Predicting early gastric cancer risk using machine learning: A population-based retrospective study.

Background: Early detection and treatment are crucial for reducing gastrointestinal tumour-related mortality. The diagnostic efficiency of the most commonly used diagnostic markers for gastric cancer (GC) is not very high. A single laboratory test cannot meet the requirements of early screening, and machine learning methods are needed to aid the early diagnosis of GC by combining multiple indicators. Methods: Based on the XGBoost algorithm, a new model was developed to distinguish between GC and precancerous lesions in newly admitted patients between 2018 and 2023 using multiple laboratory tests. We evaluated the ability of the prediction score derived from this model to predict early GC. In addition, we investigated the efficacy of the model in correctly screening for GC given negative protein tumour marker results. Results: The XHGC20 model constructed using the XGBoost algorithm could distinguish GC from precancerous disease well (area under the receiver operating characteristic curve [AUC] = 0.901), with a sensitivity, specificity and cut-off value of 0.830, 0.806 and 0.265, respectively. The prediction score was very effective in the diagnosis of early GC. When the cut-off value was 0.27, and the AUC was 0.888, the sensitivity and specificity were 0.797 and 0.807, respectively. The model was also effective at evaluating GC given negative conventional markers (AUC = 0.970), with the sensitivity and specificity of 0.941 and 0.906, respectively, which helped to reduce the rate of missed diagnoses. Conclusions: The XHGC20 model established by the XGBoost algorithm integrates information from 20 clinical laboratory tests and can aid in the early screening of GC, providing a useful new method for auxiliary laboratory diagnosis.

Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway.

PURPOSE: Considerable evidence suggests that tumor cells with stemness features contribute to initiation, progression, recurrence of gastric cancer (GC) and resistance to therapy, but involvement of underlying regulators and mechanisms remain largely unclear. However, the clinical significance and biological function of Notum in GC tumor sphere formation and tumorigenesis remain unclear. METHODS: Bioinformatics analysis, RT-qPCR, western blot and imunohistochemistry staining were applied to characterize Notum expression in GC specimens. The early diagnostic value of Notum was analyzed by logistic regression analysis method. Cancer stemness assays were used in Notum knockdown and overexpressing cells in vitro and in vivo. RNA-seq was employed to reveal the downstream effectors of Notum. RESULTS: Notum is highly expressed in early stage of GC patients and stem-like GC cells. For discriminating the early-stage and advanced GC patients, the joint analysis had a better diagnostic value. Overexpression of Notum markedly increased stemness features of GC cells to promote tumor sphere formation and tumorigenesis. Conversely, Notum knockdown attenuated the stem-like cell properties in vitro and in vivo. Mechanically, Notum upregulates Sox2 through activating the PI3K/AKT signaling pathway. Notum inhibitor Caffeine exhibited a potent inhibitory effect on stemness features by impairing the PI3K/AKT signaling pathway activity and targeting Sox2. CONCLUSION: Our findings confer a comprehensive and mechanistic function of Notum in GC tumor sphere formation and tumorigenesis that may provide a novel and promising target for early diagnosis and clinical therapy of GC.

Prmt5 deficient mouse B cells display RNA processing complexity and slower colorectal tumor progression.

Protein arginine methyltransferase 5 (Prmt5) is essential for normal B-cell development; however, the roles of Prmt5 in tumor-infiltrating B cells in tumor therapy have not been well elucidated. Here, we revealed that CD19-cre-Prmt5fl/fl (Prmt5cko) mice showed smaller tumor weights and volumes in the colorectal cancer mouse model; B cells expressed higher levels of Ccl22 and Il12a, which attracted T cells to the tumor site. Furthermore, we used direct RNA sequencing to comprehensively profile RNA processes in Prmt5 deletion B cells to explore underline mechanisms. We found significantly differentially expressed isoforms, mRNA splicing, poly(A) tail lengths, and m6A modification changes between the Prmt5cko and control groups. Cd74 isoform expressions might be regulated by mRNA splicing; the expression of two novel Cd74 isoforms was decreased, while one isoform was elevated in the Prmt5cko group, but the Cd74 gene expression showed no changes. We observed Ccl22, Ighg1, and Il12a expression was significantly increased in the Prmt5cko group, whereas Jak3 and Stat5b expression was decreased. Ccl22 and Ighg1 expression might be associated with poly(A) tail length, Jak3, Stat5b, and Il12a expression might be modulated by m6A modification. Our study demonstrated that Prmt5 regulates B-cell function through different mechanisms and supported the development of Prmt5-targeted antitumor treatments.

Cardiovascular Complications of Pan-Cancer Therapies: The Need for Cardio-Oncology.

It is more likely that a long-term survivor will have both cardiovascular disease and cancer on account of the progress in cancer therapy. Cardiotoxicity is a well-recognized and highly concerning adverse effect of cancer therapies. This side effect can manifest in a proportion of cancer patients and may lead to the discontinuation of potentially life-saving anticancer treatment regimens. Consequently, this discontinuation may adversely affect the patient's survival prognosis. There are various underlying mechanisms by which each anticancer treatment affects the cardiovascular system. Similarly, the incidence of cardiovascular events varies with different protocols for malignant tumors. In the future, comprehensive cardiovascular risk assessment and clinical monitoring should be considered for cancer treatments. Baseline cardiovascular evaluation risk should be emphasized prior to initiating clinical therapy in patients. Additionally, we highlight that there is a need for cardio-oncology to avoid or prevent cardiovascular side effects. Cardio-oncology service is based on identifying cardiotoxicity, developing strategies to reduce these toxicities, and minimizing long-term cardiotoxic effects.

M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance.

T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we reported that immunosuppressive M2 macrophages render cancer cells resistant to CD8+ T-cell-dependent tumor-killing refractory ICB efficacy by secreting exosomes. Proteomics and functional studies revealed that M2 macrophage-derived exosome (M2-exo) transmitted apolipoprotein E (ApoE) to cancer cells conferring ICB resistance by downregulated MHC-I expression curbing tumor intrinsic immunogenicity. Mechanistically, M2 exosomal ApoE diminished the tumor-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumor MHC-I expression. Sensitizing ICB efficacy can be achieved by the administration of ApoE ligand, EZ-482, enhancing ATPase activity of BiP to boost tumor-intrinsic immunogenicity. Therefore, ApoE may serve as a predictor and a potential therapeutic target for ICB resistance in M2-TAMs-enriched cancer patients. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumor cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumors with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy.

CD34+ cell-derived fibroblast-macrophage cross-talk drives limb ischemia recovery through the OSM-ANGPTL signaling axis.

CD34+ cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional role of these cells in the ischemic muscle microenvironment. Here, we combined the single-cell RNA sequencing and genetic lineage tracing technology, then provided exact single-cell atlases of normal and ischemic limb tissues in human and mouse, and consequently found that bone marrow (BM)-derived macrophages with antigen-presenting function migrated to the ischemic site, while resident macrophages underwent apoptosis. The macrophage oncostatin M (OSM) regulatory pathway was specifically turned on by ischemia. Simultaneously, BM CD34+-derived proregenerative fibroblasts were recruited to the ischemia niche, where they received macrophage-released OSM and promoted angiopoietin-like protein-associated angiogenesis. These findings provided mechanisms on the cellular events and cell-cell communications during tissue ischemia and regeneration and provided evidence that CD34+ cells serve as fibroblast progenitors promoting tissue regeneration.

Urinary exosomal long non-coding RNAs as noninvasive biomarkers for diagnosis of bladder cancer by RNA sequencing.

Introduction: Cystoscopy is the standard methodology for diagnosis of bladder cancer (BC), but it is invasive and relatively expensive. Previous studies have found that urinary exosomal long non-coding RNAs (lncRNAs) may act as potential noninvasive biomarkers for diagnosis. Here we identified urinary exosomal lncRNAs that are differentially expressed between BC and controls, and established a panel for diagnosis of BC. Methods: We performed RNA sequencing in urinary exosomes of 7 controls and 7 patients, subsequently the differentially expressed lncRNAs were detected in training cohort (50 controls and 50 patients) and validation cohort (43 controls and 43 patients). The diagnostic power of lncRNAs for BC was calculated by the area under curve (AUC). The panel for diagnosis of BC was calculated by logistic regression. Results: The results of RNA sequencing in urinary exosomes showed that 240 upregulated lncRNAs and 275 downregulated lncRNAs were differentially expressed. The levels of MKLN1-AS, TALAM1, TTN-AS1 and UCA1 in BC patients were higher than that in controls in the training and validation cohort by real-time PCR. Using logistic regression, with the combination of these four lncRNAs and NMP22, we identified a panel of five parameters capable of classifying BC patients versus controls on the basis of the training cohort (AUC=0.850). Moreover, the performance of the panel exhibited better performance than either single parameter in the validation cohort. Conclusion: Collectively, this study confirmed the diagnostic value of lncRNAs for BC by high-throughout urinary exosomal RNA sequencing.

Green finance, technological progress, and ecological performance-evidence from 30 Provinces in China.

The interaction between green finance and other factors, such as ecological environment, has been a research hotspot nowadays. Especially, the reasonable guiding of capital into energy conservation and environmental protection industries would greatly affect those factors, so as to the relation between them. This paper aimed to analyze the relationships between green finance, technological progress, and ecological performance quantitatively. The entropy method was used to respectively construct the system of index for green finance and technological progress, and index for ecological performance was measured by the super-SBM model. The panel vector autoregressive (PVAR) model was selected to empirically analyze dynamic relationships based on datasets from 30 provinces in China during 2008-2019 period. The results told that (1) from 2008 to 2019, China's overall level of green finance, technological progress and ecological performance increased to varying degrees. Spatially, the areas with high-developed green finance greatly coincided with those such as large cities or the eastern coast that had good financial development. The distribution of technological progress index were similar, except some underdeveloped areas with relatively advanced scientific research institutes. The ecological performance, however, was high in the South and low in the north. (2) In the lag for 3 years, the influence of green finance on ecological performance in different regions was all positive for that all the coefficient symbols that passed the significance test were above 0, while that on technological progress was negative first and then positive. And the effects of technological progress on ecological performance were positive in ecological regions and negative in low ecological regions (0.0893 and -0.1211 in the case of three-stage lag respectively). (3) The contribution of green finance to ecological performance was high according to the results of variance decomposition, maintained at about 30%, and that of technological progress increased year by year (from 0.000 to 0.039). Therefore, we proposed to strengthen the development of green finance in underdeveloped regions. The emphasis should be laid on the researches and applications of green technology, the formulation of financing policies in innovation compensation and the establishment of a dynamic monitoring system for the ecological environment.

Establishment and Validation of a Ferroptosis-Related Long Non-Coding RNA Signature for Predicting the Prognosis of Stomach Adenocarcinoma.

Background: Ferroptosis is a form of regulated cell death that follows cell membrane damage and mostly depends on iron-mediated oxidative. Long non-coding RNAs (LncRNAs) are associated with the development of a variety of tumors. Till date, LncRNAs have been reported to intervene in ferroptosis. Therefore, we intended to provide a prognostic ferroptosis-related-lncRNA signature in stomach adenocarcinoma (STAD). Methods: We downloaded ferroptosis-related genes from the FerrDb database and RNA sequencing data and clinicopathological characteristics from The Cancer Genome Atlas. Gene differential expression analysis was performed using the "limma" package. We used Cox regression analysis to determine the ferroptosis-related lncRNAs signature with the lowest AIC value. The Kaplan-Meier curve, ROC curve, and nomogram were used to evaluate the prognostic value of the risk score. Gene set enrichment analysis (GSEA) was used to explore the biologic functions of the three ferroptosis-related lncRNAs. LINC01615 expression in gastric cancer cell lines and tissues was measured by real-time PCR. A nuclear-cytoplasmic fractionation assay was used to analyze the subcellular localization for LINC01615. Furthermore, we used bioinformatics to predict potential target microRNAs (miRNAs) of LINC01615 and their target ferroptosis-related mRNAs. Results: Three ferroptosis-related-lncRNA signatures (AP000695.2, AL365181.3, and LINC01615) were identified, and then Kaplan-Meier, Cox regression analyses, and ROC curve confirmed that the ferroptosis-related-lncRNA model could predict the prognosis of STAD. The GSEA indicated that the three ferroptosis-related lncRNAs might be related to the extracellular matrix and cellular activities. LINC01615 is highly expressed in gastric cancer cell lines and tissues. A nuclear-cytoplasmic fractionation assay confirmed that in gastric cancer cell lines, most LINC01615 was enriched in the cytoplasm. Bioinformatics further predicts four potential target miRNAs of LINC01615 and then figured out 26 target ferroptosis-related mRNAs. Conclusion: We established a three-ferroptosis-related-lncRNA model (AP000695.2, AL365181.3, and LINC01615) that can predict the prognosis of STAD patients. We also expected to provide a promising target for LINC01615 for research in the future, which was highly expressed in gastric cancer and cell lines and acted as a ceRNA to get involved in ferroptosis.

PD-L1+CD8+ T cells enrichment in lung cancer exerted regulatory function and tumor-promoting tolerance.

Immunotherapy targeting checkpoint blockade to rescue T cells from exhaustion has become an essential therapeutic strategy in treating cancers. Till now, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We combined cytometry by time-of-flight (CyTOF) and imaging mass cytometry (IMC) approaches to analyze CD8+ T cells from primary lung cancers and discovered that PD-L1+CD8+ T cells were enriched in tumor lesions, spatially localized with PD-1+CD8+ T cells. Furthermore, PD-L1+CD8+ T cells exerted regulatory functions that inhibited CD8+ T cells proliferation and cytotoxic abilities through the PD-L1/PD-1 axis. Moreover, tumor-derived IL-27 promotes PD-L1+CD8+ T cells development through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified PD-L1+CD8+ T cells elevated in the components related to downregulation of adaptive immune response. Collectively, our data demonstrated that PD-L1+CD8+ T cells enriched in lung cancer engaged in tolerogenic effects and may become a therapeutic target in lung cancer.

PRMT5 Deficiency Enforces the Transcriptional and Epigenetic Programs of Klrg1+CD8+ Terminal Effector T Cells and Promotes Cancer Development.

Protein arginine methyltransferase 5 (PRMT5) participates in the symmetric dimethylation of arginine residues of proteins and contributes to a wide range of biological processes. However, how PRMT5 affects the transcriptional and epigenetic programs involved in the establishment and maintenance of T cell subset differentiation and roles in antitumor immunity is still incompletely understood. In this study, using single-cell RNA and chromatin immunoprecipitation sequencing, we found that mouse T cell-specific deletion of PRMT5 had greater effects on CD8+ than CD4+ T cell development, enforcing CD8+ T cell differentiation into Klrg1+ terminal effector cells. Mechanistically, T cell deficiency of PRMT5 activated Prdm1 by decreasing H4R3me2s and H3R8me2s deposition on its loci, which promoted the differentiation of Klrg1+CD8+ T cells. Furthermore, effector CD8+ T cells that transited to memory precursor cells were decreased in PRMT5-deficient T cells, thus causing dramatic CD8+ T cell death. In addition, in a mouse lung cancer cell line-transplanted tumor mouse model, the percentage of CD8+ T cells from T cell-specific deletion of PRMT5 mice was dramatically lost, but CD8+Foxp3+ and CD8+PDL1+ regulatory T cells were increased compared with the control group, thus accelerating tumor progression. We further verified these results in a mouse colon cancer cell line-transplanted tumor mouse model. Our study validated the importance of targeting PRMT5 in tumor treatment, because PRMT5 deficiency enforced Klrg1+ terminal CD8+ T cell development and eliminated antitumor activity.

Decreased expression of ATF3, orchestrated by ß-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased ß-catenin and CEMIP.

ATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of ß-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the ß-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients.

Chromium Oxide Nanoparticle Impaired Osteogenesis and Cellular Response to Mechanical Stimulus.

BACKGROUND: Release of metallic wear particles from hip replacement implants is closely associated with aseptic loosening that affects the functionality and survivorship of the prostheses. Chromium oxide nanoparticles (CrNPs) are the dominant form of the wear particles found in the periprosthetic tissues. Whether CrNPs play a role in the clinically observed particle-induced osteolysis, tissue inflammatory reactions and functional activities of human mesenchymal stem cells (MSCs) remain unknown. METHODS: A tibia-defect rat model, cytotoxicity assays and flow cytometry were applied to study the effect of CrNPs on MSCs survival and macrophage inflammatory response. Also, oscillatory fluid flow stimulation was used to analyse the osteogenic differentiation of MSCs while treated by CrNPs. In addition, the influence of CrNPs on MSC biomechanical properties was determined via atomic force microscope (AFM) and fluorescence microscopy. RESULTS: It was found that implantation of CrNPs significantly decreased bone formation in vivo. CrNPs had no obvious effects on inflammatory cytokines release of U937 macrophages. Additionally, CrNPs did not interfere with MSCs osteogenic differentiation under static culture. However, the upregulated osteogenic differentiation of MSCs due to fluid flow stimulation was reduced by CrNPs in a dose-dependent manner. Moreover, osteogenic gene expression of OPN, Cox2 and Rnux2 after mechanical stimulation was also decreased by CrNPs treatments. Furthermore, cell elasticity and adhesion force of MSCs were affected by CrNPs over 3 days of exposure. We further verified that these effects of CrNPs could be associated with its interruption on cell mechanical properties. CONCLUSION: The results demonstrated that CrNPs impaired cellular response to mechanical stimulus and osteogenesis without noticeable effects on the survival of the human MSCs.

Extracellular vesicle-mediated regulation of tumor angiogenesis- implications for anti-angiogenesis therapy.

Angiogenesis plays an important role in tumour progression. However, anti-angiogenesis therapy of inhibiting pro-angiogenic factors failed to meet expectations in certain types of tumour in clinical trials. Recent studies reveal that tumour-derived extracellular vesicles (EVs) are essential in tumour angiogenesis and anti-angiogenesis drug resistance. This function has most commonly been attributed to EV contents including proteins and non-coding RNAs. Here, we summarize the recent findings of tumour-derived EV contents associated with regulating angiogenesis and illustrate the underlying mechanisms. In addition, the roles of EVs in tumour microenvironmental cells are also illustrated with a focus on how EVs participate in cell-cell communication, contributing to tumour-mediated angiogenesis. It will help offer new perspectives on developing targets of anti-angiogenesis drugs and improve the efficacy of anti-angiogenesis therapies based on tumour-derived EVs.

Gastric cancer-secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE-cadherin.

Angiogenesis is closely associated with tumorigenesis, invasion, and metastasis by providing oxygen and nutrients. Recently, increasing evidence indicates that cancer-derived exosomes which contain proteins, coding, and noncoding RNAs (ncRNAs) were shown to have proangiogenic function in cancer. A 26-nt-long ncRNA (X26nt) is generated in the process of inositol-requiring enzyme 1 alpha (IRE1α)-induced unspliced XBP1 splicing. However, the role of X26nt in the angiogenesis of gastric cancer (GC) remains largely unknown. In the present study, we found that X26nt was significantly elevated in GC and GC exosomes. Then, we verified that X26nt could be delivered into human umbilical vein endothelial cells (HUVECs) via GC cell exosomes and promote the proliferation, migration, and tube formation of HUVECs. We revealed that exosomal X26nt decreased vascular endothelial cadherin (VE-cadherin) by directly combining the 3'UTR of VE-cadherin mRNA in HUVECs, thereby increasing vascular permeability. We further demonstrated that X26nt accelerates the tumor growth and angiogenesis in a mouse subcutaneous tumor model. Our findings investigate a unique intercellular communication mediated by cancer-derived exosomes and reveal a novel mechanism of exosomal X26nt in the regulation of tumor vasculature.

Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment.

Cancer immunotherapy has revolutionized cancer treatment, and it relies heavily on the comprehensive understanding of the immune landscape of the tumor microenvironment (TME). Here, we obtain a detailed immune cell atlas of esophageal squamous cell carcinoma (ESCC) at single-cell resolution. Exhausted T and NK cells, regulatory T cells (Tregs), alternatively activated macrophages and tolerogenic dendritic cells are dominant in the TME. Transcriptional profiling coupled with T cell receptor (TCR) sequencing reveal lineage connections in T cell populations. CD8 T cells show continuous progression from pre-exhausted to exhausted T cells. While exhausted CD4, CD8 T and NK cells are major proliferative cell components in the TME, the crosstalk between macrophages and Tregs contributes to potential immunosuppression in the TME. Our results indicate several immunosuppressive mechanisms that may be simultaneously responsible for the failure of immuno-surveillance. Specific targeting of these immunosuppressive pathways may reactivate anti-tumor immune responses in ESCC.

A novel definition of microvessel density in renal cell carcinoma: Angiogenesis plus vasculogenic mimicry.

The present study proposed the novel concept of total microvessel density (TMVD), which is the combination of the MVD and the vasculogenic mimicry (VM) status, and evaluated its clinical significance in patients with renal cell carcinoma (RCC). For that purpose, tumor samples from 183 patients with primary RCC were examined by CD34 single or periodic acid Schiff (PAS)/CD34 dual histology staining. MVD and VM were determined according to previous literature. Clinical information (tumor stage and grade, and duration of survival) was retrieved and analyzed. Survival information and VM-associated gene expression data of patients with RCC were also retrieved from The Cancer Genome Atlas (TCGA) database and the clinical significance of each individual gene was analyzed. The results indicated that MVD exhibited obvious differences among patients with RCC; however, it was not correlated with the stage/grade or length of survival in patients with RCC. In total, 81 patients (44.3%) were CD34(-)/PAS(+) and defined as VM(+), and they had a significantly shorter survival compared with that of VM(-) patients (P=0.0002). VM was not associated with MVD. TMVD was able to distinguish between patients with high and low MVD in terms of survival, thus TMVD was better compared with MVD alone at distinguishing between patients with different survival prognoses. TCGA data analysis revealed that among the VM-associated genes, nodal growth differentiation factor, caspase-3, matrix metalloproteinase-9 and galectin-3 had a statistically significant impact on the overall/disease-free survival of patients with RCC. In conclusion, the TMVD concept may be more appropriate and sensitive compared with the MVD or VM alone in predicting tumor aggressiveness and patient survival, particularly in RCC, which is a highly vascularized, VM-rich neoplasm, and certain VM formation-associated genes are negatively associated with the survival of patients with RCC.

Activation of synovial fibroblasts from patients at revision of their metal-on-metal total hip arthroplasty.

BACKGROUND: The toxicity of released metallic particles generated in metal-on-metal (MoM) total hip arthroplasty (THA) using cobalt chromium (CoCr) has raised concerns regarding their safety amongst both surgeons and the public. Soft tissue changes such as pseudotumours and metallosis have been widely observed following the use of these implants, which release metallic by-products due to both wear and corrosion. Although activated fibroblasts, the dominant cell type in soft tissues, have been linked to many diseases, the role of synovial fibroblasts in the adverse reactions caused by CoCr implants remains unknown. To investigate the influence of implants manufactured from CoCr, the periprosthetic synovial tissues and synovial fibroblasts from patients with failed MoM THA, undergoing a revision operation, were analysed and compared with samples from patients undergoing a primary hip replacement, in order to elucidate histological and cellular changes. RESULTS: Periprosthetic tissue from patients with MoM implants was characterized by marked fibrotic changes, notably an increase in collagen content from less than 20% to 45-55%, an increase in α-smooth muscle actin positive cells from 4 to 9% as well as immune cells infiltration. Primary cell culture results demonstrated that MoM synovial fibroblasts have a decreased apoptosis rate from 14 to 6% compared to control synovial fibroblasts. In addition, synovial fibroblasts from MoM patients retained higher contractility and increased responsiveness to chemotaxis in matrix contraction. Their mechanical properties at a single cell level increased as observed by a 60% increase in contraction force and higher cell stiffness (3.3 kPa in MoM vs 2.18 kPa in control), as measured by traction force microscopy and atomic force microscopy. Further, fibroblasts from MoM patients promoted immune cell invasion by secreting monocyte chemoattractant protein 1 (MCP-1, CCL2) and induced monocyte differentiation, which could also be associated with excess accumulation of synovial macrophages. CONCLUSION: Synovial fibroblasts exposed in vivo to MoM THA implants that release CoCr wear debris displayed dramatic phenotypic alteration and functional changes. These findings unravelled an unexpected effect of the CoCr alloy and demonstrated an important role of synovial fibroblasts in the undesired tissue reactions caused by MoM THAs.

KIF23 activated Wnt/ß-catenin signaling pathway through direct interaction with Amer1 in gastric cancer.

Increased expression of the kinesin family member 23 (KIF23) has been verified in gastric cancer (GC) and its upregulation contributes to cell proliferation. Even though, the role of KIF23 has not been fully elucidated in GC, and the mechanisms of KIF23 as an oncogene remain unknown. To further identify its potential role in GC, we analyzed gene expression data from GC patients in GEO and TCGA datasets. KIF23 was upregulated in GC, and increased expression of KIF23 correlated with poor prognosis. Importantly, KIF23 inhibition not only suppressed GC cell proliferation, tumorigenesis, but also migration and invasion, and arrested the cell cycle in the G2/M phase. Mechanistic investigations confirmed that KIF23 activated the Wnt/ß-catenin signaling pathway by directly interacting with APC membrane recruitment 1 (Amer1). Furthermore, KIF23 exhibited competitive binding with Amer1 to block the association of Amer1 with adenomatous polyposis coli (APC), thus relocating Amer1 from the membrane and cytoplasm to the nucleus and attenuating the ability of Amer1 to negatively regulate Wnt/ß-catenin signaling, resulting in activation of this signaling pathway. Collectively, our findings demonstrated that KIF23 promoted GC cell proliferation by directly interacting with Amer1 and activating the Wnt/ß-catenin signaling pathway.

BACH2 regulates the function of human CD4+ CD45RA- Foxp3l ° cytokine-secreting T cells and promotes B-cell response in systemic lupus erythematosus.

Although CD4+ CD45RA- Foxp3l ° cytokine-secreting T cells (Fr.III cells) have been reported to be increased in systemic lupus erythematosus (SLE), their function and effects on response of B cells are still unclear. Here, we dissect how BACH2 regulates Fr.III cells function and promotes B-cell response in active SLE patients. We measured cytokines and BACH2 expression, and found that Fr.III cells from SLE patients produce much more inflammatory cytokines and were more able to promote B- cell proliferation, IgG, IgA, and TNF-α production than controls in a co-culture system. Fr.III cells expressed high levels of ICOS and CD154, but a low level of Tfr and BACH2, BACH2 expression was negatively correlated with SLE Disease Activity Index. Overexpressed of BACH2 in Fr.III cells, decreased cytokines expression and reduced B-cell response. Furthermore, we identified a reduction of H3K27ac level binding at the BACH2 locus in the SLE Fr.III cells and SLE serum stimulation decreased H3K27ac binding at the BACH2 locus, which could be restored using trichostatin A (TSA). In conclusion, BACH2 was associated with SLE disease activity, regulated the function of Fr.III cells, and promoted B-cells response. Targeting BACH2 may be a new immune intervention therapy of SLE.