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Abstract In acute myeloid leukemia (AML), the heterogeneity of genetic and epigenetic characteristics makes treatment difficult. The prognosis for AML is therefore poor, and there is an urgent need for new treatments for this condition. Gemtuzumab ozogamicin (GO), the first antibody‐drug conjugate (ADC), targets the CD33 antigen expressed in over 90% of AML cases. GO therefore has the potential to counter the heterogeneity of AML patients. However, a major clinical problem is that drug resistance to GO diminishes its effect over time. Here, we report that the inhibition of glycogen synthase kinase 3 (GSK3) alone overcomes several forms of GO resistance at concentrations without antileukemic effects. The GSK3 inhibitors tested significantly enhanced the cytotoxic effect of GO in AML cell lines. We elucidated four mechanisms of enhancement: (1) increased expression of CD33, the target antigen of GO; (2) activation of a lysosomal function essential for hydrolysis of the GO linker; (3) reduced expression of MDR1 that eliminates calicheamicin, the payload of GO; and (4) reduced expression of the anti‐apoptotic factor Bcl‐2. A similar combination effect was observed against patient‐derived primary AML cells. Combining GO with GSK3 inhibitors may be efficacious in treating heterogeneous AML.

Abstract We aimed to identify the threshold for P0.1 in a breath-by-breath manner measured by the Hamilton C6 on quasi-occlusion for high respiratory drive and inspiratory effort. In this prospective observational study, we analyzed the relationships between airway P0.1 on quasi-occlusion and esophageal pressure (esophageal P0.1 and esophageal pressure swing). We also conducted a linear regression analysis and derived the threshold of airway P0.1 on quasi-occlusion for high respiratory drive and inspiratory effort. We found that airway P0.1 measured on quasi-occlusion had a strong positive correlation with esophageal P0.1 measured on quasi-occlusion and esophageal pressure swing, respectively. Additionally, the P0.1 threshold for high respiratory drive and inspiratory effort were calculated at approximately 1.0 cmH2O from the regression equations. Our calculations suggest a lower threshold of airway P0.1 measured by the Hamilton C6 on quasi-occlusion than that which has been previously reported.

Abstract Late Quaternary tectonic deformation of coastal areas is usually examined based on the height distribution of paleo-shorelines observed on marine terraces. However, it is difficult to examine deformation along the subduction zone, in which small, isolated islands are distributed. In this paper, the author focuses on the widespread shallow submarine terraces surrounding the Iheya–Izena islands in the middle part of the Nanseishoto Islands, Southwest Japan, where crustal deformation is not known. The islands are located in the intermediate zone between island shelf uplifted during the Late Quaternary and the rift zone occurred to the northwest, along the Okinawa trough. Detailed topographic anaglyph images and maps of the islands were produced using a digital elevation model (DEM) of the seafloor, which is stored by the Japan Coast Guard (JCG) and the Advanced Institute of Science and Technology (AIST). Topographic anaglyph images enabled us to identify the widespread distribution and deformation of the shallow seafloor above − 200 m using red–cyan glasses. Four terrace-like features divided by small steps were found on the shallow seafloor, which are named T1, T2, T3, and T4, in descending order. Topographic expressions of paleo-shoreline depths are preserved on submarine terraces formed during the last glacial period. The paleo-shoreline depths of terraces T2 and T3 are − 60 m and − 70 m on the west side and − 70 m and − 80 m, respectively, on the east side of Iheyajima Island; this indicates southeastward tilting. The tilting ratio of T2 and T3 was calculated to approximately 1‰. The tilting rate is approximately 1 × 10–4/kyr, assuming that the T2 was formed in 10–11 kyr. This is much more rapid than that of the last inter-glacial marine terraces in the Muroto peninsula of Shikoku, Japan, with a tilting rate of 4 × 10–5/kyr, which formed by steep northward tilting against the Nankai subduction zone. The author suggests that this phenomenon is not related to mega-thrusting along the subduction zone, but rather to local deformation, probably caused by the reverse faulting of nearby active submarine faults along the west side of the islands.

Background: Co-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. Methods: We enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. Results: A total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. Conclusions: A high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

BackgroundWe previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden.MethodsThe 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders.ResultsLong-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes.ConclusionsWe found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib.

Abstract Background Vitamin C is a well-documented antioxidant that reduces oxidative stress and fluid infusion in high doses; however, the association between high-dose vitamin C and reduced mortality remains unclear. This study evaluates the effect of high-dose vitamin C in severe burn patients under two varying thresholds. Methods We enrolled adult patients with severe burns (burn index ≥ 15) who were registered in the Japanese Diagnosis Procedure Combination national inpatient database from 2010 to 2016. Propensity score matching was performed between patients who received high-dose vitamin C within 1 day of admission (vitamin C group) and those who did not (control group). High-dose vitamin C was defined as a dosage in excess of 10 g or 24 g within 2 days of admission. The primary outcome was in-hospital mortality. Results Eligible patients (n = 2713) were categorized into the vitamin C group (n = 157) or control group (n = 2556). After 1:4 propensity score matching, we compared 157 and 628 patients who were administered high-dose vitamin C (> 10-g threshold) and controls, respectively. Under this particular threshold, high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio, 0.79; 95% confidence interval, 0.66–0.95; p = 0.006). In contrast, in-hospital mortality did not differ between the control and high-dose vitamin C group under the > 24-g threshold (risk ratio, 0.83; 95% confidence interval, 0.68–1.02; p = 0.068). Conclusions High-dose vitamin C therapy was associated with reduced mortality in patients with severe burns when used under a minimum threshold of 10 g within the first 2 days of admission. While “high-dose” vitamin C therapy lacks a universal definition, the present study reveals that different “high-dose” regimens may yield improved outcomes.

Aim Combination treatment with clindamycin is recommended in patients with invasive group A Streptococcus infection; however, whether the same treatment is effective in invasive group B Streptococcus and S. dysgalactiae subspecies equisimilis infections remains unknown. We aimed to investigate whether clindamycin added to standard of care therapy would be effective in patients with invasive non‐group A β‐hemolytic Streptococcus infections. Methods This was a nationwide retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database focusing on the period between 2010 and 2018. We extracted data on patients diagnosed with sepsis due to non‐group A β‐hemolytic Streptococcus. One‐to‐four propensity score‐matching was undertaken to compare patients who were treated with clindamycin within 2 days of admission (clindamycin group) and those who did not (control group). The primary outcome was in‐hospital mortality. Results We identified 3754 eligible patients during the study period. The patients were divided into the clindamycin (n = 296) and control groups (n = 3458). After one‐to‐four propensity score matching, we compared 289 and 1156 patients with and without clindamycin, respectively. In‐hospital mortality did not significantly differ between the two groups (9.7% versus 10.3%; risk difference 0.3%; 95% confidence interval, –3.5% to 4.2%). Conclusions This nationwide database study showed that combination therapy involving the use of clindamycin was not associated with lower in‐hospital mortality in patients with invasive non‐group A β‐hemolytic Streptococcus.

Aim: The present study aimed to describe the prevalence, prognosis and annual trends of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) patients, using a nationwide inpatient database in Japan. Methods: This was a nationwide retrospective cohort study, using the Japanese Diagnosis Procedure Combination inpatient database. We included OHCA patients registered in the database from July 2010 to March 2017 and analyzed the annual prevalence of OHCA patients who received ECPR. The outcomes included survival to hospital discharge and survival with favorable neurologic outcome at hospital discharge. The annual trends on the outcomes were also analyzed. Results: We identified 217,907 eligible patients. OHCA patients were divided into patients with ECPR (n = 5,612) and conventional CPR (n = 212,295). The prevalence of ECPR performed in OHCA patients was 2.6%. ECPR prevalence significantly increased from 2.1% in 2010 to 3.0% in 2016 (P

Anaglyphs produced using a digital elevation model (DEM) are effective to identify the characteristic tectono–geomorphic features. The objective of this study is to reinvestigate the tectonic geomorphology and to present novel tectonic maps of the late Quaternary in and around the Yoron island based on the interpretation of extensive topographical anaglyphs along the map areas that cover the inland and seafloor. Vintage aerial photographs are used to produce the 3-m mesh inland digital surface model (DSM); further, the 0.6-s to 2-s-mesh seafloor DEM is processed using the cloud point data generated through previous surveys. Thus, we identify anticlinal deformation on both the Pleistocene marine terrace and the seafloor to the north of the island. The deformation axis extends in a line and is parallel to the general trend of the island shelf. The Tsujimiya fault cuts the marine terraces, which extend to the Yoron basin’s seafloor. If we assume that the horizontal compressive stress axis is perpendicular to the island shelf, these properties can easily explain the distribution and style of the active faults and deformation. This study presents an effective methodology to understand the island arc tectonics, especially in case of small isolated islands.

Collembolan communities in conifer plantations (Japanese cedar, Cryptomeria japonica) and secondary deciduous broad-leaved forests of varying ages were investigated to determine the extent to which forest conversion (broad-leaved to coniferous) affects the species richness and assemblage composition of Collembola in central Japan. Density and total species richness of Collembola not differed between the broad-leaved and cedar forests except immediately after clear-cutting. The amount of forest-floor organic matter was larger in cedar forests and positively correlated with the species richness of detritus feeders. Species richness of fungal feeders and sucking feeders positively correlated with the species richness of forest-floor plants. There was difference in collembolan species composition between the forest types. The age of the forests seemed to have only small importance for the collembolan community, except during the first four years after clear-cutting. The conversion to artificial cedar stands has not reduced the abundance or species richness of collembolan communities, but has affected community composition. Differences in species composition may be related to the ground floras.As comunidades de colêmbolos nas plantações da conífera Cryptomeria japonica (cedro japonês) e florestas decíduas secundárias de várias idades foram investigadas para determinar até que ponto a conversão da floresta decídua em conífera afeta a riqueza das espécies e a composição das comunidades de colêmbolos no Japão central. A densidade e a riqueza total de espécies de Collembola não foram diferentes entre as florestas decíduas e de cedro, exceto imediatamente depois do corte raso. A quantidade de matéria orgânica acumulada no solo foi maior sob cedro e positivamente correlacionada com a riqueza de espécies de detritívoros. A riqueza de espécies de fungívoros e sugadores foi positivamente correlacionada à riqueza de espécies de plantas do estrato herbáceo da floresta. Houve diferença na composição das espécies de colêmbolos entre os tipos de floresta. A idade das florestas parece ter pouca importância para a comunidade de colêmbolos, exceto nos primeiros quatro anos após o corte raso. Concluiu-se que a conversão da floresta decídua em plantações de cedro japonês não causou diminuição na abundância e na riqueza das espécies das comunidades de colêmbolos, mas afetou a composição dessas comunidades. As diferenças na composição das espécies podem ser relacionadas ao desenvolvimento de plantas do estrato herbáceo da floresta.

In many temperate terrestrial forest ecosystems, both natural human disturbances drive the reestablishment of forests. Succession in plant communities, in addition to reforestation following the creation of open sites through harvesting or natural disturbances, can affect forest faunal assemblages. Wild bees perform an important ecosystem function in human-altered and natural or seminatural ecosystems, as they are essential pollinators for both crops and wild flowering plants. To maintain high abundance and species richness for pollination services, it is important to conserve and create seminatural and natural land cover with optimal successional stages for wild bees. We examined the effects of forest succession on wild bees. In particular, we evaluated the importance of early successional stages for bees, which has been suspected but not previously demonstrated. A range of successional stages, between 1 and 178 years old, were examined in naturally regenerated and planted forests. In total 4465 wild bee individuals, representing 113 species, were captured. Results for total bees, solitary bees, and cleptoparasitic bees in both naturally regenerated and planted conifer forests indicated a higher abundance and species richness in the early successional stages. However, higher abundance and species richness of social bees in naturally regenerated forest were observed as the successional stages progressed, whereas the abundance of social bees in conifer planted forest showed a concave-shaped relationship when plotted. The results suggest that early successional stages of both naturally regenerated and conifer planted forest maintain a high abundance and species richness of solitary bees and their cleptoparasitic bees, although social bees respond differently in the early successional stages. This may imply that, in some cases, active forest stand management policies, such as the clear-cutting of planted forests for timber production, would create early successional habitats, leading to significant positive effects for bees in general.