Sirtuins (SIRTs) belong to the nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family. They are key regulators of cellular and physiological processes, such as cell survival, senescence, differentiation, DNA damage and stress response, cellular metabolism, and aging. SIRTs also influence carcinogenesis, making them potential targets for anticancer therapeutic strategies. In this study, we investigated the anticancer properties and underlying molecular mechanisms of a novel SIRT1 inhibitor, MHY2251, in human colorectal cancer (CRC) cells. MHY2251 reduced the viability of various human CRC cell lines, especially those with wild-type TP53. MHY2251 inhibited SIRT1 activity and SIRT1/2 protein expression, while promoting p53 acetylation, which is a target of SIRT1 in HCT116 cells. MHY2251 treatment triggered apoptosis in HCT116 cells. It increased the percentage of late apoptotic cells and the sub-G1 fraction (as detected by flow cytometric analysis) and induced DNA fragmentation. In addition, MHY2251 upregulated the expression of FasL and Fas, altered the ratio of Bax/Bcl-2, downregulated the levels of pro-caspase-8, -9, and -3 proteins, and induced subsequent poly(ADP-ribose) polymerase cleavage. The induction of apoptosis by MHY2251 was related to the activation of the caspase cascade, which was significantly attenuated by pre-treatment with ZVAD-FMK, a pan-caspase inhibitor. Furthermore, MHY2251 stimulated the phosphorylation of c-Jun N-terminal kinase (JNK), and MHY2251-triggered apoptosis was blocked by pre-treatment with SP600125, a JNK inhibitor. This finding indicated the specific involvement of JNK in MHY2251-induced apoptosis. MHY2251 shows considerable potential as a therapeutic agent for targeting human CRC via the inhibition of SIRT1 and activation of JNK/p53 pathway.

Purpose: Intraoral scanners, desktop scanners, and cone-beam computed tomography (CBCT) are being used in a complementary way for diagnosis and treatment planning. Limited patient-based results are available about dimensional reproducibility among different three-dimensional imaging systems. This study aimed to evaluate dimensional reproducibility among patient-derived digital models created from an intraoral scanner, desktop scanner, and two CBCT systems. Materials and Methods: Twenty-nine arches from sixteen patients who were candidates for implant treatments were enrolled. Different types of CBCT systems (KCT and VCT) were used before and after the surgery. Polyvinylsiloxane impressions were taken on the enrolled arches after the healing period. Gypsum casts were fabricated and scanned with an intraoral scanner (CIOS) and desktop scanner (MDS). Four test groups of digital models, each from CIOS, MDS, KCT, and VCT, respectively, were compared to the reference gypsum cast group. For comparison of linear measurements, intercanine and intermolar widths and left and right canine to molar lengths were measured on individual gypsum cast and digital models. All measurements were triplicated, and the averages were used for statistics.Bland–Altman plots were drawn to assess the degree of agreement between each test group with the reference gypsum cast group. A linear mixed model was used to analyze the fixed effect of the test groups compared to the reference group (α=0.05).Result: The Bland–Altman plots showed that the bias of each test group was –0.07 mm for CIOS, –0.07 mm for MDS, –0.21 mm for VCT, and –0.25 mm for KCT. The linear mixed model did not show significant differences between the test and reference groups (P>0.05). Conclusion The linear distances measured on the digital models created from CIOS, MDS, and two CBCT systems showed slightly larger than the references but clinically acceptable reproducibility for diagnosis and treatment planning.reproducibility for diagnosis and treatment planning.plots showed that the bias of each test group was –0.07 mm for CIOS, –0.07 mm for MDS,

Purpose: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells. Materials and Methods: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5–20 nM) with or without NVP-BEZ236 (0.5–4 μM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism. Results: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin- resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17- DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 μM/mL2%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot. Conclusion HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

Purpose: The purpose of this study was to assess characteristics of SJ-815, a novel oncolytic vaccinia virus lacking a functional thymidine kinase-encoding TK gene, and instead, having two human transgenes: the IFNB1 that encodes interferon β1, and the CES2 that encodes carboxylesterase 2, which metabolizes the prodrug, irinotecan, into cytotoxic SN-38. Materials and Methods: Viral replication and dissemination of SJ-815 were measured by plaque assay and comet assay, respectively, and compared to the backbone of SJ-815, a modified Western Reserve virus named WI. Tumor cytotoxicity of SJ-815 (or mSJ-815, which has the murine IFNB1 transgene for mouse cancers) was evaluated using human and mouse cancer cells. Antitumor effects of SJ-815, with/without irinotecan, were evaluated using a human pancreatic cancer-bearing mouse model and a syngeneic melanoma-bearing mouse model. The SN-38/ irinotecan ratios in mouse melanoma tissue 4 days post irinotecan treatment were compared between groups with and without SJ-815 intravenous injection. Results: SJ-815 demonstrated significantly lower viral replication and dissemination, but considerably stronger in vitro tumor cytotoxicity than WI. The combination use of SJ-815 plus irinotecan generated substantial tumor regression in the human pancreatic cancer model, and significantly prolonged survival in the melanoma model (hazard ratio, 0.11; 95% confidence interval, 0.02 to 0.50; p=0.013). The tumor SN-38/irinotecan ratios were over 3-fold higher in the group with SJ-815 than those without (p < 0.001). Conclusion SJ-815 demonstrates distinct characteristics gained from the inserted IFNB1 and CES2 transgenes. The potent antitumor effects of SJ-815, particularly when combined with irinotecan, against multiple solid tumors make SJ-815 an attractive candidate for further preclinical and clinical studies.

PURPOSE: To determine prognostic significance of lymphovascular invasion (LVI) in prostate cancer patients who underwent adjuvant or salvage postoperative radiotherapy (PORT) after radical prostatectomy (RP) MATERIALS AND METHODS: A total of 168 patients with prostate cancer received PORT after RP, with a follow-up of ≥12 months. Biochemical failure after PORT was defined as prostate-specific antigen (PSA) ≥0.2 ng/mL after PORT or initiation of androgen deprivation therapy (ADT) for increasing PSA levels regardless of the value. We analyzed the clinical outcomes including survivals, failure patterns, and prognostic factors affecting the outcomes. RESULTS: In total, 120 patients (71.4%) received salvage PORT after PSA levels were >0.2 ng/mL or owing to clinical failure. The 5-year biochemical failure-free survival (BCFFS), clinical failure-free survival (CFFS), distant metastasis-free survival (DMFS), overall survival, and cause-specific survival rates were 78.3%, 94.3%, 95.0%, 95.8%, and 97.3%, respectively, during a follow-up range of 12–157 months (median: 64 months) after PORT. On multivariate analysis, PSA level of ≤1.0 ng/mL at the time of receiving PORT predicted favorable BCFFS, CFFS, and DMFS. LVI predicted worse CFFS (p = 0.004) and DMFS (p = 0.015). Concurrent and/or adjuvant ADT resulted in favorable prognosis for BCFFS (p < 0.001) and CFFS (p = 0.017). CONCLUSION: For patients with adverse pathologic findings, PORT should be initiated as early as possible after continence recovery after RP. Even after administering PORT, LVI was an unfavorable predictive factor, and further intensive adjuvant therapy should be considered for these patients.
Follow-Up Studies ; Humans ; Multivariate Analysis ; Prognosis ; Prostate ; Prostate-Specific Antigen ; Prostatectomy ; Prostatic Neoplasms ; Radiotherapy ; Survival Rate

OBJECTIVES: This paper describes an evaluation study on the effectiveness of developing an in-hospital medical device safety information reporting system for managing safety information, including adverse incident data related to medical devices, following the enactment of the Medical Device Act in Korea. METHODS: Medical device safety information reports were analyzed for 190 cases that took place prior to the application of a medical device safety information reporting system and during a period when the reporting system was used. Also, questionnaires were used to measure the effectiveness of the medical device safety information reporting system. The analysis was based on the questionnaire responses of 15 reporters who submitted reports in both the pre- and post-reporting system periods. RESULTS: Sixty-two reports were submitted in paper form, but after the system was set up, this number more than doubled to 128 reports in electronic form. In terms of itemized reporting, a total of 45 items were reported. Before the system was used, 23 items had been reported, but this increased to 32 items after the system was put to use. All survey variables of satisfaction received a mean of over 3 points, while positive attitude, potential benefits, and positive benefits all exceeded 4 points, each receiving 4.20, 4.20, and 4.13, respectively. Among the variables, time-consuming and decision-making had the lowest mean values, each receiving 3.53. Satisfaction was found to be high for system quality and user satisfaction, but relatively low for time-consuming and decision-making. CONCLUSIONS: We were able to verify that effective reporting and monitoring of adverse incidents and the safety of medical devices can be implemented through the establishment of an in-hospital medical device safety information reporting system that can enhance patient safety and medical device risk management.
Electronic Health Records* ; Equipment Safety* ; Hospital Information Systems ; Korea ; Patient Safety ; Risk Management ; Safety Management

Apigenin (4′,5,7-trihydroxyflavone) is a flavonoid commonly found in many fruits and vegetables such as parsley, chamomile, celery, and kumquats. In the last few decades, recognition of apigenin as a cancer chemopreventive agent has increased. Significant progress has been made in studying the chemopreventive aspects of apigenin both in vitro and in vivo. Several studies have demonstrated that the anticarcinogenic properties of apigenin occur through regulation of cellular response to oxidative stress and DNA damage, suppression of inflammation and angiogenesis, retardation of cell proliferation, and induction of autophagy and apoptosis. One of the most well-recognized mechanisms of apigenin is the capability to promote cell cycle arrest and induction of apoptosis through the p53-related pathway. A further role of apigenin in chemoprevention is the induction of autophagy in several human cancer cell lines. In this review, we discuss the details of apigenin, apoptosis, autophagy, and the role of apigenin in cancer chemoprevention via the induction of apoptosis and autophagy.
Apigenin* ; Apium graveolens ; Apoptosis* ; Autophagy* ; Cell Cycle Checkpoints ; Cell Line ; Cell Proliferation ; Chamomile ; Chemoprevention ; DNA Damage ; Fruit ; Humans ; In Vitro Techniques ; Inflammation ; Oxidative Stress ; Petroselinum ; Rutaceae ; Vegetables

Viriditoxin is a fungal metabolite isolated from Paecilomyces variotii, which was derived from the giant jellyfish Nemopilema nomurai. Viriditoxin was reported to inhibit polymerization of FtsZ, which is a key protein for bacterial cell division and a structural homologue of eukaryotic tubulin. Both tubulin and FtsZ contain a GTP-binding domain, have GTPase activity, assemble into protofilaments, two-dimensional sheets, and protofilament rings, and share substantial structural identities. Accordingly, we hypothesized that viriditoxin may inhibit eukaryotic cell division by inhibiting tubulin polymerization as in the case of bacterial FtsZ inhibition. Docking simulation of viriditoxin to beta-tubulin indicated that it binds to the paclitaxel-binding domain and makes hydrogen bonds with Thr276 and Gly370 in the same manner as paclitaxel. Viriditoxin suppressed growth of A549 human lung cancer cells, and inhibited cell division with G2/M cell cycle arrest, leading to apoptotic cell death.
Apoptosis* ; Cell Cycle Checkpoints* ; Cell Cycle* ; Cell Death ; Cell Division ; Eukaryotic Cells ; GTP Phosphohydrolases ; Humans* ; Hydrogen ; Lung Neoplasms* ; Lung* ; Paclitaxel ; Paecilomyces ; Polymerization ; Polymers ; Tubulin

No abstract available.
Fusariosis* ; Hand* ; Snake Bites* ; Wounds and Injuries*