This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November ...2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. ...Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional ‘window of opportunity’ endpoints should be included.
Butyric acid, an extracellular metabolite from periodontopathic bacteria, induces apoptosis in murine and human T- and B-cells, whereas intact gingival fibroblasts isolated from healthy humans are ...resistant to butyric-acid-induced apoptosis. We examined the susceptibility of inflamed gingival fibroblasts isolated from adult persons with periodontitis to butyric-acid-induced apoptosis. Butyric acid significantly suppressed the viability of inflamed gingival fibroblasts and induced apoptosis in a dose-dependent manner. The incubation of inflamed gingival fibroblasts with butyric acid induced DNA fragmentation and apoptotic changes such as chromatin condensation, hypodiploid nuclei, and mitochondrial injury. Furthermore, butyric-acid-induced apoptosis in inflamed gingival fibroblasts was reduced by caspase-3/7, -6, -8, and -9 inhibitors. Thus, inflamed gingival fibroblasts from adult persons with periodontitis appear to be highly susceptible to mitochondria- and caspase-dependent apoptosis induced by butyric acid, compared with healthy gingival fibroblasts.
Background and Objective
Bacteria in the dental biofilm surrounding marginal gingival grooves cause periodontal diseases. Numerous bacteria within the biofilm consume nutrients from the gingival ...crevicular fluid. Furthermore, some gram‐negative bacteria in mature dental biofilms produce butyrate. Thus, gingival epithelial cells in close proximity to mature dental biofilms are at risk of both starvation and exposure to butyrate. In the present study, we determined the combined effects of starvation and butyrate exposure on gingival epithelial cell death and the underlying mechanisms.
Material and Methods
The Ca9‐22 cell line was used as an in vitro counterpart of gingival epithelial cells. Cell death was measured as the amount of total DNA in the dead cells using SYTOX Green dye, which penetrates through membranes of dead cells and emits fluorescence when it intercalates into double‐stranded DNA. AMP‐activated protein kinase (AMPK) activity, the amount of autophagy, and acetylation of histone H3 were determined using western blot. Gene expression levels of microtubule‐associated protein 1 light chain 3b (lc3b) were determined using quantitative reverse transcription–polymerase chain reaction.
Results
Butyrate‐induced cell death occurred in a dose‐dependent manner whether cells were starved or fed. However, the induction of cell death was two to four times higher when cells were placed under starvation conditions compared to when they were fed. Moreover, both starvation and butyrate exposure induced AMPK activity and autophagy. While AMPK inactivation resulted in decreased autophagy and butyrate‐induced cell death under conditions of starvation, AMPK activation resulted in butyrate‐induced cell death when cells were fed. Combined with the results of our previous report, which demonstrated butyrate‐induced autophagy‐dependent cell death, the results of this study suggest that the combination of starvation and butyrate exposure activates AMPK inducing autophagy and subsequent cell death. Notably, this combination markedly induced LC3B production and the induction was attenuated by AMPK inhibition. LC3B knockdown, in turn, significantly decreased butyrate‐induced cell death. Therefore, AMPK‐dependent LC3B induction apparently plays an important role in butyrate‐induced cell death. There was a lack of correspondence between the levels of AMPK activation and LC3B induction; this may reflect the histone deacetylase‐inhibitory capacity of butyrate on histone proteins.
Conclusion
Taken together, starvation and butyrate exposure promote autophagy via AMPK signaling, while the histone deacetylase‐inhibitory effects of butyrate alter chromatin to transcriptionally active state, resulting in strong LC3B induction and subsequent cell death. These findings may help improve the understanding of the cellular processes underlying periodontal disease initiation.
Based on the results of the IFMIF/EVEDA project in the broader approach (BA) activities, the conceptual design of the Advanced Fusion Neutron Source (A-FNS) to obtain irradiation data of DEMO blanket ...materials is under consideration in Japan. This paper describes the progress of the A-FNS conceptual design, which consists of a 40 MeV, 125 mA deuteron beam, a liquid lithium target system, and a test and post-irradiation test facilities. the main objectives of the A-FNS are the acquisition of RAFM irradiation data up to 2035 and the tritium recovery test on the blanket. In addition, it is expected to be used for various neutron researches. The technical design activities of the A-FNS are focused on improvement of the lithium target design, review of impurity criteria, remote handling, and irradiation application plan.
Aim
To determine whether Porphyromonas endodontalis can reactivate latent Epstein–Barr virus (EBV).
Methodology
The concentrations of short‐chain fatty acids (SCFAs) in P. endodontalis culture ...supernatants were determined using high‐performance liquid chromatography. A promoter region of BamHI fragment Z leftward open reading frame 1 (BZLF‐1), which is a transcription factor that controls the EBV lytic cycle, was cloned into luciferase expression vectors. Then, the luciferase assay was performed using P. endodontalis culture supernatants. Histone acetylation using Daudi cells treated with P. endodontalis culture supernatants was examined using Western blotting. BZLF‐1 mRNA and BamHI fragment Z EB replication activator (ZEBRA) protein were also detected quantitatively using real‐time polymerase chain reaction (PCR) and Western blotting. Surgically removed periapical granulomas were examined to detect P. endodontalis, EBV DNA, and BZLF‐1 mRNA expression using quantitative real‐time PCR. Statistical analysis using Steel tests was performed.
Results
The concentrations of n‐butyric acid in P. endodontalis culture supernatants were significantly higher than those of other SCFAs (P = 0.0173). Using B‐95‐8‐221 Luc cells treated with P. endodontalis culture supernatants, the luciferase assay demonstrated that P. endodontalis induced BZLF‐1 expression. Hyperacetylation of histones was also observed with the culture supernatants. BZLF‐1 mRNA and ZEBRA protein were expressed by Daudi cells in a dose‐dependent manner after the treatment with P. endodontalis culture supernatants. P. endodontalis and BZLF‐1 in periapical granulomas were also detected. The expression levels of BZLF‐1 mRNA were similar to the numbers of P. endodontalis cells in each specimen.
Conclusions
n‐butyric acid produced by P. endodontalis reactivated latent EBV.
This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following ...deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.
Reactive oxygen species (ROS) are essential for the induction of T-cell apoptosis by butyric acid, an extracellular metabolite of periodontopathic bacteria. To determine the involvement of oxidative ...stress in apoptosis pathways, we investigated the contribution of ROS in mitochondrial signaling pathways, death-receptor-initiated signaling pathway, and endoplasmic reticulum stress in butyric-acid-induced T-cell apoptosis. N-acetyl-L-Cysteine (NAC) abrogated mitochondrial injury, cytochrome c, AIF, and Smac release, and Bcl-2 and Bcl-xL suppression and Bax and Bad activation induced by butyric acid. However, the decrease in cFLIP expression by butyric acid was not restored by treatment with NAC; increases in caspase-4 and -10 activities by butyric acid were completely abrogated by NAC. NAC also affected the elevation of GRP78 and CHOP/GADD153 expression by butyric acid. These results suggest that butyric acid is involved in mitochondrial-dysfunction- and endoplasmic reticulum stress-mediated apoptosis in human Jurkat T-cells via a ROS-dependent mechanism.
Aim
Pelvic lymphocele is a common complication that develops after pelvic lymph node dissection. The incidence of pelvic lymphocele formation has been reported to be 10.5–51% after gynaecological or ...urological procedures. However, no evidence has been reported thus far with regard to the development of pelvic lymphocele following lateral pelvic lymph node dissection (LPND) for low rectal cancer. The aim of this study was to investigate the incidence of and risk factors for lymphocele formation after LPND for low rectal cancer and to examine its clinical management.
Method
We retrospectively analysed the incidence of and risk factors for pelvic lymphocele formation after LPND for rectal cancer in our hospital between January 2012 and December 2017. We also compared the size of the lymphocele between asymptomatic and symptomatic patients by using CT volumetry and examined its clinical management.
Results
A total of 30 out of 98 patients (30.8%) developed pelvic lymphocele after rectal LPND. The number of resected nodes was significantly higher in patients with a pelvic lymphocele (P < 0.01). The median volume was significantly higher in patients with symptomatic pelvic lymphocele (P = 0.011). Among the nine symptomatic patients, two underwent CT‐guided drainage, one underwent transurethral ureteral stent placement and one underwent laparoscopic marsupialization.
Conclusion
It is essential to keep in mind the possibility of pelvic lymphocele formation during follow‐up of patients who undergo LPND, and to consider an appropriate treatment when these patients are symptomatic.