Exploring Potential Targets and Pathways of Toxicity Attenuation Through Serum Pharmacochemistry and Network Pharmacology in the Processing of Aconiti Lateralis Radix Praeparata.

Aconiti Lateralis Radix Praeparata (Fuzi, FZ) is a frequently utilized traditional Chinese medicine (TCM) in clinical settings. However, its toxic and side effects, particularly cardiac injury, are apparent, necessitating processing before use. To investigate the mechanism of toxicity induced by absorbed components and the mitigating effect of processed FZ, we established a comprehensive method combining serum pharmacochemistry and a network pharmacology approach. In total, 31 chemical components were identified in the plasma, with a general decrease in response intensity observed for these components in processed FZ. Subsequently, four components were selected for network pharmacology analysis. This analysis revealed 150 drug action targets and identified 1162 cardiac toxicity targets. Through intersection analysis, 41 key targets related to cardiac toxicity were identified, along with 9 significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The most critical targets identified were AKT1, MTOR, and PARP1. The key biological pathways implicated were adrenergic signaling in cardiomyocytes, proteoglycans in cancer, and the calcium signaling pathway. Significant differences were observed in histological staining and biochemical indicators in the cardiac tissue of rats treated with FZ, indicating that processing could indeed reduce its cardiotoxicity. Indeed, this article presents a valuable strategy for elucidating the toxification mechanism of toxic TCM.

Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

Correlation of Neuroendocrine Differentiation with a Distinctively Suppressive Immune Microenvironment in Gastric Cancer.

INTRODUCTION: Neuroendocrine neoplasms (NENs) harbored significantly suppressive tumor immune microenvironments (TIMEs). However, the immunological effects of neuroendocrine differentiation (NED) on non-NENs, such as gastric cancer (GC), were unknown. METHODS: Between pure gastric cancer (PGC) and GC-NED, TIME features were scored based on expression data and validated on serial whole-tissue sections of surgical samples, with tertiary lymphoid structures (TLSs) and the extra-TLS zone evaluated independently using multi-marker immunohistochemical staining. Risk analyses of TIME features on tumor behaviors were performed in GC-NED. The universal immunological effects of NED were explored preliminarily in adenocarcinomas arising in other organs. RESULTS: Based on over 11,500 annotated TLSs and 2,700 extra-TLS zones, compared with PGC, GC-NED harbored a distinctively more suppressive TIME characterized by increased but immature TLSs, with higher naïve B-cell and follicular regulatory T-cell densities and downregulated TLS maturation-related cell ratios inside TLSs; increased naïve B-cell and regulatory T-cell densities; and a high proportion of exhausted T cells in the extra-TLS zone. The upregulated tumor PD-L1 expression and its close correlations with TLS formation and maturation were remarkable exclusively in GC-NED. TIME features, especially those regarding TLSs, were significantly correlated with tumor growth and invasion. The desynchrony between TLS formation and maturation and increased naïve or regulatory immune cell infiltration was observed in adenocarcinomas of the colorectum, pancreas, lung, and prostate. CONCLUSION: NED highlighted a distinct GC entity with more suppressive TIME features correlated with tumor behaviors, indicating a cohort that would benefit more from immunotherapies.

Renal ischaemia-reperfusion injury is promoted by transcription factor NF-kB p65, which inhibits TRPC6 expression by activating miR-150.

AIM: To investigate the mechanism by which NF-κB p65 activates miR-150 to suppress TRPC6 expression and promote renal ischemia-reperfusion injury. METHODS: To assess the transcription of miR-150, NF-B p65, and TRPC6 in HK-2 cells treated with hypoxia reperfusion and rat kidney tissue damaged by ischemia-reperfusion (I/R), qPCR was implemented. The protein production of NF-κB p65 and TRPC6 was assessed by Western blot (WB) analysis. The histological score of rat kidney tissue was assessed using H&E (hematoxylin and eosin) staining. To assess the rate of apoptosis of renal tissue cells following I/R injury, we used the TACS TdT In Situ Apoptosis Detection Kit. To find out the impairment of renal function, blood levels of creatinine (Cr) and blood urea nitrogen (BUN) were tested in rats. Concentrations of inflammatory cytokines, including IL-1ß, IL-10, and TNF-α, were detected in HK-2 cells and rat renal tissue cells utilizing ELISA kits. FITC and CCK-8 were employed to analyze the death rate and cellular proliferation of HK-2 cells. To analyse the mechanism of engagement between NF-κB p65 and the miR-150 promoter, coupled with the detrimental impact of miR-150 on TRPC6, we adopted the dual-luciferase reporter assay. To confirm the activating effect of NF-κB p65 on miR-150,we implemented the ChIP assay. RESULTS: NF-κB p65 expression was significantly upregulated in rat renal tissue following IRI. Applying the dual-luciferase reporter assay, we demonstrated that the specific attachment of NF-B p65 with the miR-150 promoter location is viable, resulting in the promotion of the activity of the promoter. When miR-150 was overexpressed, we observed a notable reduction in cell proliferation. And it notably increased the rate of cellular apoptosis rate and amounts of the proinflammatory cytokines IL-1ß, IL-10, and TNF-α. Employing the dual-luciferase reporter assay, we demonstrated that miR-150 transfection diminished the function of luciferase in the TRPC6-WT group, whereas luciferase activity in the TRPC6-MUT group remained unchanged, indicating that miR-150 is a targeted inhibitor of TRPC6. In the rat renal I/R model, when miR-150 was inhibited or TRPC6 was overexpressed in the rat kidney I/R model, the histological score of rat kidney tissue significantly decreased, so did the quantities of proinflammatory cytokines IL-1ß, IL-10, TNF-α, creatinine (Cr) and blood urea nitrogen (BUN) contents and the rate of cell apoptosis in kidney tissue. CONCLUSION: Activation of miR-150 by NF-κB p65 results in downregulation of TRPC6 expression and promotion of IRI in the kidney.

De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.

The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.

Patient-reported outcomes of taste alterations and quality of life in patients with nasopharyngeal carcinoma.

Objective: To investigate patient-reported outcomes of taste alterations and quality of life (QoL) in patients with nasopharyngeal carcinoma (NPC). Methods: In this single-center retrospective study medical records of 191 patients with NPC undergoing chemoradiotherapy (CRT) in the Department of Radiotherapy, Jiangsu Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University from January 2021 to December 2021 were reviewed. A total of 120 patients met eligibility criteria and were included. The taste alterations and QoL at multiple time points during radiotherapy (RT) were compared. Results: There were significant differences in the intensity of taste, discomfort, phantogeusia and parageusia or overall taste alterations at multiple time points during CRT (p-Value<0.001). These four parameters were significantly higher two or four weeks after CRT, or at the end of CRT compared to before CRT (p-Value <0.001). The intensity of taste, discomfort, phantogeusia and parageusia or overall taste alterations were all significantly higher four weeks after CRT compared to two weeks after CRT (p-Value <0.001), and at the end of CRT compared to four weeks after CRT (p-Value <0.001). The chemotherapy-induced taste alteration scale (CiTAS) scores were highest at the end of CRT (p-Value <0.001). There were significant differences in QoL at multiple time points during CRT (p-Value <0.001), and each parameter differed significantly at various time points (p <0.05). The QoL of all areas at the end of CRT were significantly higher than those before CRT, or two or four weeks after CRT (p-Value <0.001). Conclusions: In patients with NPC undergoing CRT, taste alterations increasingly worsen as treatment progresses, with poor QoL outcomes.

USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis.

The functional integrity of Tregs is interwoven with cellular metabolism; however, the mechanisms governing Treg metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited c-Myc translation mediated by the RNA N6-methyladenosine (m6A) reader YTHDF1 to maintain Treg metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg signature in samples from patients with colorectal cancer and gastric cancer. USP47 ablation compromised Treg homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Tregs triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting of USP47.

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.

Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.

Effects of Calorie Restriction and Fasting on Macrophage: Potential Impact on Disease Outcomes?

Energy restriction, including calorie restriction and fasting, has garnered significant attention for its potential therapeutic effects on a range of chronic diseases (such as diabetes, obesity, and cancer) and aging. Since macrophages are critical players in many diseases, their response to energy restriction may impact disease outcomes. However, the diverse metabolic patterns and functions of macrophages can lead to variability in the effects of energy restriction on macrophages across different tissues and disease states. This review outlines the effects of energy restriction on macrophages in several diseases, offering valuable guidance for future studies and insights into the clinical applications of calorie restriction and fasting.

Diabetes and two kinds of primary tumors in a patient with thalassemia: a case report and literature review.

Background: Thalassemia is a group of common genetic hematologic disorders characterized by deficient synthesis of the hemoglobin chain. Due to effective blood transfusion and optimization of chelate therapy, the survival of thalassemia patients and their overall quality of life have improved noticeably in the past few decades. As a consequence, the longer life expectancy has led to the manifestation of several concomitant morbidities, including heart disease, infections, cirrhosis, endocrine abnormalities, various malignancies, and so on. In this context, the probability and updated literature about some malignancy cases in patients with thalassemia build new scenarios for the next few years. We describe the first report of a thalassemic patient developing diabetes and head and neck cancer and try to summarize the possible predisposing factors and mechanisms behind their phenomenon. Case presentation: The current case report describes a 50-year-old Asian man who has been diagnosed with thalassemia since childhood. In early 2017, he was also diagnosed with diabetes and started on insulin-hypoglycemic treatment. The patient was then diagnosed with primary non-keratinizing undifferentiated carcinoma of the nasopharynx in late February 2013. A biopsy of the left tongue revealed squamous cell carcinoma (SCC) in late March 2019. Conclusions: We report the first case of a thalassemic patient developing diabetes and squamous cell carcinoma of the head and neck and discuss the possibility of a link between the three diseases. This specific case should alert physicians to the possibility of endocrinopathy and malignancy in thalassemic patients.

DEPDC1B-mediated USP5 deubiquitination of ß-catenin promotes breast cancer metastasis by activating the wnt/ß-catenin pathway.

Breast cancer has become the malignant disease with the highest morbidity and mortality among female cancer patients. The prognosis of metastatic breast cancer is very poor, and the therapeutic effects still need to be improved. The molecular mechanism of breast cancer has not been fully clarified. Bioinformatics analysis was used to find the differentially expressed gene that affects the occurrence and development of breast cancer. Furthermore, scratch assays, Transwell assays, immunofluorescence, and Western blotting were used to determine the biological behavior of breast cancer cells affected by DEP domain-containing protein 1B (DEPDC1B). The molecular mechanism was investigated by mass spectrometry analysis, coimmunoprecipitation, and ubiquitin assays. Here, we found that DEPDC1B was highly expressed in breast cancer cells and tissues and was associated with lower overall survival (OS) in patients. We found that DEPDC1B interference significantly inhibited tumor invasion and migration in vitro and tumor metastasis in vivo. Mechanistically, DEPDC1B was first shown to activate the wnt/ß-catenin signaling pathway as an oncogene in breast cancer cells. In addition, we also confirmed the interaction between DEPDC1B, ubiquitin-specific protease 5 (USP5), and ß-catenin. Then, we found that DEPDC1B mediates the deubiquitination of ß-catenin via USP5, which promotes cell invasion and migration. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be considered a potential therapeutic target for breast cancer.NEW & NOTEWORTHY By using bioinformatics analysis and the experimental techniques of cell biology and molecular biology, we found that DEP domain-containing protein 1B (DEPDC1B) can promote the invasion and migration of breast cancer cells and that DEPDC1B mediates the deubiquitination of ß-catenin by ubiquitin-specific protease 5 (USP5), thus activating the wnt/ß-catenin pathway. Our findings provide new insights into the carcinogenic mechanism of DEPDC1B, suggesting that DEPDC1B can be used as a potential therapeutic target for breast cancer.

The Emerging Biological Functions of Exosomes from Dental Tissue-Derived Mesenchymal Stem Cells.

Exosomes are one kind of small-cell extracellular membranous vesicles that can regulate intercellular communication and give rise to mediating the biological behaviors of cells, involving in tissue formation, repair, the modulation of inflammation, and nerve regeneration. The abundant kinds of cells can secret exosomes, among them, mesenchymal stem cells (MSCs) are very perfect cells for mass production of exosomes. Dental tissue-derived mesenchymal stem cells (DT-MSCs), including dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, stem cells from human periodontal ligament (PDLSCs), gingiva-derived mesenchymal stem cells, dental follicle stem cells, tooth germ stem cells, and alveolar bone-derived mesenchymal stem cells, are now known as a potent tool in the area of cell regeneration and therapy, more importantly, DT-MSCs can also release numerous types of exosomes, participating in the biological functions of cells. Hence, we briefly depict the characteristics of exosomes, give a detailed description of the biological functions and clinical application in some respects of exosomes from DT-MSCs through systematically reviewing the latest evidence, and provide a rationale for their use as tools for potential application in tissue engineering.

Clinical, Morphological, and Molecular Study on Grade 2 and 3 Pleomorphic Xanthoastrocytoma.

PURPOSE: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. METHODS: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). RESULTS: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). CONCLUSION: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.

Glycolysis drives STING signaling to facilitate dendritic cell antitumor function.

Activation of STING signaling in DCs promotes antitumor immunity. Aerobic glycolysis is a metabolic hallmark of activated DCs, but how the glycolytic pathway intersects with STING signaling in tumor-infiltrating DCs remains elusive. Here, we show that glycolysis drives STING signaling to facilitate DC-mediated antitumor immune responses. Tumor-infiltrating DCs exhibited elevated glycolysis, and blockade of glycolysis by DC-specific Ldha/Ldhb double deletion resulted in defective antitumor immunity. Mechanistically, glycolysis augmented ATP production to boost STING activation and STING-dependent DC antitumor functions. Moreover, DC-intrinsic STING activation accelerated HIF-1α-mediated glycolysis and established a positive feedback loop. Importantly, glycolysis facilitated STING-dependent DC activity in tissue samples from patients with non-small cell lung cancer. Our results provide mechanistic insight into how the crosstalk of glycolytic metabolism and STING signaling enhances DC antitumor activity and can be harnessed to improve cancer therapies.

Uncovering potential diagnostic biomarkers of acute myocardial infarction based on machine learning and analyzing its relationship with immune cells.

BACKGROUND: Acute myocardial infarction (AMI) is a common cardiovascular disease. This study aimed to mine biomarkers associated with AMI to aid in clinical diagnosis and management. METHODS: All mRNA and miRNA data were downloaded from public database. Differentially expressed mRNAs (DEmRNAs) and differentially expressed miRNAs (DEmiRNAs) were identified using the metaMA and limma packages, respectively. Functional analysis of the DEmRNAs was performed. In order to explore the relationship between miRNA and mRNA, we construct miRNA-mRNA negative regulatory network. Potential biomarkers were identified based on machine learning. Subsequently, ROC and immune correlation analysis were performed on the identified key DEmRNA biomarkers. RESULTS: According to the false discovery rate < 0.05, 92 DEmRNAs and 272 DEmiRNAs were identified. GSEA analysis found that kegg_peroxisome was up-regulated in AMI and kegg_steroid_hormone_biosynthesis was down-regulated in AMI compared to normal controls. 5 key DEmRNA biomarkers were identified based on machine learning, and classification diagnostic models were constructed. The random forests (RF) model has the highest accuracy. This indicates that RF model has high diagnostic value and may contribute to the early diagnosis of AMI. ROC analysis found that the area under curve of 5 key DEmRNA biomarkers were all greater than 0.7. Pearson correlation analysis showed that 5 key DEmRNA biomarkers were correlated with most of the differential infiltrating immune cells. CONCLUSION: The identification of new molecular biomarkers provides potential research directions for exploring the molecular mechanism of AMI. Furthermore, it is important to explore new diagnostic genetic biomarkers for the diagnosis and treatment of AMI.

Pharmacokinetic Study of Triptolide Nanocarrier in Transdermal Drug Delivery System-Combination of Experiment and Mathematical Modeling.

Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the "first pass effect" of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components of Tripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin-blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three-layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery.

Dynamical Change of Cell Mechanical Properties Accompanying and Modulating Metastasis Process.

The dynamical change of cellular mechanical properties plays an important role in cell metastasis process, while how the cancer cells modulate their mechanical properties during metastasis are still not fully understood. In this report, the cellular detaching and seeding processes, two vital steps of cell metastasis, were simulated in vitro using a self-developed protocol and characterized by the dynamical mechanical properties using AFM. The measured results show that cells decrease their stiffness and increase their surface adhesion force as they are detaching from substrate, while cells present an opposite change in mechanical properties as they seeding. Additionally, the effect of anti-cancer drug (docetaxel) on the detaching and attaching process of cancer cells (PC-3) was also investigated from the aspect of mechanical properties. The results shows that the docetaxel can increase stiffness, decrease surface adhesion force of PC-3 cell, and slow down the change speed of these mechanical properties during PC-3 cell detaching and seeding process. These discoveries demonstrated that a dynamical change of cell mechanical properties is required for cancer cell metastasis, which provide a new drug development strategy for cancer treatment.

Adverse effects of low serum lipoprotein cholesterol on the immune microenvironment in gastric cancer: a case‒control study.

BACKGROUND: Cholesterol is crucial for tumor immune microenvironment (TIME) remodeling. Serum lipoprotein cholesterol is closely associated with gastric cancer (GC) progression, but whether it affects TIME remodeling is unknown. METHODS: GC patients with differential serum high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol levels were collected. After balancing the baseline, immunohistochemical staining was performed on serial whole-tissue sections to detect B-cell and T-cell subsets, macrophages, and PD-L1. Features of tertiary lymphoid structures (TLSs) and the extra-TLS zone, including TLS distribution and maturation, immune cell density, and PD-L1 expression, were measured by annotating TLSs or regions of interest (ROIs) in the extra-TLS zone. RESULTS: A total of 9,192 TLSs and over 300 ROIs from 61 patients were measured. Compared to HDL-normal patients, HDL-low patients had a decreased secondary-TLS fraction or density but an elevated NK-cell density in the extra-TLS zone. Compared to LDL-normal patients, LDL-low patients had a higher ratio of PD-1 + T follicular helper cells to CD20 + B cells in TLSs, a higher ratio of PD-1 + T cells to CD8 + T cells and increased PD-1 + T-cell density in the extra-TLS zone. Different correlations were found in groups with differential HDL or LDL levels. Cell dynamics in the immune response were weaker in patients with low lipoprotein cholesterol. TLS parameters reached their peak earlier than those of the extra-TLS zone along with tumor progression. CONCLUSION: Low serum lipoprotein cholesterol caused adverse effects on antitumor immunity in GC. Lipid management or immunometabolic drugs deserve more attention.

Prokineticin 2 promotes macrophages-mediated antibacterial host defense against bacterial pneumonia.

OBJECTIVES: Bacterial pneumonia is a common serious infectious disease with high morbidity and mortality. Prokineticin 2 (PK2) has recently been identified as a novel immunomodulator in a variety of diseases; however, its role in bacterial pneumonia remains unclear. METHODS: The levels of PK2 were measured and analyzed in patients with pneumonia and healthy controls. The effects of PK2 on the host response to pneumonia were evaluated by in vivo animal experiments and in vitro cell experiments. RESULTS: PK2 levels dramatically decreased in patients with pneumonia compared with healthy controls, and PK2 levels were lower in patients with severe pneumonia than in pneumonia. In a mouse model of bacterial pneumonia, transtracheal administration of recombinant PK2 significantly alleviated lung injury and improved the survival, which was associated with increased host's bacterial clearance capacity, as manifested by decreased pulmonary bacterial loads. PK2 enhanced the chemotaxis, phagocytosis, and killing ability of macrophages, whereas the protective efficacy of PK2 was abolished after macrophage depletion. CONCLUSION: Impaired alveolar macrophage function caused by decreased PK2 is a new endogenous cause of the occurrence and development of bacterial pneumonia. The administration of recombinant PK2 may be a potential adjuvant therapy for bacterial pneumonia.