ROS‐generating oxidases Nox1 and Nox4 contribute to oncogenic Ras‐induced premature senescence

Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species (ROS) is involved in oncogenic Ras‐induced premature senescence. However, the signaling mechanism controlling this oxidant‐mediated irreversible growth arrest is not fully understood. Here, we show that through the Ras/MEK pathway, Ras oncogene up‐regulated the expression of superoxide‐generating oxidases, Nox1 in rat REF52 cells and Nox4 in primary human lung TIG‐3 cells, leading to an increase in intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including β‐galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16^Ink4a. This suggests that Nox‐generated ROS transduce senescence signals by activating the p53 and p16^Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs inhibited both Ras‐induced DNA damage response and p38MAPK activation, whereas overexpression of Nox1 and Nox4 alone was able to induce senescence. The involvement of Nox1 in Ras‐induced senescence was also confirmed with embryonic fibroblasts derived from Nox1 knockout mice. Together, these findings suggest that Nox1‐ and Nox4‐generated ROS play an important role in Ras‐induced premature senescence, which may involve DNA damage response and p38MAPK signaling pathways.     

Clinical utility of treatment method conversion during single-session endoscopic ultrasound-guided biliary drainage

BACKGROUND Although several techniques for endoscopic ultrasound-guided biliary drainage(EUS-BD)are available at present,an optimal treatment algorithm of EUS-BD has not yet been established.AIM To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD.METHODS This was a single-center retrospective analysis using a prospectively accumulated database.Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included.The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session.Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success,clinical success,and adverse events(AEs).RESULTS A total of 208 patients underwent EUS-BD during the study period.For 18.8%(39/208)of the patients,the treatment methods were converted to another EUSBD technique from the initial plan.Biliary obstruction was caused by pancreatobiliary malignancies,other malignant lesions,biliary stones,and other benign lesions in 22,11,4,and 2 patients,respectively.The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures:Target puncture(n=13),guidewire manipulation(n=18),and puncture tract dilation(n=8).Technical success was achieved in 97.4%(38/39)of the cases and clinical success was achieved in 89.5%of patients(34/38).AEs occurred in 10.3%of patients,including bile leakage(n=2),bleeding(n=1),and cholecystitis(n=1).The puncture target and drainage technique were altered in subsequent EUSBD procedures in 25 and 14 patients,respectively.The final technical success rate with 95%CI for all 208 cases was 97.1%(95%CI:93.8%-98.9%),while that of the initially planned EUS-BD was 78.8%(95%CI:72.6%-84.2%).CONCLUSION Among multi-step procedures in EUS-BD,guidewire manipulation appeared to be the most technically challenging.When initially planned EUS-BD is technically difficult,treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.     

Establishment of mesenchymal cell line derived from human developing odontoma

Oral Diseases (2012) 18, 756-762 Objectives: An odontoma, which shows proliferating odontogenic epithelium and mesenchymal tissue, is one of the most common odontogenic tumors encountered. These are commonly found in tooth-bearing regions, although the etiology remains unknown. There are no previous reports of an established line of immortalized human odontoma cells. Methods: Using odontoma fragments obtained from a girl treated at our department, we established an immortalized human odontoma cell line and investigated cell morphology, dynamic proliferation, the presence of contamination, and karyotype. Moreover, cell characterization was examined using osteogenic and odontogenic markers. Results: We successfully established a mesenchymal odontoma cell (mOd cells). The cells were found to be fibroblastic and had a high level of telomerase activity. Cell growth was confirmed after more than 200 population doublings without significant growth retardation. mOd cells expressed mRNA for differentiation markers, including collagen type I (COLI), alkaline phosphatase, bone sialoprotein, osteopontin, osteocalcin, cementum-derived protein (CP-23), dentin sialophosphoprotein (DSPP), and distal-less homeobox 3 (DLX3), as well as bone morphogenetic proteins (BMPs). In addition, they showed a high level of calcified nodule formation activity in vitro. Conclusions: We successfully established a cell line that may be useful for investigating the mechanisms of normal odontogenesis as well as characteristics of odontoma tumors.     

The efficacy and safety of piperacillin-tazobactam for febrile neutropenic patients in Japan

The IDSA guideline for management of febrile neutropenic patients updated in 2010 recommends monotherapy with anti-pseudomonal-lactam agents, including piperacillin-tazobactam (PIPC/TAZ) for high-risk patients. However, clinical studies of PIPC/TAZ are limited in Japanese patients. In this study, we conducted an open-labeled non-randomized prospective trial to examine the efficacy and safety of PIPC/TAZ as an empirical treatment for Japanese patients with febrile neutropenia. Forty-nine febrile episodes in neutropenic patients excluding those undergoing allogeneic stem cell transplantation (high risk 36, low risk 13) were analyzed. The overall response rate was 71%, and no significant differences between the high-risk and the low-risk group were observed (high risk 72%, low risk 69%). Neither PS nor usage of G-CSF affected the response rate. No major side effects were observed in the study. The efficacy and the safety profile of PIPC/TAZ treatment were comparable to those in other previous Western studies. In conclusion, this study suggests PIPC/TAZ is effective and well tolerated as an initial empirical treatment for febrile neutropenic Japanese patients.     

Computed tomography colonography for 5 cases of pneumatosis cystoides intestinalis

Computed tomography colonography (CTC) was performed in 5 patients with pneumatosis cystoides intestinalis (PCI). The virtual colonoscopy view of CTC as well as total colonoscopy (TCS) findings showed polypoid lesions in the colon, and multiplanar reconstruction images of the colon revealed in the polypoid lesions of the colon. We confirmed the diagnosis of PCI in all cases. CTC also detected the PCI lesions in the subserosa of the colonic wall which were not detected by TCS. Accurate evaluation of the extent of PCI involvement was obtained by CT air-contrast enema images. CTC is useful for detection of PCI lesions, assessment of the exact site and final diagnosis for PCI.     

Interleukin-6-producing dermoid cyst associated with multicentric Castleman’s disease

Dysregulated overproduction of interleukin-6 (IL-6) from activated B cells in affected lymph nodes has been implicated in the pathogenesis of multicentric Castleman’s disease (MCD), a rare lymphoproliferative disorder accompanied by systemic manifestations. We here report the case of a 32-year-old female presenting with MCD associated with a dermoid cyst in the pelvic cavity. The co-occurrence of MCD and dermoid cyst has not been reported before. Immunohistochemical analysis of the tissue sections showed IL-6 production in CD68-positive macrophage cells, which had infiltrated the dermoid cyst. Removal of the cyst resulted in partial improvement in systemic symptoms accompanied by a decrease in serum IL-6, while complete improvement was obtained by treatment with an anti-IL-6 receptor antibody following resection of the dermoid cyst. To the best of our knowledge, this is the first study to provide evidence of IL-6 production by CD68⁺ cells in a dermoid cyst involved in MCD.     

Interactions of household composition and required care level with functional and cognitive status among disabled Japanese elderly living in a suburban apartment complex

Aim: In the forthcoming super‐aging society, the appropriate assessment of functional and cognitive conditions of disabled elderly people will become increasingly significant in providing care services. Care level and household composition would be key factors to assess function. There might also be an interaction between the two factors with the function. The present study examined the associations of household composition and care level with functional and cognitive status among the disabled elderly living in a suburban apartment complex with a high rate of aged residents (39% in 2009). Methods: Participants were 190 disabled elderly persons aged 65 years and over who lived in the apartment complex. Cross‐sectional data were collected between May 2009 and August 2010, including care level, household composition, basic activities of daily living (BADL), instrumental activities of daily living (IADL) and the independence level in relation to cognitive status. Lower scores meant less independence in BADL and IADL, and as determined by the cognitive/independence scale. Results: Approximately half of the participants lived alone. Generalized linear model procedure showed significant interactions with the BADL score and cognitive/independence scale between household composition and care level. Scores for BADL and the cognitive/independence scale in groups receiving a higher care level were lower; however, the slope of the trend for the elderly living alone was more gradual than for the elderly living with others. Conclusion: It is important for health‐care providers to assess in detail the status of the disabled elderly considering both their household composition and care level in planning and providing assistance for them. Geriatr Gerontol Int 2012; 12: 538–546.