Liverworts are a rich source of a diverse array of specialized metabolites, such as terpenoids and benzenoids, which are potentially useful for pharmaceutical or agrochemical applications, and also ...provide clues to elucidate the strategy by which liverworts adapt to the terrestrial environment. Liverworts, belonging to orders Marchantiales and Jungermanniales, possess oil bodies. In Marchantia polymorpha L., oil bodies are confined to scattered idioblastic oil body cells. It has been assumed that the specialized metabolites in M. polymorpha specifically accumulate in the oil bodies in oil body cells; however, no direct evidence was previously available for this specific accumulation. In this study, direct evidence was obtained using micromanipulation techniques coupled with MS analysis that demonstrated the specific accumulation of sesquiterpenoids and marchantin A in the oil body cells of M. polymorpha thalli. It was also observed that the number of oil body cells increased in thalli grown in low-mineral conditions. The amounts of sesquiterpenoids and marchantin A detected in crude extract prepared from the whole thallus were roughly proportional to the number of oil body cells found in a given volume of thallus, suggesting that oil body cell differentiation and sesquiterpenoid and marchantin A biosynthetic pathways are coordinated with each other.
Micromanipulation techniques coupled with MS analysis demonstrated the specific accumulation of sesquiterpenoids and marchantin A in the oil body cells of Marchantia polymorpha thalli. Display omitted
•Marchantia polymorpha has scattered idioblastic oil body cells largely occupied with oil bodies.•Direct analysis of the contents in oil bodies indicates accumulation of sesquiterpenoids and marchantin A.•Number of oil body cells in the thalli varies depending on the growth condition.•Oil body cell differentiation and sesquiterpenoid and marchantin A biosynthesis seem to be largely entrained with each other.
FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab.
WJOG4407G was a randomized, ...open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396.
Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively HR, 0.905; 95% confidence interval (CI) 0.723–1.133; P = 0.003 for non-inferiority. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785–1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months.
FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC.
UMIN000001396.
The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with ...refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.
A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration–time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.
In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.
In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients.
NCT01607957 (RECOURSE).
JapicCTI-090880 (J003).
•Patients with higher FTD exposure had a significantly increased risk of CIN.•In RECOURSE, FTD/TPI-treated patients who developed CIN had improved OS and PFS compared with placebo and those with no CIN.•Similar results from J003 validated the RECOURSE results.
Summary
The geometry of the rock joint is a governing factor for joint mechanical and hydraulic behaviour. A new method for evaluating the aperture distribution, based on measurement of joint ...surfaces and three dimensional characteristics of each surface, is developed. This method allows one to determine and visualize the aperture distribution under different normal stresses and shear displacements, which is difficult to observe experimentally. A new laser scanner system is designed and developed for joint surface measurements. Special attention is paid to both surfaces’ data gained by measurements and processing, such as x-y coordinate table modification, data referencing, and matching between upper and lower surfaces. The surfaces of an artificial joint in granite are measured, processed, analyzed and three dimensional approaches are carried out for surface characterization. Parameters such as “asperity’s heights”, “slope angles”, and “aspects” distribution at micro scale, local concentration of elements and their spatial localization at local scale are determined by Geographic Information System (GIS). These parameters are used for joint surfaces matching and its real behavior quantitative analysis. The upper surface is brought down to make contact with the lower surface and the distance between the two surfaces is evaluated from the joint mean experimental aperture, which is obtained from normal and shear tests. Changes of aperture distribution at different normal stresses and various shear displacements are visualized and interpreted. Increasing normal load causes negative changes in aperture frequency distribution which indicates high joint matching. However, increasing shear displacement causes a rapid increase in the aperture and positive changes in the aperture frequency distribution, which could be due to un-matching, surface anisotropy and spatial localization of contact points with proceeding shear.
Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, ...3-weekly S-1 plus cisplatin (SP3) was developed.
This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m2/day on days 1–14 and cisplatin 60 mg/m2 on day 1) was noninferior/superior to SP5 (S-1 80–120 mg/day on days 1–21 and cisplatin 60 mg/m2 on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382).
Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3–48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68–0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81–1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3.
SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.
Spatial probabilistic modeling of slope failure using a combined Geographic Information System (GIS), infinite-slope stability model and Monte Carlo simulation approach is proposed and applied in the ...landslide-prone area of Sasebo city, southern Japan. A digital elevation model (DEM) for the study area has been created at a scale of 1/2500. Calculated results of slope angle and slope aspect derived from the DEM are discussed. Through the spatial interpolation of the identified stream network, the thickness distribution of the colluvium above Tertiary strata is determined with precision. Finally, by integrating an infinite-slope stability model and Monte Carlo simulation with GIS, and applying spatial processing, a slope failure probability distribution map is obtained for the case of both low and high water levels.
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