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Background: Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7., Results: It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation., Conclusions: This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.

Background: The Fundamental Critical Care Support (FCCS) course has been introduced after minimal adaptation according to Japanese clinical settings. The original course in the USA is often used to prepare residents for rotations in the intensive care unit (ICU). Therefore, the FCCS program can be appropriate for the basic training of critical care in Japan to standardize critical care management. The purpose of this study is to evaluate whether Japanese FCCS course is useful and has a possibility to deserve a basis of critical care management in Japan., Methods: The course program was provided with the form of lecture and skills stations. Pre- and post-training knowledge was assessed. After completion of the 2-day course, a questionnaire survey was administered to all course participants. Participants were asked to fill out the questions regarding socio-demographic characteristics. Participants were also asked to identify which lectures or skill stations they thought to be useful for clinical practice. Then, they were asked to rate their performance of each field: 'Assessment,' 'Diagnosis,' 'Recognition,' 'Response,' and 'Transfer'., Results: The number of participants increased year after year and reached 1,804 during the past 4 years. Nearly 70% of the participants were physicians. Most of the others were nurses. In the established year, the percentage of physicians who had clinical experience more than 5 years exceeded 50%, however, this percentage gradually decreased. On the contrary, the percentages of residents and nurses increased. Regarding useful sessions, nearly half of the participants thought that mechanical ventilation was the most useful. With regard to the results of pre- and post-tests, the participants had already shown a high average mark (78.8 ± 14.1) at the pre-test. Furthermore, the score at the post-test was significantly improved (82.0 ± 6.6, p < 0.01). The participants' confidence in any field regarding critical care management was almost 4 points (5-point scale)., Conclusions: It is considered that Japanese FCCS course is useful and has a promising basis of critical care management in Japan. Therefore, it is reasonable to think that Japanese FCCS mission has been successfully achieved.

Background: Increased motility and invasiveness of cancer cells are reminiscent of the epithelial-mesenchymal transition (EMT), which occurs during cancer progression and metastasis. Recent studies have indicated the expression of receptor activator of nuclear factor-κB (RANK) in various solid tumors, including breast cancer. Although activation of the RANK ligand (RANKL)/RANK system promotes cell migration, metastasis, and anchorage-independent growth of tumor-initiating cells, it remains to be investigated if RANKL induces EMT in breast cancer cells. In this study, we investigated whether RANKL induces EMT in normal breast mammary epithelial cells and breast cancer cells, and the mechanism underlying such induction., Methods: Expression levels of vimentin, N-cadherin, E-cadherin, Snail, Slug, and Twist were examined by real-time polymerase chain reaction. Cell migration and invasion were assessed using Boyden chamber and invasion assays, respectively. The effects of RANKL on signal transduction molecules were determined by western blot analyses., Results: We found that stimulation by RANKL altered the cell morphology to the mesenchymal phenotype in normal breast epithelial and breast cancer cells. In addition, RANKL increased the expression levels of vimentin, N-cadherin, Snail, and Twist and decreased the expression of E-cadherin. We also found that RANKL activated nuclear factor-κB (NF-κB), but not extracellular signal-regulated kinase 1/2, Akt, mammalian target of rapamycin, c-Jun N-terminal kinase, and signal transducer and activator of transcription 3. Moreover, dimethyl fumarate, a NF-κB inhibitor, inhibited RANKL-induced EMT, cell migration, and invasion, and upregulated the expressions of Snail, Twist, vimentin, and N-cadherin., Conclusions: The results indicate that RANKL induces EMT by activating the NF-κB pathway and enhancing Snail and Twist expression. These findings suggest that the RANKL/RANK system promotes tumor cell migration, invasion, and metastasis via the induction of EMT.