glucose-induced increase in TGF-ß1, fibronectin, and collagen I. High glucose induced the overproduction of GRP78 and phosphorylation of PERK, which indicated that endoplasmic reticulum stress (ERS) was triggered in NRK-52E cells cultured under high glucose condition. Inhibition of PERK phosphorylation with GSK2606414, however, blocked the effect of JAK2/STAT3 on the production of TGF-ß1 and ECM components in NRK-52E cells. CONCLUSION: Our data indicated that the ECM accumulation induced by high glucose arouse via the PERK-dependent JAK2/STAT3-signaling pathway in renal tubular epithelial cells.

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.

Reactive oxygen species (ROS) play a dual role in the initiation, development, suppression, and treatment of cancer. Excess ROS can induce nuclear DNA, leading to cancer initiation. Not only that, but ROS also inhibit T cells and natural killer cells and promote the recruitment and M2 polarization of macrophages; consequently, cancer cells escape immune surveillance and immune defense. Furthermore, ROS promote tumor invasion and metastasis by triggering epithelial-mesenchymal transition in tumor cells. Interestingly, massive accumulation of ROS inhibits tumor growth in two ways: (1) by blocking cancer cell proliferation by suppressing the proliferation signaling pathway, cell cycle, and the biosynthesis of nucleotides and ATP and (2) by inducing cancer cell death via activating endoplasmic reticulum stress-, mitochondrial-, and P53- apoptotic pathways and the ferroptosis pathway. Unfortunately, cancer cells can adapt to ROS via a self-adaption system. This review highlighted the bidirectional regulation of ROS in cancer. The study further discussed the application of massively accumulated ROS in cancer treatment. Of note, the dual role of ROS in cancer and the self-adaptive ability of cancer cells should be taken into consideration for cancer prevention.

Candida albicans triggers qualitative and temporal responses in gut bacteria.

Interactions between commensal intestinal bacteria and fungi are collectively beneficial in maintaining the balance of the gut microflora and preventing gastrointestinal diseases. However, the contributions of specific bacterial species in response to fungal dysbiosis in the gut remain poorly defined. Here, to understand the dynamic changes, we established acute a challenge with Candida albicans in mice treated without antibiotics and analyzed the changes in the diversity of bacteria during the imbalance in intestinal C. albicans with high-throughput amplicon sequencing. Our results showed significant increases in species diversity after the first day of fungal challenge and the restoration of balance among the gut microflora on the third day of challenge. To explore the interactions between the intestinal bacteria and C. albicans, the antifungal activities of bacteria isolated from the mouse feces were also determined. Nineteen aerobic bacteria with antifungal activity were identified with whole 16S rRNA gene sequencing. These bacteria were isolated on the first day of challenge more than on the third day. These results suggested that the commensal intestinal bacteria may protect the host against fungal dysbiosis in the gut by altering their own species diversity. The interaction between bacteria and fungi in the gut may be the key to maintaining the dynamic balance of microorganisms in the context of environmental changes.

Integrative Analysis of the Expression of SIGLEC Family Members in Lung Adenocarcinoma via Data Mining.

Background: Sialic acid-binding immunoglobulin-type lectin (SIGLEC) family members are involved in regulating immune-cell activation, proliferation, and apoptosis, and they play an important role in tumor development. However, their expression and correlation with immune molecules in lung adenocarcinoma (LUAD) remain unclear. Methods: We utilized Gene Expression Profiling Interactive Analysis, Kaplan-Meier analysis, the limma package in R/Bioconductor, the University of California Santa Cruz Cancer Genome Browser, cBioPortal, STRING, Cytoscape, DAVID, and the Tumor Immune Estimation Resource for gene and protein profiling and analyses. Results: The results showed that SIGLEC10 and SIGLEC15 levels were upregulated in LUAD, whereas SIGLEC1, CD22 (SIGLEC2), CD33, myelin-associated glycoprotein (SIGLEC4), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC11, and SIGLEC14 levels were significantly downregulated, with their low expression associated with poor overall survival. Moreover, we observed high SIGLEC-mutation rates (22%) in LUAD patients, with SIGLEC functions determined as primarily involved in regulating the immune response, signal transduction, inflammatory response, and cell adhesion. Furthermore, we found that SIGLEC expression was significantly correlated with immune-cell infiltration, especially macrophages, neutrophils, and dendritic cells, and highly associated with immune molecules such as CD80, CD86, CD28, B-cell-activating factor, programmed cell death 1 ligand 2, and colony stimulating factor 1 receptor. Conclusion: These results provide insight into the potential molecular mechanism associated with SIGLEC-related development of LUAD, as well as clues for screening biomarkers and therapeutic targets.

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

Development of a Flexible and Robust Synthesis of Tetrahydrofuro[3,4-b]furan Nucleoside Analogues.

In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31-48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.

Title of article: Mucosal-associated invariant T cells in lung diseases.

The lungs are directly connected to the external environment, which makes them more vulnerable to infection and injury. They are protected by the respiratory epithelium and immune cells to maintain a dynamic balance. Both innate and adaptive immune cells are involved in the pathogenesis of lung diseases. Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells, which have attracted increasing attention in recent years. Although MAIT cells account for a small part of the total immune cells in the lungs, evidence suggests that these cells are activated by T cell receptors and/or cytokine receptors and mediate immune response. They play an important role in immunosurveillance and immunity against microbial infection, and recent studies have shown that subsets of MAIT cells play a role in promoting pulmonary inflammation. Emerging data indicate that MAIT cells are involved in the immune response against SARS-CoV-2 and possible immunopathogenesis in COVID-19. Here, we introduce MAIT cell biology to clarify their role in the immune response. Then we review MAIT cells in human and murine lung diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary tuberculosis and lung cancer, and discuss their possible protective and pathological effects. MAIT cells represent an attractive marker and potential therapeutic target for disease progression, thus providing new strategies for the treatment of lung diseases.