Time for a new language for asthma control : Results from REALISE Asia

Acknowledgments: This study was supported and funded by Mundipharma Pte Ltd. Online survey and statistical analysis were performed by Pei-Li Teh, Rachel Howard, Tsin-Li Chua, and Jie Sun of Research Partnership Pte Ltd. Medical writing support was provided by Sen-Kwan Tay of Research2Trials Clinical Solutions Pte Ltd.Peer reviewedPublisher PD

Dual Silencing of Hsp27 and c-FLIP Enhances Doxazosin-Induced Apoptosis in PC-3 Prostate Cancer Cells

We evaluated effect of dual gene silencing of Hsp27 and c-FLIP in doxazosin-induced apoptosis of PC-3 cell. After transfection using Hsp27 and c-FLIP siRNA mixture (dual silencing), doxazosin treatment was done at the concentrations of 1, 10, and 25 μM. We checked apoptosis of PC-3 cells with and TUNEL staining. We also checked interaction between Hsp27 and C-FLIP in the process of apoptosis inhibition. Spontaneous apoptotic index was 5% under single gene silencing of Hsp27 and c-FLIP and 7% under dual silencing of Hsp27 and c-FLIP. When doxazosin treatment was added, apoptotic indices increased in a dose-dependent manner (1, 10, and 25 μM): nonsilencing 10, 27, and 52%; Hsp27-silencing: 14, 35, and 68%; c-FLIP silencing: 21, 46, and 78%; dual silencing: 38, 76, and 92%. While c-FLIP gene expression decreased in Hsp27- silenced cells, Hsp27 gene expression showed markedly decreased pattern in the cells of c-FLIP silencing. The knockout of c-FLIP and Hsp27 genes together enhances apoptosis even under 1 μM, rather than low concentration, of doxazosin in PC-3 cells. This finding suggests a new strategy of multiple knockout of antiapoptotic and survival factors in the treatment of late-stage prostate cancer refractory to conventional therapy

Suggested Indications for Enucleation of Solid Pseudopapillary Neoplasms in Pediatric Patients

Background: Solid pseudopapillary neoplasms (SPNs) are rare, low-grade, malignant neoplasms that can occur in pediatric patients. Although complete resection of the tumor is the principle treatment, SPN enucleation (EN) has been reported to be effective in children. This study aimed to examine the feasibility and safety of EN by comparing it with conventional pancreatectomy (CP), and to present the indications for its use in pediatric patients.Methods: We retrospectively reviewed the medical records of 66 patients who underwent surgery for SPN at our institution from October 1992 to April 2018. Surgical methods, postoperative complications, hospital stay, and recurrence were compared.Results: Of the 66 patients, 15 (22.7%) were treated with EN and 51 (77.3%) were treated with CP. The mean duration of EN operation was 262 min (±145 min) and of CP was 345 min (±195 min). There was no statistically significant difference between the two methods (P = 0.13). To objectively compare the mass size between patients, we introduced a tumor size/intraperitoneal width ratio, which also revealed no significant difference between the 2 surgery groups (P = 0.21). The EN group had one case of recurrence at the resection site. The complications observed were fluid collection, splenic infarctions, hematomas, pancreatic fistulas, portal vein thromboses, and chylous drainage, among which pancreatic fistulas were the most frequent followed by moderate-severe fistulas in the EN group (P < 0.001). The mean postoperative fasting time (EN 17.0 ± 8.7 days vs. CP 5.1 ± 3.3 days, P < 0.001) and mean hospital stay (EN 23.4 ± 10.0 days vs. CP 13.2 ± 6.5 days, P = 0.002) showed statistically significant differences.Conclusion: Compared with CP treatment, EN of SPNs in children has the disadvantages of prolonged fasting times and hospital stays to recover from moderate pancreatic fistulas. However, if appropriate indications are applied, EN can be considered a safe and effective surgical procedure for children

Influence of anesthesia methods on surgical outcomes and renal function in retrograde intrarenal stone surgery: a prospective, randomized controlled study

Background We analyzed the influence of anesthesia methods on surgical outcomes and renal function in retrograde intrarenal surgery (RIRS) in a prospective, randomized controlled study. Methods Seventy patients who underwent RIRS from September 2015 to February 2017 were randomly allocated to general anesthesia (GA) or spinal anesthesia (SA) groups. Renal function was assessed using estimated glomerular filtration rate, and separate renal function was evaluated using nuclear medicine tests. Maneuverability and accessibility were evaluated after every surgery. All procedures were performed by a single experienced surgeon (SY Cho). Results Stone-free rate was higher in the GA (92.3%, 36 of 39) than the SA (71.0%, 22 of 31) (P = 0.019) group. Pain score was higher in the GA than in the SA group on the first postoperative morning (P = 0.025), but pain scores of the two groups were similar before discharge (P = 0.560). There were no differences in the changes of serum creatinine level (P = 0.792) and changes of estimated glomerular filtration rate (P = 0.807). Differences of separate renal function between operative and contralateral site increased significantly in patients under GA than under SA at postoperative 3 months (P = 0.014). Maneuverability and accessibility were better in SA with sedation than GA (P < 0.001). Conclusions RIRS under SA showed advantages in renal function change using renogram at postoperative 3 months and in lower pain score on the first postoperative morning. Performance of operator under SA was worse than that under GA and significantly improved with sedation. RIRS under SA showed advantages in lower pain score at postoperative first day. Trial registration Clinicaltrials.gov ID is NCT03957109, and registration date is 17th May 2019. This study was retrospectively registered.This study was supported by grant no. 04–2015-0680 from the SNUH Research Fund

Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death