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Tracking the genome diversity and evolution of virus like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the hotspot of current researches, which were essential for the developing of prevention strategies and therapeutic vaccines. In the current study, a total of 206073 oral or nasopharyngeal swab specimens were collected in 2022 from entry populations originated from Hong Kong, among which 141 whole genome sequences were obtained through next-generation sequencing and analyzed. Two major Omicron sub-lineages were identified: BA.2.2 (70.21%, 99/141) and BA.5 (24.11% 34/141). An average of 53.22 mutations was emerged in the genome, with S protein and ORF1a harboring the highest number of mutations among structure proteins and non-structure proteins (p

Abstract The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of cytokines, such as pro-inflammatory factors and proteases. It is a crucial feature of senescent cells. SASP factors induce tissue remodeling and immune cell recruitment. Previous studies have focused on the beneficial role of SASP during embryonic development, wound healing, tissue healing in general, immunoregulation properties, and cancer. However, some recent studies have identified several negative effects of SASP on fracture healing. Senolytics is a drug that selectively eliminates senescent cells. Senolytics can inhibit the function of senescent cells and SASP, which has been found to have positive effects on a variety of aging-related diseases. At the same time, recent data suggest that removing senescent cells may promote fracture healing. Here, we reviewed the latest research progress about SASP and illustrated the inflammatory response and the influence of SASP on fracture healing. This review aims to understand the role of SASP in fracture healing, aiming to provide an important clinical prevention and treatment strategy for fracture. Clinical trials of some senolytics agents are underway and are expected to clarify the effectiveness of their targeted therapy in the clinic in the future. Meanwhile, the adverse effects of this treatment method still need further study.

Abstract Background A novel interspinous distraction fusion (ISDF) device has been used to treat lumbar degenerative diseases. As a minimally invasive technique, ISDF differs from the traditional interspinous process distraction devices. Currently, biomechanical studies on ISDF are rare. Objective To investigate the biomechanical properties of the ISDF device (BacFuse) which is used to treat lumbar degenerative diseases. Methods Three-dimensional L3-L5 models were created. The models were divided into four groups: intact (M1), local decompression alone (M2), internal fixation alone (M3) and local decompression combined with internal fixation (M4), based on different surgical procedures. Local laminectomy was performed to resect the lower part of the L4 lamina and the upper part of the L5 lamina at the right lamina of L4/5 in the M2 and M4 groups. After meshing the models elements, Abaqus were used to perform the finite element (FE) analysis. The intervertebral range of motion (ROM) was measured during flexion, extension, left lateral bending, right lateral bending, left rotation and right rotation under a follower load of 400 N with a 7.5Nm moment. The distributions of disc and facet joint stresses were observed and recorded. Spinal vertebral stress was compared, and internal fixation device stress was observed. Results The ROM of L4/5 in M2 increased in flexion, extension, left lateral bending, right lateral bending, left rotation and right rotation compared with that in M1. In all motion directions, the ROM at L4/5 decreased, and the ROM at L3/4 increased after implantation of the ISDF device in M3 and M4 groups. The disc stress and facet joint stresses in the instrumented segment decreased after implantation of the ISDF device. The spinous process loaded a certain amount of stress in M3 and M4 groups. The spikes of the internal fixation device were loaded with the maximum stress. Conclusion BacFuse exhibited a reduction in intervertebral ROM, as well as decreased stress on the intervertebral disc and facet joint, while also demonstrating a discernible impact on the upper adjacent segment.

Background: Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure. We aimed to uncover MYC-associated molecular targets to provide new strategies for LIHC treatment. Methods: LIHC transcriptome datasets and clinical information were obtained from The Cancer Genome Atlas. A series of bioinformatics analyses were performed for 370 patients who were stratified based on the median MYC expression level (high-MYC group and low-MYC group). Correlation analysis was performed to determine relationships between the expression of key MYC-associated genes and prognosis, DNA promotor methylation, and immune cell infiltration. Gene ontology and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analyses were performed to elucidate the functions of these genes in LIHC. Their expression and functions in LIHC were further verified using transgenic mice overexpressing c-Myc under control of the hepatocyte-specific promoter (Alb-Cre). Results: AURKB, CCNB2, and CDKN3 were overexpressed in LIHC patients with high MYC expression and were associated with poor prognosis. Upregulation of these 3 genes was significantly correlated with hypomethylated promoter status, advanced T stage, metastasis, and immune cell infiltration in LIHC patients. Functional enrichment analyses indicated that these genes participate in the “p53 signaling pathway” and “cell cycle”. Furthermore, RT-PCR and IHC analysis revealed that their mRNA and protein expression levels were upregulated in an Alb-Cre;cMYClsl/- mouse model. Drugs that target these 3 MYC-related genes were identified. Conclusion: Taken together, our results identify biomarkers of potential utility for managing liver cancer therapy owing to their significance in tumorigenesis, proliferation, and tumor immunity.

Primary glioblastoma(pGBM) is the most malignant tumor of the central nervous system. Radiotherapy, chemotherapy and surgical treatment have little effect on the survival of pGBM patients. The prognosis is often poorly once the tumor recurs. It is urgent to develop new therapies for patients. In recent years, studies have been clarified that miRNA have a powerful regulating effect on the genes. However, the main group of miRNAs in regulating long-term survival specific related genes of pGBM is still unclear. Given that the survival period of most glioma patients is relatively short, studying long-term survival patients with pGBM is of great value for this disease. Our study aim to identify key miRNAs with long-term survival related genes present in pGBM and uncover their potential mechanisms. The gene expression profiles of GSE53733, GSE15824, GSE30563, GSE50161 were obtained from the Gene Expression Omnibus database. Firstly, samples were divided into 3 groups according to its survival time and each group compare to the normal control group. Then we obtained differential expression genes (DEGs) with a long-term survival specific (LTSDEGs) and a short-term survival specific DEGs (STSDEGs). Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted with LTSDEGs and STSDEGs together. Moreover, we used the UALCAN database to verify LTSDEGs and STSDEGs, and obtained long-term verified survival specific DEGs(LTVSDEGs) and short-term verified survival specific DEGs(STVSDEGs). Finally, we established the predicted key miRNAs-LTVSDEGs interaction network. The protein expressions of the top 4 LTVSDEGs were verified in the HPA database with immunohistochemical staining. In total, we found 260 genes changed in LTSDEGs and 822 genes changed in STSDEGs. GO and KEGG results shown that the major changes are focused on tumor metabolism. 9 LTVSDEGs and 18 STVSDEGs were verified in UALCAN database. As for protein expression verification in top 4 LTVSDEGs, ZNF630, BLVRB and RPA3 were verified, while TPBG was not detected. We obtained 59 key miRNA from the predicted key miRNAs-LTVSDEGs interaction network. 25 key miRNAs were verified using GSE90603. Finally, we constructed the key miRNAs-LTVSDEGs network using a Sankey diagram, including 25 miRNAs and 7 LTVSDEGs. In conclusion, our study shows that there is a close relationship between metabolic changes and survival in pGBM. Besides, we established a key miRNAs-LTVSDEGs network for pGBM, which could be the key path in prolonging the life of pGBM patients.

Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality.

Dye/salt separation has gained increasing attention in recent years, prompting the quest to find cost-effective and environmentally friendly raw materials for synthesizing high performance nanofiltration (NF) membrane for effective dye/salt separation. Herein, a high-performance loose-structured NF membrane was fabricated via a simple vacuum filtration method using a green nanomaterial, 2,2,6,6-tetramethylpiperidine-1-oxide radical (TEMPO)-oxidized cellulose nanofiber (TOCNF), by sequentially filtrating larger-sized and finer-sized TOCNFs on a microporous substrate, followed by crosslinking with trimesoyl chloride. The resulting TCM membrane possessed a separating layer composed entirely of pure TOCNF, eliminating the need for other polymer or nanomaterial additives. TCM membranes exhibit high performance and effective dye/salt selectivity. Scanning Electron Microscope (SEM) analysis shows that the TCM membrane with the Fine-TOCNF layer has a tight layered structure. Further characterizations via Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) confirmed the presence of functional groups and chemical bonds of the crosslinked membrane. Notably, the optimized TCM-5 membrane exhibits a rejection rate of over 99% for various dyes (Congo red and orange yellow) and 14.2% for NaCl, showcasing a potential candidate for efficient dye wastewater treatment.

ABSTRACT Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating urological chronic pelvic pain condition. In search of a potential treatment, we investigated the effect of emodin on IC/BPS inflammation and fibrosis, and explore the potential mechanism. Methods: An experimental model of interstitial cystitis was induced by cyclophosphamide, and human bladder smooth muscle cells were treated with lipopolysaccharide to establish the cell model in vitro. In both models, inflammation- and fibrosis-related indexes were measured after emodin administration. Furthermore, the specific antagonists were used to dig for the mechanisms underlying the response to emodin treatment. Results: Emodin significantly ameliorated management of cystitis, reduced the amount of inflammatory cytokines (tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1β, interleukin-8, and interleukin-6) in models, as well as reducing the synthesis of fibrosis marker including collagen1, collagen3, vimentin, fibronectin and α-smooth muscle actin. Further mechanism studies demonstrated that emodin inhibited inflammatory reaction and fibrosis through blocking lysine-specific demethylase 6B (JMJD3) expression via JAK/STAT, NF-κB and TGF-β/SMAD pathways. Conclusions: Our study reveals the critical role of emodin-JMJD3 signaling in interstitial cystitis by regulating inflammation, fibrosis, and extracellular matrix deposition in cells and tissues, and these findings provide an avenue for effective treatment of patients with cystitis.

Background: Tumor antigenicity and efficiency of antigen presentation jointly influence tumor immunogenicity, which largely determines the effectiveness of immune checkpoint blockade (ICB). However, the role of altered antigen processing and presentation machinery (APM) in breast cancer (BRCA) has not been fully elucidated. Methods: A series of bioinformatic analyses and machine learning strategies were performed to construct APM-related gene signatures to guide personalized treatment for BRCA patients. A single-sample gene set enrichment analysis (ssGSEA) algorithm and weighted gene co-expression network analysis (WGCNA) were combined to screen for BRCA-specific APM-related genes. The non-negative matrix factorization (NMF) algorithm was used to divide the cohort into different clusters and the fgsea algorithm was applied to investigate the altered signaling pathways. Random survival forest (RSF) and the least absolute shrinkage and selection operator (Lasso) Cox regression analysis were combined to construct an APM-related risk score (APMrs) signature to predict overall survival. Furthermore, a nomogram and decision tree were generated to improve predictive accuracy and risk stratification for individual patients. Based on Tumor Immune Dysfunction and Exclusion (TIDE) method, random forest (RF) and Lasso logistic regression model were combined to establish an APM-related immunotherapeutic response score (APMis). Finally, immune infiltration, immunomodulators, mutational patterns, and potentially applicable drugs were comprehensively analyzed in different APM-related risk groups. IHC staining was used to assess the expression of APM-related genes in clinical samples. Results: In this study, APMrs and APMis showed favorable performances in risk stratification and therapeutic prediction for BRCA patients. APMrs exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. APMrs was closely associated with distinct mutational patterns, immune cell infiltration and immunomodulators expression. Furthermore, the two APM-related gene signatures were independently validated in external cohorts with prognosis or immunotherapeutic responses. Potential applicable drugs and targets were mined in the APMrs-high group. APM-related genes were further validated in our in-house samples. Conclusion: The APM-related gene signatures established in our study could improve the personalized assessment of survival risk and guide ICB decision-making for BRCA patients.

Abstract Background The metastasis of breast cancer (BC) is a complex multi-step pathological process, strictly dependent on the intrinsic characteristics of BC cells and promoted by a predisposing microenvironment. Although immunotherapy has made important progress in metastasis BC, the heterogeneity of PD-L1 in tumor associated macrophages (TAMs) in BC and the underlying mechanisms in the metastasis development of BC are still not completely elucidated. Small extracellular vesicles (sEVs) represent essential interaction mediators between BC cells and TAMs. It is worth noting to explore the underlying mechanisms typical of sEVs and their role in the metastasis development of BC. Methods The structure of sEVs was identified by TEM, while the particle size and amounts of sEVs were detected by BCA and NTA analysis. The specific PD-L1 + CD163 + TAM subpopulation in metastasis BC was identified by scRNA-seq data of GEO datasets and verified by IHC and IF. The function of TAMs and sEVs in metastasis BC was explored by RT-qPCR, WB, IF, flow cytometry and in vivo experiment. The expression profiles of plasma sEVs-miRNA in relation to BC metastasis was analyzed using next-generation sequencing. Further detailed mechanisms of sEVs in the metastasis development of BC were explored by bioinformatics analysis, RT-qPCR, WB and luciferase reporter assay. Results In this study, we identified that the immunosuppressive molecule PD-L1 was more abundant in TAMs than in BC cells, and a specific PD-L1 + CD163 + TAM subpopulation was found to be associated with metastasis BC. Additionally, we found that BC cells-derived sEVs can upregulate the PD-L1 expression and induce the M2 polarization, enhancing the metastasis development both in vitro and in vivo. Also, Clinical data showed that sEV-miR-106b-5p and sEV-miR-18a-5p was in relation to BC metastasis development and poor prognosis of BC patients. Further mechanistic experiments revealed that BC-derived sEV-miR-106b-5p and sEV-miR-18a-5p could synergistically promoted the PD-L1 expression in M2 TAMs by modulating the PTEN/AKT and PIAS3/STAT3 pathways, resulting in the enhancement of the BC cells invasion and metastasis. Conclusions Our study demonstrated that BC-derived sEVs can induce metastasis in BC through miR-106b-5p/PTEN/AKT/PD-L1 and miR-18a-5p/PIAS3/STAT3/PD-L1 pathways in TAMs. Therefore, the inhibition of these specific interactions of signaling pathways would represent a promising target for future therapeutic strategies for treatment of BC.

Abstract Purpose To investigate the mechanism underlying the modulation of M1 macrophage polarization by exosomes released from hyperthermia-treated triple-negative breast cancer (TNBC) cells. Materials and methods In this study, the effects of hyperthermia on TNBC cells were examined using cell counting kit-8, apoptosis, and cell cycle assays. Transmission electron microscopy was used to identify the structure of exosomes, while bicinchoninic acid and nanoparticle tracking analysis were used to detect particle size and amounts of exosomes released after hyperthermia. The polarization of macrophages incubated with exosomes derived by hyperthermia-pretreated TNBC cells were assessed by RT-qPCR and flow cytometry analysis. Next, RNA sequencing was performed to determine the targeting molecules changed in hyperthermia-treated TNBC cells in vitro. Finally, the mechanism underlying the modulation of macrophage polarization by exosomes derived from hyperthermia-treated TNBC cells was examined by using RT-qPCR, immunofluorescence and flow cytometry analysis. Results Hyperthermia markedly reduced cell viability in TNBC cells and promoted the secretion of TNBC cell-derived exosomes. The hub genes of hyperthermia-treated TNBC cells were significantly correlated with macrophage infiltration. Additionally, hyperthermia-treated TNBC cell-derived exosomes promoted M1 macrophage polarization. Furthermore, the expression levels of heat shock proteins, including HSPA1A, HSPA1B, HSPA6, and HSPB8, were significantly upregulated upon hyperthermia treatment, with HSPB8 exhibiting the highest upregulation. Moreover, hyperthermia can induce M1 macrophage polarization by promoting exosome-mediated HSPB8 transfer. Conclusion This study demonstrated a novel mechanism that hyperthermia can induce M1 polarization of macrophages via exosome-mediated HSPB8 transfer. These results will help with future development of an optimized hyperthermia treatment regime for clinical application, especially for combination treatment with immunotherapy.

The fouling of separation membranes has consistently been a primary factor contributing to the decline in membrane performance. Enhancing the surface hydrophilicity of the membrane proves to be an effective strategy in mitigating membrane fouling in water treatment processes. Zwitterionic polymers (containing an equimolar number of homogeneously distributed anionic and cationic groups on the polymer chains) have been used extensively as one of the best antifouling materials for surface modification. The conventional application of zwitterionic compounds as surface modifiers is intricate and inefficient, adding complexity and length to the membrane preparation process, particularly on an industrial scale. To overcome these limitations, zwitterionic polymer, directly used as a main material, is an effective method. In this work, a novel zwitterionic polymer (TB)—zwitterionic Tröger’s base (ZTB)—was synthesized by quaternizing Tröger’s base (TB) with 1,3-propane sultone. The obtained ZTB is blended with TB to fabricate microfiltration (MF) membranes via the vapor-induced phase separation (VIPS) process, offering a strategic solution for separating emulsified oily wastewater. Atomic force microscopy (AFM), scanning electron microscopy (SEM), water contact angle, and zeta potential measurements were employed to characterize the surface of ZTB/TB blended membranes, assessing surface morphology, charge, and hydrophilic/hydrophobic properties. The impact of varying ZTB levels on membrane surface morphology, hydrophilicity, water flux, and rejection were investigated. The results showed that an increase in ZTB content improved hydrophilicity and surface roughness, consequently enhancing water permeability. Due to the attraction of water vapor, the enrichment of zwitterionic segments was enriched, and a stable hydration layer was formed on the membrane surface. The hydration layer formed by zwitterions endowed the membrane with good antifouling properties. The proposed mechanism elucidates the membrane’s proficiency in demulsification and the reduction in irreversible fouling through the synergistic regulation of surface charge and hydrophilicity, facilitated by electrostatic repulsion and the formation of a hydration layer. The ZTB/TB blended membranes demonstrated superior efficiency in oil–water separation, achieving a maximum flux of 1897.63 LMH bar−1 and an oil rejection rate as high as 99% in the oil–water emulsion separation process. This study reveals the migration behavior of the zwitterionic polymer in the membrane during the VIPS process. It enhances our comprehension of the antifouling mechanism of zwitterionic membranes and provides guidance for designing novel materials for antifouling membranes.

Abstract Background N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism. Methods We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8+ T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC. Results METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8+ T-cell proliferation, and in vivo, METTL3 overexpression increased CD8+ T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2). Conclusions Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.

Abstract Objective To explore the influence and the underlying mechanism of vaspin (visceral adipose tissue‐derived serpin) on the development of triple‐negative breast malignancy. Methods First, we analyzed medical records and screened out 22 breast cancer patients with different BMI according to inclusion and exclusion criterion, and measured serum vaspin of those patients. Then we studied the effects of vaspin on TNBC cell lines by using EdU assay, colony formation, transwell and wound‐healing assay. Later, we used bioinformatics analysis to identify downstream effectors and verify with qRT‐PCR, luciferase assay, western blot, etc. Results We found the vaspin level was positively correlated with BMI in breast malignant patients and vaspin could significantly enhance the proliferation, infiltration and transferring of triple‐negative breast cancer cells by restraining the expression of miR‐33a‐5p. By using bioinformatic analysis and luciferase assay, we identified miR‐33a‐5p directly regulating ABHD2. Conclusion Vaspin, as a cancer‐promoting cytokine, may inhibit miR‐33a‐5p thus increasing the level of ABHD2 to promote the development of the triple‐negative breast cancer.

Abstract Background Glucose metabolism disorder is a common feature in cancer. Cancer cells generate much energy through anaerobic glycolysis, which promote the development of tumors. However, long non‐coding RNA may play an important role in this process. Our aim is to explore a prognostic risk model based on the glucose metabolism‐related lncRNAs which provides clues that lncRNAs predict a clinical outcome through glucose metabolism in breast cancer. Methods 1222 RNA‐seq were extracted from the TCGA database, and 74 glucose metabolism‐related genes were loaded from the GSEA website. Then, 7 glucose metabolism‐related lncRNAs risk score model was developed by univariate, Lasso, and multivariate regression analysis. The lncRNA risk model showed that high‐risk patients predict a poor clinical outcome with high reliability (P=2.838×10‐6). Univariate and multivariate independent prognostic analysis and ROC curve analysis proved that the risk score was an independent prognostic factor in breast cancer with an AUC value of 0.652. Finally, Gene set enrichment analysis showed that cell cycle‐related pathways were significantly enriched in a high‐risk group. Results Our results showed that glucose metabolism‐related lncRNAs can affect breast cancer progression. 7 glucose metabolism‐related lncRNAs prognostic signature was established to evaluate the OS of patients with breast cancer. PICSAR, LINC00839, AP001505.1, LINC00393 were risk factors and expressed highly in the high‐risk group. A Nomogram was made based on this signature to judge patients' living conditions and prognosis. Conclusion 7 glucose metabolism‐related lncRNAs risk score model had a high prognostic value in breast cancer. PICSAR, LINC00839, AP001505.1, LINC00393 were risk factors. AP001505.1 expression was increased in most triple‐negative breast cancer cells treated with high glucose, which may also take part in breast cancer progression and potential therapeutic targets

Background: Head and neck squamous cell carcinoma (HNSCC) represents a predominant type of cancer found in the head and neck region, characterized by a high incidence and unfavorable prognosis. The IGF2BPs gene family, which belongs to the RNA-binding protein class, has been critically implicated in several cancers, and its involvement in HNSCC necessitates further exploration. Objective: To explore the clinical significance and potential biological functions of the IGF2BPs gene family in HNSCC. Methods: A bioinformatic methodology was employed to examine the expression profile, diagnostic and prognostic significance, and biological mechanisms of the IGF2BPs gene family in HNSCC, with a particular emphasis on its involvement in the immune function of HNSCC. This was followed by in vitro investigations to unravel the biological roles of the IGF2BPs gene family in HNSCC. Results: This investigation has demonstrated that, in contrast with normal control tissue, HNSCC has a substantial elevation in the expression level of the IGF2BPs gene family. Patients with a high level of IGF2BPs gene family expression demonstrated higher prediction accuracy for HNSCC. Furthermore, patients with HNSCC and elevated IGF2BPs gene family expression levels exhibited poor survival outcomes. The IGF2BPs gene family displayed a significant association with a variety of immune infiltrating cells and immune genes in HNSCC. Studies conducted in vitro have confirmed that IGF2BP2 silencing suppressed the migration, proliferation, and invasion of HNSCC cells. Conclusions: It has been determined that the IGF2BPs gene family plays a crucial part in the onset and progression of HNSCC, and its association with tumor immunity has been established. The IGF2BPs gene family holds promising potential as a diagnostic and prognostic biomarker for HNSCC.

Objectives: NLR family CARD domain containing 5 (NLRC5) could promote major histocompatibility complex class I (MHC-I)-dependent CD8+ T cell-mediated anticancer immunity. In this study, the immunosurveillance role and underlying mechanisms of NLRC5 in endometrial cancer (EC) were characterized. Methods: CD8+ T cells were separated from healthy women's peripheral blood by using magnetic beads. The effect of NLRC5 and interferon-β (IFN-β) on immunosurveillance of EC were examined through a mouse tumor model and a CD8+ T cell-EC cell coculture system after NLRC5 overexpression and IFN-β overexpression or depletion. The effect of NLRC5 on IFN-β expression was examined with gain- and loss-of-function experiments. Results: NLRC5 overexpression in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation and migration and promoted EC cell apoptosis and CD8+ T cell proliferation. In vivo, NLRC5 overexpression increased the proportion of CD8+ T cells and inhibited EC progression. Furthermore, IFN-β overexpression in the EC cell and CD8+ T cell coculture system activated CD8+ T cell proliferation; however, genetic depletion of IFN-β exerted the opposite effects. In addition, NLRC5 could negatively regulate IFN-β expression in EC cells. Mechanistically, NLRC5 potentiated the antitumor responses of CD8+ T cells to EC by activating IFN-β. Conclusions: Taken together, our findings demonstrated that NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-β in EC, suggesting that genetically escalated NLRC5 and IFN-β may act as potential candidates for the clinical translation of adjuvant immunotherapies to patients with EC.

Background and Aims: Heavy alcohol consumption and genetic factors represent the 2 major etiologies of chronic pancreatitis (CP). However, little is so far known about the clinical features and genetic basis of light-to-moderate alcohol consumption-related CP (LMA-CP). Methods: A cross-sectional analysis was performed on 1061 Chinese CP patients between 2010 and 2015. CP was classified as classical alcoholic CP (ACP; n = 206), LMA-CP (n = 154), and idiopathic CP (ICP; n = 701). Clinical features and genetic characteristics (PRSS1, SPINK1, CTRC, CFTR variant status) were compared between the different groups. Odds ratios (ORs) with 95% confidence intervals were calculated to ascertain the combinatorial effect of alcohol consumption and gene mutation. Results: Compared with ICP, the clinical features of LMA-CP were characterized by higher rates of developing pancreatic stones, pseudocyst, diabetes, and steatorrhea, which were similar to those associated with ACP. The prevalence of CP-related gene variants in LMA-CP was 38.3%, similar to ACP (39.8%), although significantly lower than ICP (56.2%). Alcohol consumption enhanced the risk of a poor clinical outcome, whereas genetic factors amplified alcohol’s effects. Compared with ICP, LMA-CP and ACP were associated with a high risk of pancreatic stones (patients without variants, OR = 2.01 and 2.54; patients with variants, OR = 2.17 and 1.07), pseudocyst (patients without variants, OR = 1.03 and 1.43; patients with variants, OR = 1.67 and 2.14), diabetes mellitus (patients without variants, OR = 0.86 and 1.31; patients with variants, OR = 2.05 and 1.55), and steatorrhea (patients without variants, OR = 1.56 and 2.10; patients with variants, OR = 2.11 and 1.60). Conclusion: Evidence was presented to show that LMA-CP was clinically and genetically similar to ACP but significantly different from ICP. Our findings provide support to the growing view that there is no safe level of alcohol consumption.

Background Improvements in screening and imaging technologies and treatment of liver disease have influenced the trend in diagnosis for stage I liver cancer. In this article, recent trends in age, incidence, tumour size, and survival of different stages of liver cancer are analysed.Methods Surveillance, Epidemiology, and end results data from the National Cancer Institute were used to analyse trends in age-adjusted incidence rate, mean tumour size at diagnosis, age at diagnosis, and 5-year survival probability for stage I liver cancer.Results Stage I cases of liver cancer increased most tremendously over the study period, with a greater increase from 2004 to 2012 following a smaller increase from 2012 to 2015. Moreover, the mean age of stage I liver cancer increased by 1.72 years from 2004 to 2015. The 5-year-overall survival for stage I liver cases worsened from 97.9% to 83.7% from 2004 to 2011, whereas the 10-year survival probability for stage I cases worsened from 97.3% in 2004 to 79.6% in 2006. Comparing with higher stage cases, stage I liver cancer were more likely to be females, be married, live in metro areas, receive chemotherapy, and carry medical insurance.Conclusions The incidence of stage I liver cancer has increased over the study period, with an increase in age of diagnosis, decrease in tumour size, and generally stable overall survival rate with slight decrease. These trends emphasized the importance of early detection of liver cancer and regular screening and better treatment for high-risk populations.RESEARCH HIGHLIGHTSImprovements in screening and imaging technologies and treatment of liver disease have influenced the trend in diagnosis for liver cancer.Stage I cases of liver cancer increased most tremendously over the study period, with a greater increase from 2004 to 2012 following a smaller increase from 2012 to 2015.These trends emphasized the importance of early detection of liver cancer and regular screening and better treatment for high-risk populations.

Purpose To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. Materials and Methods We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. Results Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. Conclusions Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Abstract Background Most previous studies attempting to prove the phenomenon of mother-to-infant microbiota transmission were observational, performed only at genus/species-level resolution, and relied entirely on non-culture-based methodologies, impeding interpretation. Results This work aimed to use a biomarker strain, Bifidobacterium animalis subsp. lactis Probio-M8 (M8), to directly evaluate the vertical transmission of maternally ingested bacteria by integrated culture-dependent/-independent methods. Our culture and metagenomics results showed that small amounts of maternally ingested bacteria could translocate to the infant gut via oral-/entero-mammary routes through lactation. Interestingly, many mother-infant-pair-recovered M8 homologous isolates exhibited high-frequency nonsynonymous mutations in a sugar transporter gene (glcU) and altered carbohydrate utilization preference/capacity compared with non-mutant isolates, suggesting that M8 underwent adaptive evolution for better survival in simple sugar-deprived lower gut environments. Conclusions This study presented direct and strain-level evidence of mother-to-infant bacterial transmission through lactation and provided insights into the impact of milk microbiota on infant gut colonization. Video Abstract

Abstract Background More initial clinical node‐positive breast cancer patients achieve axillary pathological complete response (ax‐pCR) after neoadjuvant systemic therapy (NST). Restaging axillary status and performing de‐escalated surgical procedures to replace routine axillary lymph nodes dissection (ALND) is urgently needed. Targeted axillary lymph node biopsy (TLNB) is a novel de‐escalated surgical strategy marking metastatic axillary nodes before NST and targeted dissection and biopsy intraoperatively to tailor individual axillary management. Methods This study provided a systematic review and meta‐analysis to evaluate the feasibility and diagnosis accuracy of TLNB. Prospective and retrospective clinical trials on TLNB were searched from Pubmed, Embase, and Cochrane. Identification rate (IFR), false‐negative rate (FNR), negative predictive value (NPV), and rate of ax‐pCR were the outcomes of this meta‐analysis. Results One thousand nine hundred and twenty patients attempted TLNB, with an overall IFR of 93.5% (95% confidence interval [CI] 90.1%–96.2%). IFR of three nodal marking methods, namely iodine seeds, clips, and carbon dye, was 95.6% (95% CI 91.2%–98.7%), 91.7% (95% CI 87.3%–95.4%), and 97.1% (95% CI 89.1%–100.0%), respectively. Of them, 847 patients received ALND, with an overall FNR of 5.5% (95% CI 3.3%–8.0%), and NPV ranged from 90.1% to 96.1%. Regression analysis showed that the overlap of targeted and sentinel biopsied nodes might associate with IFRs and FNRs. Conclusion TLNB is a novel, less invasive surgical approach to distinguish initial node‐positive breast cancer that achieves negative axillary conversion after NST. It yields an excellent IFR with a low FNR and a high NPV. A combination of preoperative imaging, intraoperative TLNB with SLNB, and postoperative nodal radiotherapy might affect the future treatment paradigm of primary breast cancer with nodal metastases.

Abstract Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract

Abstract Background Several studies have reported that circulating tumor cells (CTCs) are a promising marker for the diagnosis of thyroid cancer (TC) with recurrence or distant metastasis (DMs). However, some studies emerged with conflicting results. Therefore, we provide a meta-analysis to evaluate the diagnostic performance of CTC for detection of recurrence in patients of TC. Methods We searched PubMed, Web of Science, Cochrane library with the keywords “thyroid cancer” and “circulating tumor cells”. Data extraction and risk of bias assessment were performed independently by two reviewers. The summary receiver operating characteristic curve (SROC) and other parameters were adopted to summarize the overall test performance. The sensitivity of CTCs in the detection of recurrent TC was reviewed. All analyses were performed by STATA 12.0 and Meta-disc software. Results For CTCs expressing epithelial cell adhesion molecule (EpCAM), seven studies were included in our meta-analysis. Pooled sensitivity, specificity, and diagnostic odds ratio were 0.71 (95% CI: 0.63–0.78), 0.89 (95% CI: 0.84–0.94), and 26.75 (95% CI: 9.11–78.53); 0.78 (95% CI: 0.65–0.89), 0.88 (95% CI: 0.76–0.96), and 40.01 (95% CI: 10.49–152.63) for CTCs expressing thyroid stimulating hormone receptor (TSHR). The area under the SROC for EpCAM and TSHR were both 0.91. Conclusion CTC was a reliable marker for the diagnosis of TC patients with recurrence and DMs, and the sensitivity of CTCs expressing TSHR was higher than that of EpCAM. Additional research is warranted in order to establish uniformity in international guidelines, make up the drawbacks of conventional diagnostic methods and to prevent futile surgery.

Extracting process of potassium fertilizer with potassium feldspar-phosphogypsum-coke system is a feasible industrialization route to utilize insoluble potassium resources, in which the reaction process of coke and phosphogypsum is the key to raise the potassium extraction rate. In this paper, the influence of the ratio of activated carbon to phosphogypsum on potassium extraction rate is studied under N2 or CO2 atmosphere. Two different roasting temperature systems, heating up with the furnace and feeding at constant temperature, are used to compare the potassium extraction rate and roasted products under different atmospheres. The results showed that as the content of activated carbon in the system increased, the potassium extraction rate increased first and then decreased. Under N2 atmosphere, the rate of potassium extraction in samples that heating with constant temperature is greater than that of samples heating with the furnace. In CO2 atmosphere, when the ratio of activated carbon to phosphogypsum is less than 3:6, the potassium extraction rate of samples heating with constant temperature is greater than that of samples heating with the furnace; when the ratio of activated carbon to phosphogypsum is greater than 3∶6, the potassium extraction rate of samples heating with the furnace is greater than that of samples heating with constant temperature.

Objective: To investigate the effectiveness of a Chinese patent medicine, Jintiange capsules with the main component of artificial tiger bone powder, combined with alfacalcidol on muscle strength and balance of the lower extremities in patients with primary osteoporosis. Design: A randomized, double-blind, double-dummy, positive-controlled, multicenter clinical trial. Subjects and methods: A total of 400 patients diagnosed with primary osteoporosis or osteopenia were recruited and randomized into the Jintiange or control groups. During the 52-week treatment, the participants in the Jintiange group were treated with Jintiange capsules (1.2 ​g each time, 3 times per day) and calcium carbonate simulant, while those in the control group were treated with calcium carbonate (element calcium 0.3 ​g, twice a day) and a Jintiange capsule simulant. Alfacalcidol (0.25 ​μg/d) was applied in both groups. The timed up and go test (TUG), chair rising test (CRT), and tandem gait test (TGT) were performed to evaluate balance, muscle strength and fall risk of the participants. Results: There were 154 participants in the Jintiange group, and 157 participants in the control group were included in the per-protocol set. Comparing the data at week 52 from those at baseline, the TUG time decreased from 9.60 ​± ​2.25 ​s to 8.53 ​± ​2.06 ​s (p ​

Abstract Background Lumbar spinal stenosis (LSS) is a common disease among elderly individuals, and surgery is an effective treatment. The development of minimally invasive surgical techniques, such as the lumbar interspinous process device (IPD), has provided patients with more surgical options. Objective To investigate the biomechanical properties of different IPDs, including BacFuse, X-Stop and Coflex, in the treatment of LSS. Methods Based on the computed tomography images of a patient with LSS, four finite element (FE) models of L3-S5 were created in this study. The FE models included a surgical model of the intact lumbar spine and surgical models of the lumbar IPDs BacFuse, X-Stop, and Coflex. After validating the models, they were simulated for four physiological motions: flexion, extension, lateral bending and axial rotation, and range of motion (ROM). Stress distribution of discs and facet joints in each segment, stress distribution of the spinous process in the operated section, and stress distribution of the internal fixation were compared and analysed. Results Compared to the model of the intact lumbar spine, the other three models showed a decrease in ROM and disc and facet joint stresses in the surgical segment during movement and an increase in ROM and disc and facet joint stresses in the adjacent segments. These effects were greater for the proximal adjacent segment with BacFuse and more pronounced for the distal adjacent segment with Coflex, while X-Stop had the greatest stress effect on the spinous process in the surgical segment. Conclusion BacFuse, Coflex and X-Stop could all be implemented to effectively reduce extension and disc and facet joint stresses, but they also increase the ROM and disc and facet joint stresses in adjacent segments, which may cause degeneration.

Abstract The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.

TED (Technology, Entertainment, Design) is an internationally based open access platform where professionals from various fields are invited to give speeches, and to share ideas with like-minded people. In recent years, topics related to the coronavirus disease (COVID-19) or the COVID-19 pandemic have become the most popular speech topics on TED. This paper selects speech-related topics on TED during the pandemic, by using systemic functional linguistics to study how discourses are expressed on the platform. Unlike traditional textual analyses, content on TED are normally verbalized, requiring original texts to be presented in an understandable format. As a result, this paper focuses on the functional innovation of new forms of expression on TED. In other words, the functional perspective of the presentation in relation to COVID-19 based topics may rely on the explanation of the meta-meaning of the keywords, posting images and other techniques as auxiliary means for expression, to some extent. These auxiliary techniques offer traditional systemic functional linguistics new meanings in terms of ideational and interpersonal aspects.