The tyrosine kinase v-Src modifies cytotoxicities of anticancer drugs targeting cell division.

v-Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v-Src-mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities-mediated chromosome instability. v-Src directly phosphorylates Tyr-15 of cyclin-dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v-Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v-Src restores cancer cell viability reduced by various microtubule-targeting agents (MTAs), although v-Src does not alter cytotoxicity of DNA-damaging anticancer drugs. v-Src causes mitotic slippage of MTAs-treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v-Src also restores cell viability reduced by a polo-like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v-Src. These results suggest that the v-Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src-induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs.

Comparison of the effects of forefoot joint-preserving arthroplasty and resection-replacement arthroplasty on walking plantar pressure distribution and patient-based outcomes in patients with rheumatoid arthritis.

PURPOSE: The purpose of this retrospective study is to clarify the difference in plantar pressure distribution during walking and related patient-based outcomes between forefoot joint-preserving arthroplasty and resection-replacement arthroplasty in patients with rheumatoid arthritis (RA). METHODS: Four groups of patients were recruited. Group1 included 22 feet of 11 healthy controls (age 48.6 years), Group2 included 36 feet of 28 RA patients with deformed non-operated feet (age 64.8 years, Disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.3), Group3 included 27 feet of 20 RA patients with metatarsal head resection-replacement arthroplasty (age 60.7 years, post-operative duration 5.6 years, DAS28-CRP 2.4), and Group4 included 34 feet of 29 RA patients with metatarsophalangeal (MTP) joint-preserving arthroplasty (age 64.6 years, post-operative duration 3.2 years, DAS28-CRP 2.3). Patients were cross-sectionally examined by F-SCAN II to evaluate walking plantar pressure, and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty joint-preserving arthroplasty feet were longitudinally examined at both pre- and post-operation. RESULTS: In the 1st MTP joint, Group4 showed higher pressure distribution (13.7%) than Group2 (8.0%) and Group3 (6.7%) (P<0.001). In the 2nd-3rd MTP joint, Group4 showed lower pressure distribution (9.0%) than Group2 (14.5%) (P<0.001) and Group3 (11.5%) (P<0.05). On longitudinal analysis, Group4 showed increased 1st MTP joint pressure (8.5% vs. 14.7%; P<0.001) and decreased 2nd-3rd MTP joint pressure (15.2% vs. 10.7%; P<0.01) distribution. In the SAFE-Q subscale scores, Group4 showed higher scores than Group3 in pain and pain-related scores (84.1 vs. 71.7; P<0.01) and in shoe-related scores (62.5 vs. 43.1; P<0.01). CONCLUSIONS: Joint-preserving arthroplasty resulted in higher 1st MTP joint and lower 2nd-3rd MTP joint pressures than resection-replacement arthroplasty, which were associated with better patient-based outcomes.