Search

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease characterized by cartilage, bone damage, synovial inflammation, hyperplasia, autoantibody production, and systemic features. To obtain an overall profile of the immune environment in RA patients and its association with clinical features, we performed single-cell transcriptome and T-cell receptor sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SF) from RA patients, integrated with two large cohorts with bulk RNA sequencing for further validation and investigation. Dendritic cells (DCs) exhibited relatively high functional heterogeneity and tissue specificity in relation to both antigen presentation and proinflammatory functions. Peripheral helper T cells (TPHs) are likely to originate from synovial tissue, undergo activation and exhaustion, and are subsequently released into the peripheral blood. Notably, among all immune cell types, TPHs were found to have the most intense associations with disease activity. In addition, CD8 effector T cells could be clustered into two groups with different cytokine expressions and play distinct roles in RA development. By integrating single-cell data with bulk sequencing from two large cohorts, we identified interactions among TPHs, CD8 cells, CD16 monocytes, and DCs that strongly contribute to the proinflammatory local environment in RA joints. Of note, the swollen 28-joint counts exhibited a more pronounced association with this immune environment compared to other disease activity indexes. The immune environment alternated significantly from PBMCs to SF, which indicated that a series of immune cells was involved in proinflammatory responses in the local joints of RA patients. By integrating single-cell data with two large cohorts, we have uncovered associations between specific immune cell populations and clinical features. This integration provides a rapid and precise methodology for assessing local immune activation, offering valuable insights into the pathophysiological mechanisms at play in RA., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161 + T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161 + T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161 + T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161 + T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161 + T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161 + CD103 + T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161 + T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161 + CD8 + T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161 + T cells in the advancement and relapse of CRSwNPs., Competing Interests: Declaration of competing interest The authors have decleared that no conflict of interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pathogens commonly enter mucosal barrier tissues and tissue-resident memory T cells (T RM ) are essential for preventing mucosal lesions. However, the immunological properties of T RM cells in nasal mucosa are poorly known. In comparison with control tissues, decreasing CD103 + T RM cells were observed in Chronic rhinosinusitis with nasal polyps (CRSwNPs) and sinonasal inverted papilloma (SNIP), which presented high capability to produce effector cytokines. In CRSwNPs, we found that CD103 + T RM cells with higher cytokine and Granzyme B coexpressed high PD-1, CD103 - T RM cells expressed higher IL-10. Homogenates isolated from CRSwNPs induced CD103 expression on peripheral T cells which could be inhibited by blocking TGF-β. The frequencies of CD103 + T RM cells in CRSwNPs were extremely negatively correlated with neutrophil infiltration. CD103 + T RM cells from Staphylococcus aureus positive CRSwNPs had a stronger response to SEB. Taken together, two phenotypically and functionally distinct subsets of T RM cells exist in nasal tissues and play critical roles in the progress of CRSwNPs and SNIPs., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2023. Published by Elsevier Inc.)

Background: In addition to being secreted into the intercellular spaces by exocytosis, insulin-like growth factor binding protein 5 (IGFBP5) may also remain in the cytosol or be transported to the nucleus. Depending on the different cellular context and subcellular distribution, IGFBP5 can act as a tumor suppressor or promoter through insulin-like growth factor -dependent or -independent mechanisms. Yet, little is known about the impacts of IGFBP5 on acute myeloid leukemia (AML) and its underlying mechanism., Methods: Here we investigated the roles of IGFBP5 in human AML by using recombinant human IGFBP5 (rhIGFBP5) protein and U937 and THP1 cell lines which stably and ectopically expressed IGFBP5 or mutant IGFBP5 (mtIGFBP5) with the lack of secretory signal peptide. Cell counting kit-8 and flow cytometry assay were conducted to assess the cell viability, cell apoptosis and cell cycle distribution. Cytotoxicity assay was used to detect the chemosensitivity. Leukemia xenograft model and hematoxylin-eosin staining were performed to evaluate AML progression and extramedullary infiltration in vivo., Results: In silico analysis demonstrated a positive association between IGFBP5 expression and overall survival of the AML patients. Both IGFBP5 overexpression and extrinsic rhIGFBP5 suppressed the growth of THP1 and U937 cells by inducing cell apoptosis and arresting G1/S transition and promoted the chemosensitivity of U937 and THP1 cells to daunorubicin and cytarabine. However, overexpression of mtIGFBP5 failed to demonstrate these properties. An in vivo xenograft mouse model of U937 cells also indicated that overexpression of IGFBP5 rather than mtIGFBP5 alleviated AML progression and extramedullary infiltration. Mechanistically, these biological consequences depended on the inactivation of insulin-like growth factor 1 receptor -mediated phosphatidylinositol-3-kinase/protein kinase B pathway., Conclusions: Our findings revealed secreted rather than intracellular IGFBP5 as a tumor-suppressor and chemosensitizer in AML. Upregulation of serum IGFBP5 by overexpression or addition of extrinsic rhIGFBP5 may serve as a suitable therapeutic approach for AML., Competing Interests: Declaration of Competing Interest The authors declare no competing interests exist., (Copyright © 2023. Published by Elsevier Inc.)

Landscape fragmentation affected the structure and function of the ecosystem, resulting in an impact on ecosystem service value (ESV). This paper analyzed the correlation between landscape fragmentation and ESV using land-use data from northern Shaanxi covering three periods from 2000 to 2020. The paper employed the granularity deduction method, spatial autocorrelation analysis, and value equivalent method to study the fragmentation characteristics of the regional landscape and the spatial-temporal evolution of ESV. The research findings indicated that the optimal granularity was 150 m, and the amplitude was 5 km × 5 km. The study found that the degree of landscape fragmentation was positively correlated with patch density (PD), division index (DIVISION), and Shannon's diversity index (SHDI), while negatively correlated with the largest patch index (LPI), patch cohesion index (COHESION), and effective mesh size (MESH). Moreover, the total ESV in the study area showed a decreasing trend, with grass, forest, and cultivated land being the three land-use types that contributed the most value. The analysis indicated that there was a negative correlation between the degree of landscape fragmentation and ESV. As the degree of landscape fragmentation increased, ESV decreased. The correlation between landscape fragmentation and ESV discussed in this paper provided valuable insights into the optimal utilization and sustainable development of regional land resources., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Tumor heterogeneity plays essential roles in developing cancer therapies, including therapies for breast cancer (BC). In addition, it is also very important to understand the relationships between tumor microenvironments and the systematic immune environment., Methods: Here, we performed single-cell, VDJ sequencing and spatial transcriptome analyses on tumor and adjacent normal tissue as well as axillar lymph nodes (LNs) and peripheral blood mononuclear cells (PBMCs) from 8 BC patients., Results: We found that myeloid cells exhibited environment-dependent plasticity, where a group of macrophages with both M1 and M2 signatures possessed high tumor specificity spatially and was associated with worse patient survival. Cytotoxic T cells in tumor sites evolved in a separate path from those in the circulatory system. T cell receptor (TCR) repertoires in metastatic LNs showed significant higher consistency with TCRs in tumor than those in nonmetastatic LNs and PBMCs, suggesting the existence of common neo-antigens across metastatic LNs and primary tumor cites. In addition, the immune environment in metastatic LNs had transformed into a tumor-like status, where pro-inflammatory macrophages and exhausted T cells were upregulated, accompanied by a decrease in B cells and neutrophils. Finally, cell interactions showed that cancer-associated fibroblasts (CAFs) contributed most to shaping the immune-suppressive microenvironment, while CD8 + cells were the most signal-responsive cells., Conclusions: This study revealed the cell structures of both micro- and macroenvironments, revealed how different cells diverged in related contexts as well as their prognostic capacities, and displayed a landscape of cell interactions with spatial information., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer cachexia is a complex syndrome that leads to an ongoing loss of skeletal muscle mass in many malignant tumors. Our previous studies have evaluated the effectiveness of Baoyuan Jiedu decoction (BJD) in alleviating cancer-induced muscle atrophy. However, the mechanisms of BJD regulating muscle atrophy could not be fully understood. Therefore, we further investigated the mechanisms of BJD mitigating muscle atrophy both in an Apc Min/+ mouse model and the Lewis-conditioned medium-induced C2C12 myotube atrophy model. We confirmed the quality of BJD extracts by HPLC. In an In vivo study, body weight loss and muscle atrophy were alleviated with BJD treatment. GO analysis suggested that ATP metabolism and mitochondria were involved. The results of the electron microscope show that BJD treatment may have a healing effect on mitochondrial structure. Moreover, ATP content and mitochondrial numbers were improved with BJD treatment. Furthermore, both in vivo and in vitro , we demonstrated that the BJD treatment could improve mitochondrial function owing to the increased number of mitochondria, balanced dynamic, and regulation of the electron transport chain according to the protein and mRNA expressions. In addition, oxidative stress caused by mitochondrial dysfunction was ameliorated by BJD treatment in Apc Min/+ mice. Consequently, our study provides proof for BJD treatment alleviating cancer cachexia-induced muscle atrophy by modulating mitochondrial function in Apc Min/+ mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Bi, Huang, Lv, Zong, Wang and Ji.)

Interaction between stromal cells and acute myeloid leukemia (AML) cells in bone marrow (BM) is known to contribute importantly to chemoresistance and disease recurrence. Therefore, disruption of a crosstalk between AML cells and BM microenvironment may offer a promising therapeutic strategy for AML treatment. Here, we demonstrate that in a niche-like co-culture system, AML cells took up functional mitochondria from bone marrow stromal cells (BMSCs) and inhibition of such mitochondrial transfer by metformin, the most commonly prescribed drug for type 2 diabetes mellitus, significantly enhanced the chemosensitivity of AML cells co-cultured with BMSCs. The chemo-sensitizing effect of metformin was acted through reducing the mitochondrial transfer and mitochondrial oxidative phosphorylation (OXPHOS) in the recipient AML cells. In addition, metformin potentiated the antitumor efficacy of cytarabine (Ara-C) in vivo in an NCG immunodeficient mouse xenograft model by inhibiting the mitochondrial transfer and OXPHOS activity in the engrafted human AML cells. Altogether, this study identifies a potential application of metformin in sensitizing AML cells to chemotherapy and unveils a novel mechanism by which metformin executes such effect via blocking the mitochondrial transfer from stromal cells to AML cells., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer remains the leading cause of cancer-related deaths worldwide. Traditional Chinese medicine (TCM) is a valuable resource of active natural products and plays an important role in cancer treatment with the advantages of high efficiency and safety. Wenxia Changfu formula (WCF) is modified from Dahuang Fuzi decoction from Han Dynasty and has been used for treating lung cancer in China. Our previous research showed that WCF had an antitumor effect in vivo and in vitro, while the mechanism has not been well illustrated. In this study, the effect of WCF on the proliferative ability in three lung cancer cells and one noncancerous human cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. WCF suppressed A549, H460, and PC-9 cell viability in a dose-dependent manner, with no inhibition of noncancerous MRC-5 cells after 48 h treatment with WCF (0-50 mg/mL). Furthermore, we screened for genes in A549 cells using four WCF-treated samples and four control samples on a gene expression profile microarray. 21 genes were significantly downregulated by WCF, which may potentially play an important role in the proliferation of A549 cells. High-content screening evaluated whether silencing the 21 genes affected A549 cell growth. The results showed that PIF1 knockdown exhibited the most potent inhibition of cell proliferation compared with the other genes. Downregulation of PIF1 increased A549 cell apoptosis and the activity of caspase 3/7. Besides, RT-PCR showed that the expression levels of PIF1 mRNA decreased significantly in A549, H460, and PC-9 cells after WCF treatment. In conclusion, the present observations indicate that WCF may inhibit lung cancer cell proliferation by promoting apoptosis via regulating the expression of PIF1., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Xiangjun Yin et al.)

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single-cell RNA sequencing (RNA-seq) on intra- and peri-tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed "resting" and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA-seq of 65 GIST samples. T cells were the largest cell type in our single-cell data. Two groups of CD8 + effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell-to-cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

An overall workflow based on gas chromatography-mass spectrometry (GC-MS) was established for the analysis of the serum amino acid profile between urolithiasis patients ( n =80, age (46.82±13.39) years) and healthy controls ( n =37, age (43.46±12.79) years). The raw data from GC-MS analysis were processed by multivariate statistical methods to build the model. Following this, student's t -test and logistic regression were performed and receiver operator characteristic (ROC) curve was plotted to identify the potential biomarkers. Good linearities were observed for the target amino acids, with correlation coefficients ( R 2 ) greater than 0.9985. The limits of detection (LODs) were 0.1-4.0 μmol/L. The results indicated a significant discrimination between the urolithiasis and control groups. Five significantly differentially expressed amino acids (variable importance in projection (VIP)>1 and p <0.05) were found to provide the scientific evidence for the early diagnosis of urolithiasis, while the sensitivity of the integrated five differential amino acids was up to 97.3%. In particular, the area under the curve (AUC) of serine reached 0.819, which suggested a great clinical screening value.