Exosomes from cancer cells, which contain microRNA and reach metastasis loci prior to cancer cells, stimulate the formation of a metastatic microenvironment. Previous studies have shown that exosomal miR-141-3p is associated with metastatic prostate cancer (PCa). However, the role and regulatory mechanism of miR-141-3p in the microenvironment of bone metastases require further study. In this study, we performed a series of experiments in vivo and in vitro to determine whether exosomal miR-141-3p from MDA PCa 2b cells regulates osteoblast activity to promote osteoblastic metastasis. We demonstrate that extracts obtained from cell culture supernatants contained exosomes and that miR-141-3p levels were significantly higher in MDA PCa 2b cell exosomes. Via confocal imaging, numerous MDA PCa 2b exosomes were observed to enter osteoblasts, and miR-141-3p was transferred to osteoblasts through MDA PCa 2b exosomes in vitro. Exosomal miR-141-3p from MDA PCa 2b promoted osteoblast activity and increased osteoprotegerin OPG expression. miR-141-3p suppressed the protein levels of the target gene DLC1, indicating its functional significance in activating the p38MAPK pathway. In animal experiments, exosomal miR-141-3p had bone-target specificity and promoted osteoblast activity. Mice injected with miR-141-3p-mimics exosomes developed apparent osteoblastic bone metastasis. Exosomal miR-141-3p from MDA PCa 2b cells promoted osteoblast activity and regulated the microenvironment of bone metastases, which plays an important role in the formation of bone metastases and osteogenesis damage in PCa. Clarifying the specific mechanism of bone metastasis will help generate new possibilities for the treatment of PCa.

In patients with prostate cancer (PCa), bone lesions appear osteoblastic in radiographs; however, pathological fractures frequently occur in PCa patients, and bone resorption is observed in all metastatic lesions under histopathologic assessment. The mechanisms that balance the activities of osteoblasts and osteoclasts in PCa patients remain unclear. We unexpectedly discovered that PCa exosomes are critical mediators in the regulation of bone homeostasis that results in osteoclastic lesions and thereby promotes tumor growth in bone. We evaluated how exosomes derived from osteoblastic, osteoclastic, and mixed PCa cell lines affect osteoblast and osteoclast differentiation, revealing that all three types of PCa exosomes promoted osteoclastogenesis in vitro and induced osteolysis in vivo. Mechanistically, microRNAs (miRNAs) delivered by PCa exosomes were found to play several key roles in bone homeostasis. Among the delivered miRNAs, miR-92a-1-5p, the most abundant miRNA, downregulated type I collagen expression by directly targeting COLA, and thus promoting osteoclast differentiation and inhibiting osteoblastogenesis. Furthermore, PCa exosomes also markedly reduced type I collagen expression in vivo. Our findings not only offer a novel perspective on tumor bone metastasis, where-contrary to our initial hypothesis-exosomes derived from an osteoblastic tumor induce osteoclast differentiation, but also suggest potential therapeutic targets for PCa bone metastasis. K E Y WO R D S bone homeostasis, bone metastasis, COLA, exosomes, extracellular vesicles, miR-92a-1-5p, prostate cancer  INTRODUCTION Prostate cancer (PCa) is the most common cause of new cancer cases and the second leading cause of cancer-related deaths in males (Siegel et al., 2020). Bone is the most common target organ for high-grade metastatic prostate cancer (Probert et al., 2019). Bone metastasis is detected at autopsy in ∼90% of all PCa patients and remains incurable; the 5-year survival of patients is ∼30%

No abstract

AimsTo evaluate the prevalence, incidence and their related risk factors of strabismus among preschool children in China.MethodsChildren born between September 2011 and August 2012 in Yuhuatai District of Nanjing were invited to participate in the Nanjing Eye Study for a comprehensive eye examination annually since 2015. The data presented in this paper were obtained from 2015 to 2017, when these children grew from the age of 3 to 5 years. Eye examinations included visual acuity, anterior segment, posterior segment, refraction, and ocular alignment and motility. Risk factors were evaluated using univariable and multivariable logistic regression models for prevalent and incident strabismus.ResultsIn 2015, a total of 2018 children (87.7% response rate) of 2300 eligible preschoolers completed the baseline eye examination when they were 3 years old. Among the 2018 participants, 50 had strabismus (prevalence rate, 2.48%). In multivariable analysis, prevalent strabismus was independently associated with parental strabismus history (OR=11.60, p<0.001), hyperopia (OR=6.22, p<0.001), prematurity (OR=3.07, p=0.01) and astigmatism (OR=2.15, p=0.04). Among 1766 children followed up for 2 years, 63 developed strabismus (annual incidence rate, 1.78%), of whom 57 had exotropia and 6 had esotropia. In multivariable analysis, incident strabismus was significantly associated with parental strabismus history (OR=5.55, p=0.04) and prematurity (OR=3.77, p<0.001).ConclusionsIn this population-based cohort study, we found a higher incidence of strabismus and a higher exotropia:esotropia ratio than previous studies in preschool children. Parental strabismus history and prematurity were associated with a higher risk for both prevalent and incident strabismus.

Postmenopausal osteoporosis (PMOP) is a systemic metabolic bone disease in postmenopausal women. It has been known that long non-coding RNAs (lncRNAs) play a regulatory role in the progression of osteoporosis. However, the mechanism underlying the effects of exosome-derived lncRNA on regulating the occurrence and development of PMOP remains unclear. Exosomes in the serum of patients PMOP were collected and identified. RNA sequencing was performed to obtain the expression profile of exosome-derived lncRNAs in the serum of PMOP patients. RNA sequencing identified 26 differentially expressed lncRNAs from the exosomes between healthy people and PMOP patients. Among them, the expression of TCONS_00072128 was dramatically down-regulated. A co-location method was employed and searched its potential target gene caspase 8. TCONS_00072128 knockdown notably decreased the expression of caspase 8, while the osteogenic differentiation of BMSCs was also reduced. Reversely, TCONS_00072128 overexpression enhanced caspase 8 expression and osteogenic differentiation of BMSCs. Moreover, the continuous expression of caspase 8 regulated by TCONS_00072128 significantly activated inflammation pathways including NLRP3 signaling and NF-κB signaling. Simultaneously, RIPK1 which has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases, was also phosphorylated. The results of the present study suggested that exosome-derived lncRNA TCONS_00072128 could promote the progression of PMOP by regulating caspase 8. In addition, caspase 8 expression in BMSCs was possible to be a key regulator that balanced cell differentiation and inflammation activation.

The aqueous two-phase copolymerization (ATPP) of acrylamide and cationic monomers was carried out in poly(ethylene glycol) (PEG) aqueous solution. The effects of inorganic salts on the ATPP process were systematically investigated and obvious differences were observed between univalent and multivalent anions. For the ATPP system with added univalent anions such as Cl À , the critical conversion for the phase separation decreased as the particle size increased, but the polymerization kinetics and final molecular weight of the copolymers were similar with that of the salt-free system. However, after adding multivalent anions such as SO 4 2À into the ATPP system, the critical conversion for the phase separation decreased sharply, the polymerization rate slowed down, the final molecular weight of the copolymers increased, and the particle size greatly increased. Moreover, the system underwent a unique particle formation process. A mechanism for the role of anions in the ATPP process was proposed. The saltingout effects of the univalent anions screen the electrostatic repulsion between cationic species and lead to the formation of gravel-like particles. But for multivalent anions, when the concentration is low, their salting-out effect is involved in the particle formation process and results in the formation of gravel-like particles as well. When the concentration becomes high, their bridge effect is dominant, making large and spherical particles appear.

No abstract