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Inflammation can initiate osteolysis, which is the breakdown of bone by fully developed osteoclasts. The compound Oleandrin is recognized for its effects against inflammation and tumors. Our objective was to examine the effects of Oleandrin on osteoclastogenesis and osteolysis, both in vitro and in vivo. In vitro, the impact of Oleandrin on osteoclastogenesis was assessed using CCK-8 assays, TRAP staining, and bone resorption assays. Additionally, a mouse model of osteolysis caused by LPS injection into the calvaria was used to conduct an in vivo investigation, examining bone histomorphology, histology, and immunohistochemistry. In vitro, concentrations of 5 nM and 10 nM of Oleandrin were found to be non-cytotoxic based on the results obtained. In vitro, Oleandrin hindered the osteoclastogenesis and bone resorption induced by RANKL. Oleandrin successfully inhibited the phosphorylation of NF-κB p65 and PI3K p85 in osteolytic tissue, thereby suppressing LPS-induced inflammatory osteolysis in mice calvaria during the in vivo study. Furthermore, the Oleandrin-treated group exhibited a noteworthy decrease in the expression level of NFATc1, which is a crucial controller of osteoclastogenesis. To sum up, our discoveries indicate that Oleandrin could hinder osteoclastogenesis and bone resorption, thereby having the ability to suppress inflammation-induced osteolysis. The underlying mechanism involves the NF-κB/PI3K pathway and inhibition of NFATc1 activation. Therefore, the findings suggest that Oleandrin holds potential as a therapeutic remedy for osteolytic ailments.

Abstract Objects Colorectal cancer (CRC) is one of the most common cancers in the world. Approximately two-thirds of patients with CRC will develop colorectal cancer liver metastases (CRLM) at some point in time. In this study, we aimed to construct a prognostic model of CRLM and its competing endogenous RNA (ceRNA) network. Methods RNA-seq of CRC, CRLM and normal samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Limma was used to obtain differential expression genes (DEGs) between CRLM and CRC from sequencing data and GSE22834, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were performed, respectively. Univariate Cox regression analysis and lasso Cox regression models were performed to screen prognostic gene features and construct prognostic models. Functional enrichment, estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, single-sample gene set enrichment analysis, and ceRNA network construction were applied to explore potential mechanisms. Results An 8-gene prognostic model was constructed by screening 112 DEGs from TCGA and GSE22834. CRC patients in the TCGA and GSE29621 cohorts were stratified into either a high-risk group or a low-risk group. Patients with CRC in the high-risk group had a significantly poorer prognosis compared to in the low-risk group. The risk score was identified as an independent predictor of prognosis. Functional analysis revealed that the risk score was closly correlated with various immune cells and immune-related signaling pathways. And a prognostic gene-associated ceRNA network was constructed that obtained 3 prognosis gene, 14 microRNAs (miRNAs) and 7 long noncoding RNAs (lncRNAs). Conclusions In conclusion, a prognostic model for CRLM identification was proposed, which could independently identify high-risk patients with low survival, suggesting a relationship between local immune status and prognosis of CRLM. Moreover, the key prognostic genes-related ceRNA network were established for the CRC investigation. Based on the differentially expressed genes between CRLM and CRC, the prognosis model of CRC patients was constructed.

Abstract Background The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40–45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC. Methods The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1β and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry. Results Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1β-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC. Conclusions CD8+ T cells and IL-1β were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1β-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1β antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.

ObjectiveExamine patients with locally advanced rectal cancer (LARC) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) who received neoadjuvant immunotherapy (nIT), and compare the outcomes of those who chose a watch-and-wait (WW) approach after achieving clinical complete response (cCR) or near-cCR with those who underwent surgery and were confirmed as pathological complete response (pCR).MethodsLARC patients with dMMR/MSI-H who received nIT were retrospectively examined. The endpoints were 2-year overall survival (OS), 2-year disease-free survival (DFS), local recurrence (LR), and distant metastasis (DM). The efficacy of programmed cell death protein-1 (PD-1) inhibitor, immune-related adverse events (irAEs), surgery-related adverse events (srAEs), and enterostomy were also recorded.ResultsTwenty patients who received a PD-1 inhibitor as initial nIT were examined. Eighteen patients (90%) achieved complete response (CR) after a median of 7 nIT cycles, including 11 with pCR after surgery (pCR group), and 7 chose a WW strategy after evaluation as cCR or near-cCR (WW group). Both groups had median follow-up times of 25.0 months. Neither group had a case of LR or DM, and the 2-year DFS and OS in each group was 100%. The two groups had similar incidences of irAEs (P=0.627). In the pCR group, however, 2 patients (18.2%) had permanent colostomy, 3 (27.3%) had temporary ileostomy, and 2 (18.2%) had srAEs.ConclusionNeoadjuvant PD-1 blockade had high efficacy and led to a high rate of CR in LARC patients with dMMR/MSI-H. A WW strategy appears to be a safe and reliable option for these patients who achieve cCR or near-cCR after nIT.

ObjectiveTo explore the efficacy and safety of single-agent programmed cell death protein-1 (PD-1) inhibitor in the neoadjuvant treatment of patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer (LACRC) through single-center large⁃sample analysis based on real⁃world data in China.MethodsThis study was a retrospective, single-center, case series study. 33 colorectal cancer (CRC) patients with clinical stage of T3~4N0~2M0 treated in Yunnan Cancer Hospital from June 2019 to June 2021 were analyzed retrospectively. Among them, 32 patients were dMMR or MSI-H or both dMMR and MSI-H, and one patient was both dMMR and microsatellite stability (MSS) (excluded in the final analysis). All 32 patients received neoadjuvant immunotherapy (nIT) with single-agent PD⁃1 inhibitor.ResultsAmong the 32 patients, 8 (25%) were locally advanced rectal cancer (LARC) and 24 (75%) were locally advanced colon cancer (LACC); 4 (12.55%) were stage II and 28 (87.5%) were stage III. The median number of cycles of 32 patients with dMMR/MSI-H LACRC receiving nIT with single-agent PD-1 blockade was 6 (4~10), and the median number of cycles to achieve partial response (PR) was 3 (2~4). Among them, three LARC patients achieved clinical complete response (cCR) and adopted the watch-and-wait (W&W) strategy. The objective response rate (ORR) of the other 29 patients with radical surgery was 100% (29/29), the pathological response rate was 100% (29/29), the rate of major pathological response (MPR) was 86.2% (25/29), and the rate of pathological complete response (pCR) was 75.9% (22/29). The incidence of immune-related adverse events (irAEs) in 32 patients during nIT was 37.5% (12/32), while the incidence of irAEs in 22 patients with operation during adjuvant immunotherapy was 27.3% (6/22), all of which were grade 1~2. No grade 3 or above irAEs were occured. The median time from the last nIT to surgery was 27 (16~42) days. There were no delayed radical resection due to irAEs in these patients. All 29 patients achieved R0 resection. The incidence of surgical-related adverse events (srAEs) in perioperative period was 10.3% (3/29).ConclusionsNeoadjuvant monoimmunotherapy with PD-1 inhibitor has favorable ORR and pCR rate, and relatively low incidences of irAEs and srAEs for patients with dMMR/MSI-H LACRC, suggesting that this nIT regimen of single-agent PD-1 inhibitor is significantly effective and sufficiently safe.

Introduction Osteoporosis is a major cause of bone fracture in post-menopausal women. We evaluated the effects of pristimerin treatment on ovariectomy-induced osteoporosis, and its possible molecular mechanism. Material and methods Rats were ovariectomised and biochemical markers of bone formation were determined from serum samples. The microarchitectures of bone tissues were analyzed via micro-CT scans and Western blotting assays. The cytotoxic effects of pristimerin, the differentiation of osteoclasts, and bone reabsorption were evaluated in vitro using RAW 264.7 cells. Results Treatment with pristimerin attenuated changes in markers of bone formation and reabsorption such as creatine kinase (CK), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), collagen type I fragments (CTX), bone Gla-protein (BGP), and osteocalcin (OC) in the serum of ovariectomised rats. It also appeared to restore the microarchitecture of bone tissue. The expression levels of TNF receptor-associated factor 6 (TRAF-6), nuclear factor k light chain enhancer of activated B cells (NF-κB p65), and receptor activator of nuclear factor-κB ligand (RANKL) protein were significantly lower, while those of Akt and PI3K were significantly higher, in the bone tissues of the pristimerin-treated group than in negative controls. Pristimerin had no cytotoxic effect on RAW 264.7 cells and reduced the differentiation of osteoclasts, bone reabsorption, and translocation of p65 in RANKL-stimulated RAW 264.7 cells in vitro . Conclusions Pristimerin reduces the effects of osteoporosis by restoring the altered RANKL/TRAF-6/NF-κB pathway in ovariectomised rats.

BackgroundMicroRNAs are known to regulate carcinogenesis of osteosarcoma. Although, miR-16-5p is known to exert inhibitory effects on several forms of cancers, its effects on the growth and invasion of osteosarcoma have not been studied.MethodsWe collected human osteosarcoma specimens and adjacent tissues to detect the expression of miR-16-5p by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. The proliferation, migration, and invasion of MG63 and HOS cells following miR-16-5p overexpression and inhibition were detected with cell counting kit-8, wound healing assay, and Transwell assay, respectively. An expression vector carrying a mutated 3′-untranslated region of mothers against decapentaplegic homolog 3 (Smad3) was constructed.ResultsThe results showed that miR-16-5p expression was downregulated in osteosarcoma tissues and cells as compared with adjacent counterparts, while Smad3 was overexpressed in osteosarcoma cells. The overexpression of miR-16-5p resulted in the inhibition of the proliferation, migration, and invasion of osteosarcoma cells and enhanced the therapeutic effect of cisplatin. These effects were attenuated with miR-16-5p expression inhibition. In cells transfected with miR-16-5p mimic, Smad3 expression decreased, while this effect was absent in the cells carrying mutated Smad3.ConclusionsTherefore, miR-16-5p inhibits the growth and invasion of osteosarcoma by targeting Smad3.

Inflammation can promote the maturity of osteoclasts and bone resorption in many bone disease such as osteoporosis and arthritis. Here, we aimed to investigate the inhibitory effects of deacylcynaropicrin (DAC) on osteoclastogenesis and bone resorption induced by RANKL. Bone-marrow-derived macrophages were used for assessing the influence of DAC on polarization of macrophages and osteoclastogenesis in vitro. Inducible nitric oxide synthase (iNOS) and CD206, as well as osteoclastogenesis markers, nuclear factor of activated T-cells 1 (NFATc1), and c-Fos, were qualitatively analyzed by immunofluorescence, flow cytometry, reverse transcription polymerase chain reaction, and Western blotting. The results showed that DAC significantly inhibited osteoclastogenesis by suppressing the expression levels of c-Fos and NFATc1 through nuclear factor-κB, c-Jun N-terminal kinase (JNK), and Akt pathway. Moreover, immunohistochemistry and enzyme-linked immunosorbent assays showed that DAC reduced the release of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in vivo. Finally, DAC also promoted macrophage polarization from M1 to M2 types. In conclusion, these results demonstrated that DAC suppressed RANKL-induced inflammation and osteoclastogenesis and therefore it can be used as a potential treatment for osteoporosis, arthritis, osteolysis, and aseptic loosening of artificial prostheses.

The luxury goods industry has always been a highly anticipated area in the market. With the development of the global economy and the improvement of people's living standards, the luxury goods market has also flourished. However, overall, according to the quarterly or fiscal annual reports released by major luxury brands in the luxury industry in recent years, their common characteristic is the sharp decline in revenue in China; from a regional perspective, the decline in sales in China has the greatest impact on the decreasing total revenue of brands over the years. Such as STUART WEITZMAN, the representative head luxury women's shoe brand, total direct sales, which include stores and e-commerce, in FY23 both declined by as much as 24% compared to FY22. This article takes STUART WEITZMAN as an example to study the specific reasons for the decline in sales volume of luxury in China market in recent years compared to previous years. This study uses the market mix model to analyze STUART WEITZMAN 's marketing strategy in the market, Using the PEST model to analyze the macro environment, Use SWOT to analyze the internal and external environment of STUART WEITZMAN. Research has found that the main reason for the decline in luxury goods sales in recent years is luxury brands have been raising prices, and consumers are psychologically unable to accept the increasing premium. The middle class is more inclined to consider practicality and cost-effectiveness, pursuing the ultimate cost-effectiveness. Secondly, consumers have more other options. In addition to luxury brands, high-end niche brands, designer brands, high-end custom brands, and traditional Chinese brands have also begun to be favored by luxury consumers. Finally, in the post pandemic era, outbound tourism has resumed, and consumers can purchase the same products overseas at more favorable prices. [ABSTRACT FROM AUTHOR]

Abstract Triple cation halide perovskite (TCP) stands out as a superior photoelectric material, with a broader absorption range, higher absorption efficiency, and improved environmental stability. Due to its excellent synaptic plasticity, TCP facilitates advanced neural morphological operations like light-assisted learning. Here, a modifying layer of polythiophene (P3HT) was incorporated onto the TCP thin film to enhance the resistive switching (RS) characteristics of the synaptic device, which exhibits excellent stability (103 endurance cycles and > 103 s retention time) and low energy consumption (~ 6.3 pJ for electrical stimulus and ~ 6 pJ for optical stimulus). Additionally, the synaptic properties of the perovskite / P3HT heterojunction synaptic device were explored under optoelectric coordinated modulation, encompassing Long-Term Potentiation (LTP), Long-Term Depression (LTD), frequency-dependent plasticity (SRDP) and voltage-dependent plasticity (SVDP). By leveraging the linear characteristics of synaptic plasticity, arithmetic operations, Pavlovian conditioned reflex and vision recognition are achieved. The recognition accuracies of 89.8% / 88.1% (electric synapse) are enhanced to 92.4% / 92.2% after the introduction of optoelectronic cooperative stimulation on the 8 × 8 and 28 × 28 modified national institute of standards and technology (MNIST) handwritten digit datasets. This study holds significant implications for guiding the optoelectronic co-regulation of perovskite synaptic devices in the field of synaptic electronics.

Abstract An abundance of complex dynamical phenomena exists in nature and human society, requiring sophisticated analytical tools to understand and explain. Causal analysis through observational time series data is essential in comprehending complex systems when controlled experiments are not feasible or ethical. Although data-based causal discovery methods have been widely used, there is still a lack of direct ways more aligned with the intuitive definition of causality, i.e., whether interventions on one element lead to changes in the subsequent development of others. To solve this problem, we propose the method of intervened reservoir computing (IRC) based on constructing a neural network replica of the original system and applying interventions to it. This approach enables controlled trials, thus observing the intervened evolution, in the digital twins of the underlying systems. Simulated and real-world data are used to test our approach and demonstrate its accuracy in inferring causal networks. Given the importance of causality in understanding complex dynamics, we anticipate that IRC could serve as a powerful tool for various disciplines to decipher the intrinsic mechanisms of natural systems from observational data.

Introduction: Osteoporosis is a major cause of bone fracture in post-menopausal women. We evaluated the effects of pristimerin treatment on ovariectomy- induced osteoporosis, and its possible molecular mechanism. Material and methods: Rats were ovariectomised and biochemical markers of bone formation were determined from serum samples. The microarchitectures of bone tissues were analyzed via micro-CT scans and Western blotting assays. The cytotoxic effects of pristimerin, the differentiation of osteoclasts, and bone reabsorption were evaluated in vitro using RAW 264.7 cells. Results: Treatment with pristimerin attenuated changes in markers of bone formation and reabsorption such as creatine kinase (CK), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), collagen type I fragments (CTX), bone Gla-protein (BGP), and osteocalcin (OC) in the serum of ovariectomised rats. It also appeared to restore the microarchitecture of bone tissue. The expression levels of TNF receptor-associated factor 6 (TRAF-6), nuclear factor k light chain enhancer of activated B cells (NF-κB p65), and receptor activator of nuclear factor-κB ligand (RANKL) protein were significantly lower, while those of Akt and PI3K were significantly higher, in the bone tissues of the pristimerin-treated group than in negative controls. Pristimerin had no cytotoxic effect on RAW 264.7 cells and reduced the differentiation of osteoclasts, bone reabsorption, and translocation of p65 in RANKL-stimulated RAW 264.7 cells in vitro. Conclusions: Pristimerin reduces the effects of osteoporosis by restoring the altered RANKL/TRAF-6/NF-κB pathway in ovariectomised rats. [ABSTRACT FROM AUTHOR]

Remote sensing technologies are frequently employed in monitoring and evaluating agricultural meteorological disasters because they can provide high throughput and cost-effective accesses to obtain a variety of real-time spatial data related to crop growth information. Accurately and timely estimating the drought dynamics using remote sensing is valuable for improving crop management level and promoting agricultural sustainable development. In this study, the responses of winter wheat during the critical growth stages to different drought levels from 2010 to 2020 in the Huang-Huai-Hai (HHH) region of China were evaluated based on Google Earth Engine. Four critical developmental stages of winter wheat were highlighted: greening－jointing, jointing－heading, heading－milking maturity, and milking maturity－maturity stages. The temperature vegetation dryness index (TVDI) was constructed for evaluating the drought of winter wheat. Our results indicated that the winter wheat in the HHH region during 2010－2020 was clearly impacted by drought disasters, mainly mild to moderate droughts. In particular, the TVDI index during the critical development stages of winter wheat from 2010 to 2020 wavered in the scope of 0.48 and 0.61, and the soil moisture content at a depth of 10 cm tended to obviously reducing with a rate of − 0.1615/a. For critical growth stages, the winter wheat in the HHH Region was the most prone to threatened by drought during the stage of jointing－heading, following the stage of milking maturity－maturity. The high probability incidence of drought in winter wheat gradually shifted from the nutritional growth to the reproductive growth stages, which increased the risk of drought affecting yield. Furthermore, the notable spatial variations of drought in winter wheat in the HHH region were found. The winter wheat was evidently threatened by moderate and severe droughts in certain areas such as southern Hebei province, northern Jiangsu province, Anhui province, etc. Our results provide new insights into the studies on monitoring and evaluating agricultural meteorological disasters based on remote sensing technology.

Abstract Background The influences of oncogenic Ezh2 on the progression and prognosis of gastric cancer (GC) and the underlying mechanisms are still poorly understood. Here, we aimed at investigating clinicopathological significance of Ezh2 in GC and the mechanisms underlying its function in GC development. Methods The expression level of Ezh2 was determined by qRT-PCR, immunoblot, and immunohistochemistry analysis in 156 pairs of GC tissues and adjacent normal gastric mucosa tissues. The biological functions of Ezh2 were assessed by in vitro and in vivo functional experiments. Chromatin immunoprecipitation (ChIP), luciferase, and Western blotting analyses were utilized to identify the relationship between Ezh2 and the PTEN/Akt signaling. Results The expression of Ezh2 was higher in gastric cancer tissues in comparison with para-nontumorous epithelium. High expression of Ezh2 was associated with more aggressive biological behavior and poor prognosis in GC. In vitro studies indicated that Ezh2 promoted GC cells’ proliferation and clonogenicity. Besides, Ezh2 led to the acquisition of epithelial–mesenchymal transition (EMT) phenotype of GC cells and enhanced GC cell migration and invasion capacity. In particular, Ezh2 strengthened sphere-forming capacity of GC cells, indicating its role in the enrichment of GC stem cells. Furthermore, we found that PTEN/Akt signaling contributed to the effects of Ezh2 on cancer stem cells (CSC) and EMT phenotype in GC cells, and blocking PTEN signaling significantly rescued the effects of Ezh2. Conclusions Taken together, Ezh2 has a central role in regulating diverse aspects of the pathogenesis of GC in part by involving PTEN/Akt signaling, indicating that it could be an independent prognostic factor and potential therapeutic target.

Abstract Background B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) plays an important role in regulating stemness in some kinds of cancer. However, the mechanisms remain unclear. This study was to investigate whether and how Bmi-1 regulates stemness of gastric cancer. Methods We firstly explored the role of Bmi-1 in regulating stem cell-like features in gastric cancer. Secondly, we screened out its downstream miRNAs and clarified whether these miRNAs are involved in the regulation of stemness. Finally, we investigated the mechanisms how Bmi-1 regulates miRNAs. Results Bmi-1 positively regulates stem cell-like properties of gastric cancer and upregulates miR-21 and miR-34a. There was a positive correlation between Bmi-1 and miR-21 expression in gastric cancer tissues. MiR-21 mediated the function of Bmi-1 in regulating stem cell-like properties, while miR-34a negatively regulates stem cell-like characteristics via downregulating Bmi-1. Bmi-1 binds to PTEN promoter and directly inhibits PTEN and thereafter activates AKT. Bmi-1 also regulates p53 and PTEN via miR-21. Bmi-1 activated NF-kB via AKT and enhanced the binding of NF-kB to the promoter of miR-21 and miR-34a and increased their expression. Conclusions Bmi-1 positively regulates stem cell-like properties via upregulating miR-21, and miR-34a negatively regulates stem cell-like characteristics by negative feedback regulation of Bmi-1 in gastric cancer. Bmi-1 upregulates miR-21 and miR-34a by activating AKT-NF-kB pathway.