CCL25/CCR9 interaction promotes the malignant behavior of salivary adenoid cystic carcinoma via the PI3K/AKT signaling pathway.

Background: CC chemokine receptor 9 (CCR9), an organ-specific chemokine receptor, interacts with its exclusive ligand CCL25 to promote tumor proliferation and metastasis. However, the effect of CCR9 on salivary adenoid cystic carcinoma (SACC) malignant behavior remains unknown. This study aimed to investigate the specific molecular mechanism by which CCR9/CCL25 modulates malignant progression in SACC. Methods: Immunohistochemistry staining and RT-qPCR analyses were performed to detect the correlation of CCR9 expression and tumor progression-associated markers in SACC. In vitro, SACC cell proliferation and apoptosis were evaluated using Cell Counting Kit-8 and colon formation, and cell migration and invasion were detected by wound healing and transwell assays. Vercirnon was used as an inhibitor of CCR9, and LY294002 was used as an inhibitor of the PI3K/AKT pathway in this study. Western blot and RT-qPCR assays were carried out to measure the downstream factors of the interaction of CCL25 and CCR9. The effect of CCL25 on the development of SACC in vivo was examined by a xenograft tumor model in nude mice following CCL25, Vercirnon and LY294002 treatment. Results: CCR9 was highly expressed in SACC compared with adjacent salivary gland tissues, and its level was associated with tumor proliferation and metastases. CCL25 enhanced cell proliferation, migration, and invasion through its interaction with CCR9 and exerted an antiapoptotic effect on SACC cells. Targeting CCR9 via Vercirnon significantly reduced the phosphorylation level of AKT induced by CCL25. CCL25/CCR9 could activate its downstream factors through the PI3K/AKT signaling pathway, such as cyclin D1, BCL2 and SLUG, thus promoting SACC cell proliferation, antiapoptosis, invasion and metastasis. The in vivo data from the xenograft mouse models further proved that CCL25 administration promoted malignant tumor progression by activating the PI3K/AKT pathway. Conclusion: The interaction of CCL25 and CCR9 promotes tumor growth and metastasis in SACC by activating the PI3K/AKT signaling pathway, offering a promising strategy for SACC treatment.

A Novel Antibacterial Titanium Modification with a Sustained Release of Pac-525.

For the benefit of antibacterial Ti on orthopedic and dental implants, a bioactive coating (Pac@PLGA MS/HA coated Ti) was deposited on the surface of pure titanium (Ti), which included two layers: an acid-alkali heat pretreated biomimetic mineralization layer and an electrosprayed Poly (D,L-lactide-co- glycolic acid) (PLGA) microsphere layer as a sustained-release system. Hydroxyapatite (HA) in mineralization layer was primarily prepared on the Ti followed by the antibacterial coating of Pac-525 loaded by PLGA microspheres. After observing the antimicrobial peptides distributed uniformly on the titanium surface, the release assay showed that the release of Pac-525 from Pac@PLGA MS/HA coated Ti provided a large initial burst followed by a slow release at a flat rate. Pac@PLGA MS/HA coated Ti exhibited a strong cytotoxicity to both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). In addition, Pac@PLGA MS/HA coated Ti did not affect the growth and adhesion of the osteoblast-like cell line, MC3T3-E1. These data suggested that a bionic mineralized composite coating with long-term antimicrobial activity was successfully prepared.

Mediastinal Small Cell Carcinoma with Primary Cutaneous Cryptococcosis: A Rare Case Report.

Cutaneous cryptococcosis, an infectious disease resulting from Cryptococcus neoformans, primarily affects immunodeficient individuals. Here, we report a case of mediastinal small cell carcinoma (MSCC) complicated with multiple skin and soft tissue infections mimicking erysipelas and cellulitis. Antibiotics for bacteria were ineffective and a culture of pus from the infected areas revealed Cryptococcus neoformans in this patient. The absence of any evidence indicative of systemic cryptococcal infection leads to a final diagnosis of primary cutaneous cryptococcosis (PCC). Following two weeks of fluconazole at 400 mg/day and 200 mg/day for the subsequent three months, combined with incision, irrigation and drainage, the wound gradually healed. An analysis and discussion of the clinical features of this patient are presented. This case alerts clinicians as to the possibility of Cryptococcus neoformans in patients with advanced malignant tumors complicated with multiple skin and soft tissue infections. While a timely diagnosis and treatment of PCC in this patient resulted in a favorable outcome, the patient succumbed to the malignant tumor at six months post-discharge.

Integrative Analysis for Elucidating Transcriptomics Landscapes of Glucocorticoid-Induced Osteoporosis.

Osteoporosis is the most common bone metabolic disease, characterized by bone mass loss and bone microstructure changes due to unbalanced bone conversion, which increases bone fragility and fracture risk. Glucocorticoids are clinically used to treat a variety of diseases, including inflammation, cancer and autoimmune diseases. However, excess glucocorticoids can cause osteoporosis. Herein we performed an integrated analysis of two glucocorticoid-related microarray datasets. The WGCNA analysis identified 3 and 4 glucocorticoid-related gene modules, respectively. Differential expression analysis revealed 1047 and 844 differentially expressed genes in the two datasets. After integrating differentially expressed glucocorticoid-related genes, we found that most of the robust differentially expressed genes were up-regulated. Through protein-protein interaction analysis, we obtained 158 glucocorticoid-related candidate genes. Enrichment analysis showed that these genes are significantly enriched in the osteoporosis related pathways. Our results provided new insights into glucocorticoid-induced osteoporosis and potential candidate markers of osteoporosis.

Comprehensive Analysis of the Genetic and Epigenetic Mechanisms of Osteoporosis and Bone Mineral Density.

Osteoporosis is a skeletal disorder characterized by a systemic impairment of bone mineral density (BMD). Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for osteoporosis and BMD. However, the vast majority of susceptibility loci are located in non-coding regions of the genome and provide limited information about the genetic mechanisms of osteoporosis. Herein we performed a comprehensive functional analysis to investigate the genetic and epigenetic mechanisms of osteoporosis and BMD. BMD and osteoporosis are found to share many common susceptibility loci, and the corresponding susceptibility genes are significantly enriched in bone-related biological pathways. The regulatory element enrichment analysis indicated that BMD and osteoporosis susceptibility loci are significantly enriched in 5'UTR and DNase I hypersensitive sites (DHSs) of peripheral blood immune cells. By integrating GWAS and expression Quantitative Trait Locus (eQTL) data, we found that 15 protein-coding genes are regulated by the osteoporosis and BMD susceptibility loci. Our analysis provides new clues for a better understanding of the pathogenic mechanisms and offers potential therapeutic targets for osteoporosis.

A Mendelian Randomization Analysis to Expose the Causal Effect of IL-18 on Osteoporosis Based on Genome-Wide Association Study Data.

Accumulating evidence showed that Interleukin (IL) level is associated with Osteoporosis. Whereas, most of these associations are based on observational studies. Thus, their causality was still unclear. Mendelian randomization (MR) is a widely used statistical framework that uses genetic instrumental variables (IVs) to explore the causality of intermediate phenotype with disease. To classify their causality, we conducted a MR analysis to investigate the effect of IL-18 level on the risk of Osteoporosis. First, based on summarized genome-wide association study (GWAS) data, 8 independent IL-18 SNPs reaching genome-wide significance were deemed as IVs. Next, Simple median method was used to calculate the pooled odds ratio (OR) of these 8 SNPs for the assessment of IL-8 on the risk of Osteoporosis. Then, MR-Egger regression was utilized to detect potential bias due to the horizontal pleiotropy of these IVs. As a result of simple median method, we get the SE (-0.001; 95% CI-0.002 to 0; P = 0.042), which means low IL-18 level could increases the risk of the development of Osteoporosis. The low intercept (0; 95% CI -0.001 to 0; P = 0.59) shows there is no bias due to the horizontal pleiotropy of the IVs.

H19 Facilitates Tongue Squamous Cell Carcinoma Migration and Invasion via Sponging miR-let-7.

The long noncoding RNA (lncRNA) H19 has been described to participate in the metastasis of various tumors. Nevertheless, whether H19 promotes or impedes tongue squamous cell carcinoma (TSCC) cell migration and invasion remains controversial. Here we found that the expression of H19 was elevated in TSCC tissues compared with adjacent normal tissues. Moreover, we demonstrated that the expression of H19 was higher in metastasized tumors compared with unmetastasized tumors. Consistently, TSCC cells express higher levels of H19 than human squamous cells. Subsequently, depletion of H19 impaired the migration and invasion abilities of TSCC cells. Mechanistically, we demonstrated that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7a, leading to an increase in a let-7a target, the key regulator of tumor metastasis HMGA2, which is enriched in TSCC tissues and cell lines. Intriguingly, inhibition of let-7a significantly rescued the short hairpin H19 (shH19)-induced decrease in TSCC migration and invasion. These findings revealed that the H19/let-7a/HMGA2/EMT axis plays a critical role in the regulation of TSCC migration and invasion, which may provide a new therapeutic target for TSCC.

Bio-Oss(®) for delayed osseointegration of implants in dogs: a histological study.

We evaluated the effects of Bio-Oss® (a natural bone substitute derived from the mineral portion of bovine bone) on delayed osseointegration of implants. The bilateral third and fourth mandibular premolars of 4 adult, healthy, male and female dogs were extracted. We randomly selected 2 extraction sockets in each dog to be filled with Bio-Oss® (the experimental group); the other 2 extraction sockets, which were not treated, served as controls. Dental implants were inserted into the alveolar bone of the experimental group and the control group 3 months after insertion of the Bio-Oss®. The osteogenic activity in the bone around the implants was assessed by evaluating the histological morphology and estimating histomorphometric variables at 3 and 6 months after delayed implantation. After 3 months, Goldner's trichrome staining analysis showed that the rate of content between the bone and the implant and the mineralised area of bone around the implant were significantly higher in the experimental group (76%(9%) and 69.5% (9.6%), respectively) than those in the control group (56.1% (8.2%) and 52.8% (7.3%), respectively, p=0.003 and 0.000). However, the 2 groups did not differ significantly at 6 months. Fluorescence microscopy showed that the mean rates of mineralisation of the bony tissue around the implant in the experimental group at months 3 and 6 were 6.8 (0.4) µm and 8.4 (0.8) µm, respectively, which were significantly higher than those in the control group (p=0.000 and 0.03). These data indicate that putting Bio-Oss® into the extraction sockets can promote osseointegration after delayed implantation, and may be a promising option for clinical use.