CCL7 playing a dominant role in recruiting early OCPs to facilitate osteolysis at metastatic site of colorectal cancer.

BACKGROUND: Chemoattractant is critical to recruitment of osteoclast precursors and stimulates tumor bone metastasis. However, the role of chemoattractant in bone metastasis of colorectal cancer (CRC) is still unclear. METHODS: Histochemistry analysis and TRAP staining were utilized to detect the bone resorption and activation of osteoclasts (OCs) after administration of CCL7 neutralizing antibody or CCR1 siRNA. qRT-PCR analysis and ELISA assay were performed to detect the mRNA level and protein level of chemoattractant. BrdU assay and Tunel assay were used to detect the proliferation and apoptosis of osteoclast precursors (OCPs). The migration of OCPs was detected by Transwell assay. Western blots assay was performed to examine the protein levels of pathways regulating the expression of CCL7 or CCR1. RESULTS: OCPs-derived CCL7 was significantly upregulated in bone marrow after bone metastasis of CRC. Blockage of CCL7 efficiently prevented bone resorption. Administration of CCL7 promoted the migration of OCPs. Lactate promoted the expression of CCL7 through JNK pathway. In addition, CCR1 was the most important receptor of CCL7. CONCLUSION: Our study indicates the essential role of CCL7-CCR1 signaling for recruitment of OCPs in early bone metastasis of CRC. Targeting CCL7 or CCR1 could restore the bone volume, which could be a potential therapeutical target. Video Abstract.

IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors.

BACKGROUND: Bone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is still unclear. METHODS: In this study, mice bone metastatic model of CRC was established through injection of MC-38 or CT-26 cells. BrdU assays showed primary CD115 ( +) osteoclast precursors (OCPs) proliferated at the first 2 weeks. Transcriptomic profiling was performed to identify differentially expressing genes and pathways in OCPs indirectly co-cultured with CRC cells RESULTS: The expression of IL4Rα was found to be significantly upregulated in OCPs stimulated by tumor conditioned medium (CM). Further investigation indicated that IL-4 signaling regulated proliferation of OPCs through interacting with type I IL4 receptor, and neutrophils were the main source of IL-4 in bone marrow. The proliferation of OCPs can be inhibited in IL4 deficiency mice. In addition, ERK pathway was activated by IL4/IL4R signaling. Ravoxertinib, an ERK antagonists, could significantly prevent bone destruction through inhibiting the proliferation of OCPs. CONCLUSION: Our study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC.

The effect of two endodontic sealers and interval before post-preparation and cementation on the bond strength of fiber posts.

OBJECTIVES: To evaluate the effect of different endodontic sealers (epoxy resin-based and bioceramic-based) and the time of post-cementation on the bond strength of a fiber post cemented with resin cement. METHODS: Forty human premolars were instrumented and divided into 4 groups. According to the type of sealer and the time of post-cementation: AH-IM (AH Plus, post-cemented immediately after root canal treatment), SP-IM (iRoot SP, post-cemented immediately after root canal treatment), AH-OW (AH Plus, post-cementation after one week), and SP-OW (iRoot SP, post-cementation after one week). In each group, the samples were submitted to push-out test, and failure mode was assessed. Levene's test, one-way ANOVA, and Kruskal-Wallis analysis were applied for statistical analysis (α = 5%). RESULTS: The highest mean push-out bond strength was obtained from the SP-IM group in the apical part (10.45 ± 5.15MPa), while the lowest was observed in samples from the AH-OW group in the middle part (2.63 ± 1.54 MPa). One-way ANOVA showed that within the same root region, the time of post-cementation had a negative influence on the bonding strength in the SP groups in the middle and apical portion (P<0.05), however, when comparing the effect of type of sealers on bonding strength between the OW groups or IM groups within the same root region, no significant difference was observed regardless of the post cementation time (P>0.05). CONCLUSIONS: The bond strength of the fiber post was higher when the post was cemented immediately after root canal treatment when the bioceramic sealer was applied. CLINICAL RELEVANCE: The correct choice of an endodontic sealer and the proper time of post-cementation may help to obtain the best quality of post-and-core restoration.

Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia.

Through bibliometric analysis, we aim to comprehensively understand the research dynamics in this field, reveal key scientific research achievements and breakthrough discoveries, and provide valuable reference and guidance for future research directions. Utilizing the Web of Science, we retrieved the literature pertaining to ultrasonics-guided regional anesthesiology (1994-2022). CiteSpace and VOSviewer were used for bibliometric and knowledge mapping analysis. Our examination encompassed publication trends, authorship patterns, institutional contributions, frequently occurring keywords, keyword clustering, and emerging terminology trends. Of the 570 papers reviewed, there was a rising trend in publications each year. The main keywords in regional anesthesia were ultrasound guidance, nerve, analgesia, and pain score. Key research areas were regional anesthesia, ultrasound guidance, approach, pain score, and plane block. The U.S. led in research. Stanford University, University of Toronto, and Cork University Hospital were central institutions. Chan V was the top author with 24 articles, while Marhofer P was the most cited at 150 times. Regional anesthesia and pain medicine were the predominant journal in both publications and citations. In conclusion, research in this field consistently grew yearly, and visualization showcased trends in ultrasound-guided regional anesthesia. These visuals provided key bibliometric insights, helping researchers further explore and understand this domain.

GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer.

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.

Cyclic GMP-AMP Synthase in Cancer Prevention.

Cyclic GMP-AMP (cGAMP), synthesized by cGAMP synthase (cGAS), serves as a secondary messenger that modulates various cellular processes, including cell proliferation, cell death, immune response, and inflammation. cGAS is activated upon detecting cytoplasmic DNA, which may originate from damaged genomic and mitochondrial DNA or from viral and bacterial infections. The presence of DNA in the cytoplasm can trigger a substantial inflammatory reaction and cytokine production via the cGAS-STING signaling pathway. Consequently, specific inhibitors targeting this pathway hold significant potential as chemopreventive agents. In this review, we explore the potential effectiveness of modulating cGAS activity. We discuss the role of cGAMP, the mechanism of action for distinguishing between self and foreign DNA, and the possible functions of cGAS within the nucleus.

Experiences and Needs of Patients and Relatives During Hospitalization in an Intensive Care Unit in China: A Qualitative Study.

INTRODUCTION: In comparison with Western cultures, the closed management system makes it difficult to implement family-centered nursing in many intensive care unit (ICU) in China. There are differences in cultural cognition and social environment between China and the West. The purpose of this study was to explore the experience and needs of critically ill patients and their relatives from a Chinese cultural perspective. METHOD: This was a qualitative study using semistructured interviews conducted in a 26-bed integrated ICU at a Tertiary Grade A comprehensive hospital in Nantong, China. The participants included patients admitted in the ICU and their relatives. We used Colaizzi's seven-step procedure to analyze interview data. FINDINGS: A total of 15 participants were recruited. Main categories within the patient perspective were variety of feelings, staff assistance required, and expectations for relatives. Patient opinions differed about the feelings of hospitalization and whether they needed the help of staff and relatives. The main categories from the relatives' perspective were life is disrupted, information needs, and emotional needs. Relatives of patients in the ICU experienced a lot of physical and mental pressure. The lack of timely understanding of the patient's condition and needs made them feel anxious. CONCLUSION: The closed management system currently used in China limits contact between ICU patients and their relatives, increasing their physical and emotional discomfort. Hospitals in China should consider updating to a more open visiting policy based on current guidelines for family-centered care. Such policies enable staff to continue providing quality care for their patients while addressing patient and family needs.

Colorectal cancer cells promote osteoclastogenesis and bone destruction through regulating EGF/ERK/CCL3 pathway.

Bone metastasis of colorectal cancer (CRC) cells leads to osteolysis. Aberrant activation of osteoclasts is responsible for bone resorption in tumor. In general, bone marrow-derived monocytes (BMMs) differentiate into osteoclasts, however, how CRC cells interact with BMMs and how to regulate the differentiation is elusive. We here report that CRC cells promote bone resorption in bone metastasis. Transcriptomic profiling revealed CCL3 up-regulated in MC-38 conditional medium treated BMMs. Further investigation demonstrated that CCL3 produced by BMMs facilitated cell infusion and thus promoted the osteoclastogenesis. In addition, CRC cells derived EGF stimulated the production of CCL3 in BMMs through activation of ERK/CREB pathway. Blockage of EGF or CCL3 can efficiently attenuate the osteolysis in bone metastasis of CRC.

Paclitaxel-loaded Pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization.

The objective of this study was to optimize and characterize a novel polymeric mixed micelle composed of Pluronic P123 and F127 loaded with paclitaxel (PTX). A Doehlert matrix design was utilized to investigate the effect of four variables, namely P123 mass fraction, amount of water, feeding of PTX and hydration temperature on the responses including drug-loading coefficient (DL %), encapsulation ratio (ER %) and the percentage of PTX precipitated from the drug-loaded mixed micelles after 48 h at 37 (PTX precipitated %) for improvement of drug solubilization efficiency and micelle stability. PTX-loaded P123/F127 mixed micelles were prepared by thin-film hydration method. The optimized formulation showed a particle size of about 25 nm with ER %>90%, and a sustained release behavior compared to Taxol. Micelle formation was confirmed by NMR spectroscopy. The mixed micelles had a low CMC of 0.0059% in water. In addition, micelle stability studies implied that introduction of Pluronic F127 (33 wt%) into P123 micelle system significantly increased the stability of PTX-loaded micelles. More importantly, in vitro cytotoxicity was assessed using human lung adenocarcinoma cell lines SPC-A1 and A-549 and was compared to Taxol and the free drug. The cell viability assay against A-549 cells exhibited the 50% inhibition concentration (IC50) of PTX-loaded P123/F127 mixed micelles (0.1 microg/ml) was much lower than those of Taxol injection (0.4 microg/ml) and the free PTX (1.7 microg/ml). Therefore, PTX-loaded P123/F127 mixed micelles may be considered as an effective anticancer drug delivery system for cancer chemotherapy.