Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.

BackgroundEffective and efficient interprofessional collaboration (IPC) is needed between departments in a healthcare setting. Although Japanese physicians are expected to provide leadership in IPC, it has been suggested that their perception of IPC is more negative than among other healthcare professionals. The purpose of this study was to clarify Japanese physician’s perceptions of IPC and what factors influenced their views.MethodsThis cross-sectional study surveyed 732 medical doctors at a university hospital and six foundation hospitals in a prefecture located in Tohoku district, northeastern Japan. Those hospitals were approved for delivery of postgraduate clinical training. Physician’s perceptions of IPC were investigated for three items, namely providing patient-centered care, preventing medical accidents, and improving the quality of medical care. A total of 409 doctors who were engaged in clinical practice, responded adequately to the survey. Factors associated with negative perceptions towards IPC among physicians were analyzed using a logistic regression model.ResultsThe proportion of negative perceptions of IPC for providing patient-centered care, preventing medical accidents, and improving the quality of medical care were 41.1%, 34.0% and 33.7%, respectively. Negative perceptions of IPC for providing patient-centered care were associated with older age (50 + years; odds ratio (OR): 2.73; 95% confidence interval (CI): 1.11 - 6.68) and a lower frequency of interprofessional meetings (no meetings; OR: 2.95; 95%CI: 1.43 - 6.08). Negative perceptions of IPC for preventing medical accidents were associated with a lower frequency of interprofessional meetings (no meetings, OR: 3.23; 95%CI: 1.58 - 6.62). Negative perceptions of IPC for improving the quality of medical care were associated with middle age (40 - 49 years, OR: 2.93; 95%CI: 1.20 - 7.12) and a lower frequency of interprofessional meetings (no meetings; OR: 2.75; 95%CI: 1.34 - 5.66).ConclusionsPhysician’s negative perceptions of IPC in our study were associated with age and a lower frequency of interprofessional meetings. Our findings suggest that effective regular interprofessional meetings serve to share information about patients, and to allow physicians to understand each other better, which should have a positive impact on the quality of patient-centered care.

The aim of this study was to evaluate the clinical factors, drug-related genetic polymorphisms, and human leukocyte antigen (HLA) types to determine the association with sorafenib-induced high-grade skin rash (HGSR) in Japanese patients with advanced renal cell carcinoma (RCC). A total of 55 patients with advanced RCC treated with sorafenib were analyzed retrospectively. Of these, 33 patients were subjected to HLA typing and polymorphism analyses of CYP3A5, ABCB1, ABCC2, and UGT1A1, which are involved in the metabolism and membrane transport of sorafenib. Grade 3 or higher SR developed in 12 (22%), and a higher incidence was observed in female patients than in male patients (40 vs. 15%, P=0.046). The initial dose, initial dose per body weight, and initial dose per body surface area in patients with HGSR were significantly higher than those in patients without HGSR. Patients with the ABCC2 -24CC genotype were at a significantly higher risk of SR than those with the CT genotype (35 vs. 0%, P=0.032). HLA-A*24 was significantly associated with the occurrence of HGSR (P=0.049). Our finding suggested that women, higher initial dose per body weight or body surface area, the ABCC2 -24CC genotype, and HLA-A*24 are associated with the risk of sorafenib-induced HGSR in Japanese RCC patients.

No abstract

No abstract