Recently, novel mechanisms underlying the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified in several cancers, including breast cancer. CAFs can secrete exosomes that are loaded with proteins, lipids, and RNAs to affect tumor microenvironment. Herein, we identify CAF-derived exosomes that can transfer miR-181d-5p to enhance the aggressiveness of breast cancer. Cancerous tissues and matched paracancerous tissues were surgically resected from 122 patients with breast cancer. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were employed to identify interaction between homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2), as well as between CDX2 and miR-181d-5p, respectively. Human breast cancer Michigan Cancer Foundation-7 (MCF-7) cells were cocultured with CAF-derived exosomes. 5-Ethynyl-2 0 -deoxyuridine (EdU) assay, TUNEL staining, Transwell invasion assays, and scratch tests were carried out to evaluate MCF-7 cell functions. Nude mice bearing xenografted MCF-7 cells were injected with CAF-derived exosomes, and the tumor formation was evaluated. HOXA5 expressed at a poor level in breast cancer tissues, and its overexpression retarded MCF-7 cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and facilitated its apoptosis in vitro. miR-181d-5p targets CDX2, a transcription factor binding to HOXA5 promoter. Coculture of CAFs and MCF-7 cells showed that CAFs prolonged proliferation and antagonized apoptosis of MCF-7 cells via release of exosomes. Coculture of MCF-7 cells and exosomes derived from CAFs identified miR-181d-5p as a mediator of the exosomal effects on MCF-7 cells, in part, via downregulation of CDX2 and HOXA5. CAF-derived exosomes containing miR-181d-5p promoted the tumor growth of nude mice bearing xenografted MCF-7 cells. In conclusion, exosomal miR-181d-5p plays a key role in CAF-mediated effects on tumor environment in breast cancer, likely via CDX2 and HOXA5.

An M/M/1 queue is subject to mass exodus at rate β and mass immigration at rate when idle. A general resolvent approach is used to derive occupation probabilities and high-order moments. This powerful technique is not only considerably easier to apply than a standard direct attack on the forward p.g.f. equation, but it also implicitly yields necessary and sufficient conditions for recurrence, positive recurrence and transience.

We study a modified Markovian bulk-arrival and bulk-service queue incorporating state-dependent control. The stopped bulk-arrival and bulk-service queue is first investigated and the relationship with our queueing model is examined and exploited. Equilibrium behaviour is studied and the probability generating function of the equilibrium distribution is obtained. Queue length behaviour is also examined and the Laplace transform of the queue length distribution is presented. The important questions regarding hitting time and busy period distributions are answered in detail and the Laplace transforms of these distributions are presented. Further properties including expectations of hitting times and busy period are also explored. A. Chen ( )

We derive necessary and sufficient conditions for the existence of bounded or summable solutions to systems of linear equations associated with Markov chains. This substantially extends a famous result of G. E. H. Reuter, which provides a convenient means of checking various uniqueness criteria for birth-death processes. Our result allows chains with much more general transition structures to be accommodated. One application is to give a new proof of an important result of M. F. Chen concerning upwardly skip-free processes. We then use our generalization of Reuter's lemma to prove new results for downwardly skip-free chains, such as the Markov branching process and several of its many generalizations. This permits us to establish uniqueness criteria for several models, including the general birth, death, and catastrophe process, extended branching processes, and asymptotic birth-death processes, the latter being neither upwardly skip-free nor downwardly skip-free.