Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. METHODS: Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. RESULTS: It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. CONCLUSIONS: Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

Deep learning-based multi-parametric magnetic resonance imaging (mp-MRI) nomogram for predicting Ki-67 expression in rectal cancer.

PURPOSE: To explore the value of deep learning-based multi-parametric magnetic resonance imaging (mp-MRI) nomogram in predicting the Ki-67 expression in rectal cancer. METHODS: The data of 491 patients with rectal cancer from two centers were retrospectively analyzed and divided into training, internal validation, and external validation sets. They were categorized into high- and low-expression group based on postoperative pathological Ki-67 expression. Each patient's mp-MRI data were analyzed to extract and select the most relevant features of deep learning, and a deep learning model was constructed. Independent predictive risk factors were identified and incorporated into a clinical model, and the clinical and deep learning models were combined to obtain a nomogram for the prediction of Ki-67 expression. The performance characteristics of the DL-model, clinical model, and nomogram were assessed using ROCs, calibration curve, decision curve, and clinical impact curve analysis. RESULTS: The strongest deep learning features were extracted and screened from mp-MRI data. Two independent predictive factors, namely Magnetic Resonance Imaging T (mrT) staging and differentiation degree, were identified through clinical feature selection. Three models were constructed: a deep learning (DL)-model, a clinical model, and a nomogram. The AUCs of clinical model in the training, internal validation, and external validation set were 0.69, 0.78, and 0.67, respectively. The AUCs of the deep model and nomogram ranged from 0.88 to 0.98. The prediction performance of the deep learning model and nomogram was significantly better than the clinical model (P < 0.001). CONCLUSION: The nomogram based on deep learning can help clinicians accurately and conveniently predict the expression status of Ki-67 in rectal cancer.

Managing government debt.

To construct a stochastic version of [R. J. Barro, J. Polit. Econ. 87, 940-971 (1979)] normative model of tax rates and debt/GDP dynamics, we add risks and markets for trading them along lines suggested by [K. J. Arrow, Rev. Econ. Stud. 31, 91-96 (1964)] and [R. J. Shiller, Creating Institutions for Managing Society's Largest Economic Risks (OUP, Oxford, 1994)]. These modifications preserve Barro's prescriptions that a government should keep its debt-gross domestic product (GDP) ratio and tax rate constant over time and also prescribe that the government insure its primary surplus risk by selling or buying the same number of shares of a Shiller macro security each period.

Effectiveness of Butorphanol in alleviating intra- and post-operative visceral pain following microwave ablation for hepatic tumor: a dual-central, randomized, controlled trial.

Many patients who underwent hepatic percutaneous microwave ablation (MWA) reported experiencing pain during the procedure. This study utilized a well-designed multicentral, randomized, and placebo-controlled format to investigate the effects of Butorphanol. Patients who underwent MWA were randomly assigned to either Butorphanol or normal saline group. The primary outcomes of the study were assessed by measuring the patients' intraoperative pain levels using a 10-point visual analog scale (VAS). Secondary outcomes included measuring postoperative pain levels at the 6-h mark (VAS) and evaluating comprehensive pain assessment outcomes. A total of 300 patients were divided between the control group (n = 100) and the experimental group (n = 200). Butorphanol showed statistically significant reductions in intraoperative pain levels compared to the placebo during surgery (5.00 ± 1.46 vs. 3.54 ± 1.67, P < 0.001). Significant differences were observed in postoperative pain levels at the 6-h mark and in the overall assessment of pain (1.39 + 1.21 vs. 0.65 + 0.81, P < 0.001). Butorphanol had a significant impact on reducing the heart rate of patients. The empirical evidence supports the effectiveness of Butorphanol in reducing the occurrence of visceral postoperative pain in patients undergoing microwave ablation for hepatic tumor. Furthermore, the study found no noticeable impact on circulatory and respiratory dynamics.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism.

Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

Association between preoperative sarcopenia and prognosis of pancreatic cancer after curative-intent surgery: a updated systematic review and meta-analysis.

BACKGROUND: Sarcopenia is associated with poor outcomes in many malignancies. However, the relationship between sarcopenia and the prognosis of pancreatic cancer has not been well understood. The aim of this meta-analysis was to identify the prognostic value of preoperative sarcopenia in patients with pancreatic cancer after curative-intent surgery. METHODS: Database from PubMed, Embase, and Web of Science were searched from its inception to July 2023. The primary outcomes were overall survival (OS), progression-free survival (PFS), and the incidence of major complications. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CIs) were used to assess the relationship between preoperative sarcopenia and the prognosis of patients with pancreatic cancer. All statistical analyses were conducted by Review Manager 5.3 and STATA 17.0 software. RESULTS: A total of 23 retrospective studies involving 5888 patients were included in this meta-analysis. The pooled results demonstrated that sarcopenia was significantly associated with worse OS (HR = 1.53, P < 0.00001) and PFS (HR = 1.55, P < 0.00001). However, this association was not obvious in regard to the incidence of major complications (OR = 1.33, P = 0.11). CONCLUSION: Preoperative sarcopenia was preliminarily proved to be associated with the terrible prognosis of pancreatic cancer after surgery. However, this relationship needs to be further validated in more prospective studies.

Comparison of in-patient glucose team based management with conventional blood glucose management- a retrospective study from China.

BACKGROUND: Glycemic control for patients with diabetes in the surgical department is often unsatisfactory. Compounding this issue is the fact that conventional glucose management models are often inefficient and difficult to monitor over time. OBJECTIVE: To investigate the impact of inpatient glucose team-based management on glycemic control and hospital days in surgical patients with diabetes. METHODS: A retrospective analysis was conducted on 4156 patients with diabetes in the surgical department who received inpatient management of diabetes at a tertiary medical center from June 2020 to May 2022. Based on whether they received inpatient glucose team-based management, the surgical patients with diabetes were divided into two groups: the inpatient glucose team-based management (GM group, consisting of 1698 participants) and the conventional blood glucose management group (control group, consisting of 2458 participants). We compared the two groups in terms of glycemic control, hospital days, and health-care costs. Multiple logistic regression analysis was performed to build the hospital days prediction model and nomogram. Finally, the performance of the model was evaluated. RESULTS: The rate of glucose detection was higher in the GM group at 2 h postprandial (P < 0.01). The incidence of hypoglycemia and severe hyperglycemia, blood glucose attainment time, pre-operative preparation days, hospital days, and health-care costs were lower in the GM group than in the control group (P < 0.01). The linear regression model revealed that blood glucose attainment time, incidence of hypoglycemia (< 3.9mmol/L), preoperative preparation days, perioperative complications, and health-care costs were the factors influencing the hospital days (Total Point 83.4 points, mean hospital days 9.37 days). Receiver operating characteristic (ROC) curve analysis demonstrated that the nomogram had good accuracy for predicting hospital days (area under the ROC curve 0.83, 95% confidence interval [CI], 0.74 to 0.92). CONCLUSION: Inpatient glucose team-based management demonstrated significant improvements in glycemic control among surgical patients with diabetes, resulting in reduced hospital days and associated costs. The developed nomogram also exhibited promising potential in predicting hospital days, offering valuable clinical applications.

Diagnostic performance of metagenomic next-generation sequencing for the detection of pathogens in cerebrospinal fluid in pediatric patients with central nervous system infection: a systematic review and meta-analysis.

BACKGROUND: Detecting pathogens in pediatric central nervous system infection (CNSI) is still a major challenge in medicine. In addition to conventional diagnostic patterns, metagenomic next-generation sequencing (mNGS) shows great potential in pathogen detection. Therefore, we systematically evaluated the diagnostic performance of mNGS in cerebrospinal fluid (CSF) in pediatric patients with CNSI. METHODS: Related literature was searched in the Web of Science, PubMed, Embase, and Cochrane Library. We screened the literature and extracted the data according to the selection criteria. The quality of included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and the certainty of the evidence was measured by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) score system. Then, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odd's ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic curve (sROC) were estimated in Stata Software and MetaDisc. Subgroup analyses were performed to investigate the potential factors that influence the diagnostic performance. RESULTS: A total of 10 studies were included in the meta-analysis. The combined sensitivity was 0.68 (95% confidence interval [CI]: 0.59 to 0.76, I2 = 66.77%, p < 0.001), and the combined specificity was 0.89 (95% CI: 0.80 to 0.95, I2 = 83.37%, p < 0.001). The AUC of sROC was 0.85 (95% CI, 0.81 to 0.87). The quality level of evidence elevated by the GRADE score system was low. CONCLUSIONS: Current evidence shows that mNGS presents a good diagnostic performance in pediatric CNSI. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

Facilitating Lung Collapse for Thoracoscopic Surgery Utilizing Endobronchial Airway Occlusion Preceded by Pleurotomy and One-minute Suspension of Two-lung Ventilation.

OBJECTIVES: To assess when and whether clamping the double-lumen endobronchial tube (DLT) limb of the non-ventilated lung is more conducive to a rapid and effective lung deflation than simply allowing the open limb of the DLT to communicate with the atmosphere. DESIGN: This was a single-center, single-blind, randomized, controlled trial. SETTING: The trial was performed in a single institutional setting. PARTICIPANTS: The participants were 60 patients undergoing elective video-assisted thoracoscopic surgery. INTERVENTIONS: Patients were randomized to the open-clamp airway technique (OCAT group) or control group. Patients in the control group had one-lung ventilation initiated upon being placed in the lateral decubitus position. The OCAT group had two-lung ventilation maintained until the pleural cavity was opened with the introduction of a planned thoracoscopic access port to allow the operated lung to fall away from the chest wall. Thereafter, ventilation was suspended (temporarily ceased) for 1 minute before the DLT lumen of the isolated lung was clamped. The primary outcome of the trial was the time to complete lung collapse scored as determined from video clips taken during surgery. The secondary outcomes were (1) lung collapse score at 30 minutes after pleural incision, (2) surgeon satisfaction with surgery, and (3) intraoperative hypoxemia. MEASUREMENTS AND MAIN RESULTS: The median time to reach complete lung collapse in the OCAT group was 10 minutes (odds ratio 10.0, 95% CI 6.3-13.7), which was much shorter than that of the control group (25 minutes [odds ratio 25.0, 95% CI 13.6-36.4]). The difference in complete lung collapse at 30 minutes between the 2 groups was significant (p < 0.001). The surgeon's satisfaction with surgery was higher in the OCAT group than in the control group (8.5 ± 0.2 vs 6.8 ± 0.2; p < 0.001). There was no difference regarding intraoperative hypoxemia. CONCLUSIONS: Suspending ventilation of both DLT limbs for 1 minute after pleural cavity opening and then clamping the DLT lumen of the isolated lung resulted in a more rapid deflation of the surgical lung. This open-clamp airway technique is an effective technique for rapid surgical lung collapse during thoracoscopic surgery.

Copper Single-Atom Catalysts-A Rising Star for Energy Conversion and Environmental Purification: Synthesis, Modification, and Advanced Applications.

Future renewable energy supply and green, sustainable environmental development rely on various types of catalytic reactions. Copper single-atom catalysts (Cu SACs) are attractive due to their distinctive electronic structure (3d orbitals are not filled with valence electrons), high atomic utilization, and excellent catalytic performance and selectivity. Despite numerous optimization studies are conducted on Cu SACs in terms of energy conversion and environmental purification, the coupling among Cu atoms-support interactions, active sites, and catalytic performance remains unclear, and a systematic review of Cu SACs is lacking. To this end, this work summarizes the recent advances of Cu SACs. The synthesis strategies of Cu SACs, metal-support interactions between Cu single atoms and different supports, modification methods including modification for carriers, coordination environment regulating, site distance effect utilizing, and dual metal active center catalysts constructing, as well as their applications in energy conversion and environmental purification are emphatically introduced. Finally, the opportunities and challenges for the future Cu SACs development are discussed. This review aims to provide insight into Cu SACs and a reference for their optimal design and wide application.

Non-invasive biomarkers for identification of vanishing bile duct syndrome among children with acute cholestatic hepatitis.

Background: The identification of vanishing bile duct syndrome (VBDS) is still challenging before liver biopsy. This study tried to explore non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis. Methods: Between January 2017 and December 2021, 192 children underwent native-liver biopsy for acute cholestatic hepatitis with onset after 6 months of age. VBDS was diagnosed by liver biopsy. Differences of liver biochemical indices were compared between children with and without VBDS. Diagnostic performances for VBDS were tested by receiver operating characteristic (ROC) curve analyses. Results: Among the 192 patients, 24 (12.5%) were diagnosed with VBDS based on liver biopsy. At biopsy, their levels of total bilirubin (TB), direct bilirubin (DB), γ-glutamyl transpeptidase (GGT), total bile acid, triglyceride, and total cholesterol (TCH) were higher than patients without VBDS (all P<0.05). However, only GGT and TCH could distinguish patients with VBDS from patients without VBDS with an area under ROC curve (AUC) >0.850. Using GGT >446 U/L as a cut-off value, the sensitivity was 87.5%, the specificity was 91.6%, and the AUC was 0.948 (P<0.001). Using TCH >6.4 mmol/L as a cut-off value, the sensitivity was 100.0%, the specificity was 89.8%, and the AUC was 0.983 (P<0.001). A total of 28 patients had both GGT >446 U/L and TCH >6.4 mmol/L, including 21 patients with VBDS and 7 without VBDS (21/28 vs. 3/143, P<0.0001). Three patients with VBDS would be missed for GGT <446 U/L. Conclusions: Both GGT and TCH can be used as non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis.

Nonlocal effective medium theory for phononic temporal metamaterials.

We have developed a nonlocal effective medium theory (EMT) for phononic temporal metamaterials using the multiscale technique. Our EMT yields closed-form expressions for effective constitutive parameters and reveals these materials as reciprocal media with symmetric band dispersion. Even without spatial symmetry breaking, nonzero Willis coupling coefficients emerge with time modulation and broken time-reversal symmetry, when the nonlocal effect is taken into account. Compared to the local EMT, our nonlocal version is more accurate for calculating the bulk band at high wavenumbers and essential for understanding nonlocal effects at temporal boundaries. This nonlocal EMT can be a valuable tool for studying and designing phononic temporal metamaterials beyond the long-wavelength limit.

Efficacy and safety of tenofovir disoproxil fumarate versus entecavir in the treatment of acute-on-chronic liver failure with hepatitis B: a systematic review and meta-analysis.

BACKGROUND: Oral nucleoside (acid) analogues (NAs) are recommended for patients with acute-on-chronic liver failure (ACLF) associated with hepatitis B virus (HBV-ACLF). The efficacy and safety of tenofovir (TDF) and entecavir (ETV) in these patients remain unclear. METHODS: A comprehensive literature search in PubMed, Web of Science, The Cochrane Library, and Embase database was conducted to select studies published before December 2022 on TDF or ETV for HBV-ACLF. The primary outcomes were survival rates at 4, 12, and 48 weeks. Secondary outcomes were virologic and biochemical responses, serum antigen conversion, liver function score, and safety. RESULTS: Four prospective and one retrospective cohort studies were selected. The overall analysis showed comparable survival rates at 4, 12, and 48 weeks for all patients receiving TDF or ETV (4-week: RR = 1.17, 95% CI: 0.90-1.51, p = 0.24; 12-week: RR = 1.00, 95% CI: 0.88-1.13, p = 0.94; 48-week: RR = 0.96, 95% CI: 0.58-1.57, p = 0.86). Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease (MELD) score at 12 weeks were comparable in both groups but lower than baseline (CTP: SMD = -0.75, 95% CI:-2.81-1.30, p = 0.47; MELD: SMD = -1.10, 95% CI:-2.29-0.08, p = 0.07). At 48 weeks, estimated glomerular filtration rate (eGFR) levels were found to decrease to different degrees from baseline in both the TDF and ETV groups, and the decrease was greater in the TDF group than in the ETV group. No significant differences were found in biochemical, virologic response, and serum antigen conversion between the two groups during the observation period. CONCLUSION: TDF treatment of HBV-ACLF is similar to ETV in improving survival, liver function, and virologic response but the effects on renal function in two groups in the long term remain unclear. More and larger long-term clinical trials are required to confirm these findings.

Plant-Derived Vesicles: A New Era for Anti-Cancer Drug Delivery and Cancer Treatment.

Lipid-structured vesicles have been applied for drug delivery system for over 50 years. Based on their origin, lipid-structured vesicles are divided into two main categories, namely synthetic lipid vesicles (SLNVEs) and vesicles of mammalian origin (MDVEs). Although SLNVEs can stably transport anti-cancer drugs, their biocompatibility is poor and degradation of exogenous substances is a potential risk. Unlike SLNVEs, MDVEs have excellent biocompatibility but are limited by a lack of stability and a risk of contamination by dangerous pathogens from donor cells. Since the first discovery of plant-derived vesicles (PDVEs) in carrot cell supernatants in 1967, emerging evidence has shown that PDVEs integrate the advantages of both SLNVEs and MDVEs. Notably, 55 years of dedicated research has indicated that PDVEs are an ideal candidate vesicle for drug preparation, transport, and disease treatment. The current review systematically focuses on the role of PDVEs in cancer therapy and in particular compares the properties of PDVEs with those of conventional lipid vesicles, summarizes the preparation methods and quality control of PDVEs, and discusses the application of PDVEs in delivering anti-cancer drugs and their underlying molecular mechanisms for cancer therapy. Finally, the challenges and future perspectives of PDVEs for the development of novel therapeutic strategies against cancer are discussed.

Integrative dissection of 5-hydroxytryptamine receptors-related signature in the prognosis and immune microenvironment of breast cancer.

Background: Depression increases the risk of breast cancer recurrence and metastasis. However, there lacks potential biomarkers for predicting prognosis in breast cancer. 5-hydroxytryptamine (5-HT) plays a key role in the pathogenesis and treatment of depression. In this study, we developed a prognostic signature based on 5-HT receptors (5-HTRs) and elucidated its potential immune regulatory mechanisms for breast cancer prognosis. Methods: Oncomine, GEPIA, UALCAN, cBioPortal, Kaplan-Meier plotter, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of HTRs in breast cancer patients. The model training and validation assays were based on the analyses of GSE1456 and GSE86166. A risk signature was established by univariate and multivariate Cox regression analyses. The transwell assay was utilized to verify the effect of the 5-HTRs expression on breast cancer invasion. Effects of HTR2A/2B inhibitor on CD8+ T cell proliferation and infiltration as well as apoptosis of 4T1 cells in the tumor microenvironment were detected by flow cytometry and TUNEL assay. Zebrafish and mouse breast cancer xenografts were used to determine the effect of HTR2A/2B inhibitor on breast cancer metastasis. Results: The expression levels of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR4, and HTR7 were significantly downregulated in highly malignant breast cancer types. 5-HTRs were significantly associated with recurrence-free survival (RFS) in breast cancer patients. The genetic alteration of HTR1D, HTR3A, HTR3B, and HTR6 in breast cancer patients was significantly associated with shorter overall survival (OS). Finally, HTR2A and HTR2B were determined to construct the risk signature. The expression of HTR2A/2B was positively correlated with the infiltration of immune cells such as CD8+ T cells and macrophages. Furthermore, inhibition of HTR2A expression could suppress CD8+ T cell proliferation and enhance invasion and metastasis of breast cancer cells in both zebrafish and mice model. Conclusions: The HTR2A/2B risk signature not only highlights the significance of HTRs in breast cancer prognosis by modulating cancer immune microenvironment, but also provides a novel gene-testing tool for early prevention of depression in breast cancer patients and lead to an improved prognosis and quality of life.

Broadband frequency translation by space-time interface with weak permittivity temporal change.

Breaking spatial and temporal homogeneities simultaneously incurs the combination of wavenumber and frequency translations. In this work, broadband frequency translations with both redshifts and blueshifts triggered by a single photonic space-time interface (PSTI) with weak temporal change of permittivity across which a homogeneous medium suddenly becomes a one-dimensional photonic crystal is proposed. Mode conversions induced by the PSTI are analyzed, according to which the frequency translation amplitudes are independent of the change of permittivity and the initial frequency but are given by the product of the phase speed of the homogeneous medium and the spatial modulation frequency of the photonic crystal. Hence, a static field can be partially converted into dynamic fields by imposing the PSTI. Our findings pave the way for the study of PSTIs and provide a new scheme to realize broadband frequency translations.

Icariin inhibits prostate cancer bone metastasis and destruction via suppressing TAM/CCL5-mediated osteoclastogenesis.

BACKGROUND: Bone metastasis occurs in nearly 70% of patients with metastatic prostate cancer (PCa), and represents the leading cause of death in patients with PCa. Emerging evidence has demonstrated the potential activities of icariin in modulating bone metabolism and remodelling the tumor microenvironment (TME). However, whether icariin could inhibit PCa bone metastasis and destruction by modulating the TME as well as the underlying mechanisms remains unclear. PURPOSE: This study investigated whether icariin could inhibit PCa bone metastasis and destruction by modulating the bone TME as well as the underlying mechanisms. METHODS: Osteoclasts were induced from mouse bone marrow-derived macrophages (BMMs) or Raw264.7 cells. PCa cells were cultured in the conditional medium (CM) of macrophages in vitro or co-injected with macrophages in vivo to simulate their coexistence in the TME. Multiple molecular biology experiments and the mouse RM1-Luc PCa bone metastasis model were used to explore the inhibitory activity and mechanism of icariin on PCa metastasis and bone destruction. RESULTS: Icariin treatment significantly suppressed PCa growth, bone metastasis and destruction as well as osteoclastogenesis in vivo. Furthermore, icariin remarkably inhibited osteoclast differentiation, even in the presence of the CM of tumor-associated macrophages (TAMs), while exhibiting no obvious effect on osteoblasts. Moreover, icariin suppressed the M2 phenotype polarization of Raw264.7-derived TAMs and transcriptionally attenuated their CC motif chemokine ligand 5 (CCL5) expression and secretion via inhibiting SPI1. Additionally, CCL5 induced the differentiation and chemotaxis of osteoclast precursor cells by binding with its receptor CCR5. The clinicopathological analysis further verified the positive correlation between the TAM/CCL5/CCR5 axis and osteoclastogenesis within the TME of PCa patients. More importantly, icariin remarkably suppressed PCa metastasis-induced bone destruction in vivo by inhibiting osteoclastogenesis via downregulating the TAM/CCL5 pathway. CONCLUSION: Altogether, these results not only implicate icariin as a promising candidate immunomodulator for PCa bone metastasis and destruction but also shed novel insight into targeting TAM/CCL5-mediated osteoclastogenesis as a potential treatment strategy for osteolytic bone metastasis. This study helps to advance the understanding of the crosstalk between bone TME and bone homeostasis.

Photo-induced scandium-catalyzed biomimetic skeleton conversion of lathyrane to naturally rare eupholathone Euphorbia diterpenes.

The naturally scarce eupholathone-type euphornin E (1) was efficiently prepared from abundant lathyrane-type Euphorbia factor L1via a visible-light-induced Sc(OTf)3-catalyzed tandem process. Eupholathones 2 and 3 were also smoothly obtained by changing the reaction solvent. This route provides a convenient method for easily constructing scarce eupholathone- from lathyrane-type Euphorbia diterpenes, and confirms the biogenetic relationship between them from a chemical standpoint. Notably, compound 1 exhibited good anti-HIV activity.

The application of metagenomic next-generation sequencing in pathogen diagnosis: a bibliometric analysis based on Web of Science.

Background: Infectious disease is a large burden on public health globally. Metagenomic next-generation sequencing (mNGS) has become popular as a new tool for pathogen diagnosis with numerous advantages compared to conventional methods. Recently, research on mNGS increases yearly. However, no bibliometric analysis has systematically presented the full spectrum of this research field. Therefore, we reviewed all the publications associated with this topic and performed this study to analyze the comprehensive status and future hotspots of mNGS for infectious disease diagnosis. Methods: The literature was searched in the Web of Science Core Collection and screened without year or language restrictions, and the characteristics of the studies were also identified. The outcomes included publication years, study types, journals, countries, authorship, institutions, frontiers, and hotspots with trends. Statistical analysis and visualization were conducted using VOSviewer (version 1.6.16) and CiteSpace (version 6.1. R3). Results: In total, 325 studies were included in the analysis after screening. Studies were published between 2009 and 2022 with a significantly increasing number from 1 to 118. Most of the studies were original articles and case reports. Frontiers in Cellular and Infection Microbiology and Clinical Infectious Disease were the most commonly cited and co-cited journals. Institutions and researchers from China contributed the most to this field, followed by those from the USA. The hotspots and frontiers of these studies are pneumonia, tuberculosis, and central nervous system infections. Conclusion: This study determined that mNGS is a hot topic in the diagnosis of infectious diseases with development trends and provides insights into researchers, institutions, hotspots and frontiers in mNGS, which can offer references to related researchers and future research.