Search

Neural crest-derived cells (NCDCs), a class of adult stem cells not restricted to embryonic tissues, are attractive tissue regenerative therapy candidates because of their ease of isolation, self-renewing properties, and multipotency. Although adult NCDCs can undergo osteogenic differentiation in vitro, whether they induce bone formation in vivo remains unclear. Previously, our group reported findings showing high amounts of NCDCs scattered throughout nasal concha tissues of adult mice. In the present study, NCDCs in nasal conchae labeled with enhanced green fluorescent protein (EGFP) were collected from adult P0-Cre/CAG-CAT-EGFP double transgenic mice, then cultured in serum-free medium to increase the number. Subsequently, NCDCs were harvested and suspended in type I atelocollagen gel, then an atelocollagen sponge was used as a scaffold for the cell suspension. Atelocollagen scaffolds with NCDCs were placed on bone defects created in a mouse calvarial bone defect model. Over the ensuing 12 weeks, micro-CT and histological analysis findings showed that mice with scaffolds containing NCDCs had slightly greater bone formation as compared to those with a scaffold alone. Furthermore, Raman spectroscopy revealed spectral properties of bone in mice that received scaffolds with NCDCs similar to those of native calvarial bone. Bone regeneration is important not only for gaining bone mass but also chemical properties. These results are the first to show the validity of biomolecule-free adult nasal concha-derived NCDCs for bone regeneration, including the chemical properties of regenerated bone tissue.

Purpose The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. Methods This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1–5 and 8–12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. Results A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9–4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7–8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). Discussion The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. Trial registration number UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network)

Background Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal in vivo ATP distribution and dynamics has hindered further analysis. Methods A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase. Results Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues. Conclusions Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information.

Introduction We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Patients and Methods We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384). Conclusion The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

The indolylmaleimide (IM) derivative IM-17 shows inhibitory activity against oxidative-stress-induced necrotic cell death and cardioprotective activity in rat ischemia-reperfusion injury models. In order to develop a more potent derivative, we conducted a detailed structure–activity relationship study of IM derivatives and identified IM-93 as the most potent derivative with good water solubility. IM-93 inhibited ferroptosis and NETosis, but not necroptosis or pyroptosis. In contrast, ferrostatin-1 (Fer-1), a ferroptosis inhibitor, did not inhibit NETosis, although the accompanying lipid peroxidation was partially inhibited by Fer-1, as well as by IM-93. Thus, IM derivatives have a unique activity profile and appear to be promising candidates for in vivo application.

A simple analytical method was developed to determine the arsenite (As(III)) concentration using a DNA aptamer and gold nanoparticles (AuNPs). Prior to sample measurements, the method sensing mechanism was confirmed by analyzing the particle size of the AuNPs at each step of the analysis procedure, and the key operational parameters that affect the method performance were optimized. The optimal final NaCl concentration, incubation time with NaCl and pH of a 3-(N-morpholino) propanesulfonic acid buffer were 60 mM, 10 min and 7.3, respectively. A calibration curve was created under optimized operational conditions. The calibration curve was linear from a 1.0- to 10-μM As(III) concentration. The detection limit was 2.1 μM (161 μg/L). Using the calibration curve, we evaluated groundwater samples spiked with As(III). As(III) concentrations in groundwater pretreated with a 0.2-μm-pore-size membrane filter and cation-exchange resin were determined by using the method, which suggests that the proposed method can be used to determine the As(III) concentration in groundwater.

INTRODUCTION AND OBJECTIVE:Although several large-scale studies reported a robust benefit of upfront therapy for mHNPC, not all patients with mHNPC experienced mCRPC progression. As there is a conc...

Monitoring of Escherichia coli concentrations at wastewater treatment plants (WWTPs) is important to ensure process performance and protect public health. However, conventional E. coli enumeration methods are complicated and time- and labor-consuming. Here, we report a novel simple and reliable method based on β- d -glucuronidase (GUS) activity assay to enumerate E. coli concentrations in wastewater (WW) samples. An aliquot (20 μL) of the medium with fluorogenic enzyme substrate for E. coli and 180 μL of a WW sample were added to one well of a 96-well microplate. The microplate was placed in a microplate reader at 37 °C. To this end, the fluorescence intensity of a fluorogenic enzyme substrate for E. coli was measured every 10 min over 3 h to determine GUS activity. The linear increase in the fluorescence intensity representing the GUS activities showed a positive correlation with E. coli concentrations in wastewater samples. However, the correlation equations were specific to WWTPs, which could be due to the difference in the E. coli population structures among WWTPs. We observed that the wastewater matrix is not a limitation to measure the GUS activity, and a WWTP-specific correlation equation can be used as a calibration curve to estimate the E. coli concentrations in the samples collected from that site. A comparison of the results with those of culture-dependent Colilert method proved that the current method is simple and useful for the enumeration of E. coli concentrations in wastewater samples reliably.

This paper reviews a new method of dentin surface modification, smear layer-deproteinization for self-etch adhesive systems, particularly in relation to improving the adhesion to caries-affected dentin. Remnants of smear debris, which forms hybridized smear layer with self-etch adhesives, can prevent monomer infiltration and interfere with the chemical interaction of adhesive monomers and the underlying dentin. The hybridized smear layer weakens the physical and chemical properties of the resin-dentin hybridized complex both immediately and over time. Smear layer-deproteinization with NaOCl and HOCl solutions can improve the quality of resin-dentin interface of self-etch adhesives through elimination of the hybridized smear layer, development of monomer infiltration, and enhancement of the chemical interaction of adhesive monomers with hydroxyapatite due to an increase in the mineral/organic ratio on the dentin surface. These positive effects are influenced by the types of oxidizing solution and their application time and also depend upon the adhesive materials used because compromising effects of residual oxidized-byproducts at the dentin surface on the polymerization behavior of the adhesives are different between the materials. However, applying antioxidant/reducing agents can eliminate this problem. Smear layer-deproteinization is more effective for improving the bonding efficacy of self-etch adhesives to caries-affected dentin than normal dentin because caries-affected dentin produces a thicker organic-rich smear layer. Smear layer-deproteinization with HOCl solution, which has a rapid and broad-spectrum antimicrobial activity with less irritating and sensitizing properties, along with the subsequent application of antioxidant/reducing agents could enhance the longevity of composite restoration with self-etch adhesives.

Digital Dermatitis is a localized infectious dermatitis caused by Treponema-like spirochetes. Antibiotics, such as lincomycin, are currently used for treatment, but their use imposes a withdrawal period. This study investigated the therapeutic effect of topical application of the natural component allyl isothiocyanate, in combination with maintenance hoof trimming, on bovine Digital Dermatitis. Study cows were divided into two groups, the Trimming Group and Non-Trimming Group. The day when allyl isothiocyanate was applied, along with hoof trimming, was set as Day 0. Lesion scores, pain, and the presence of Treponema-like spirochetes on the surface of hooves and in biopsy samples of the tissues were evaluated until Day 6. Both groups showed improvement of lesion scores and improved elimination of Treponema-like spirochetes from within the tissues. The presence of Treponema-like spirochetes on the surface of lesions was significantly higher in the Non-Trimming Group by Day 6. These results suggest that allyl isothiocyanate has therapeutic effects on Digital Dermatitis, when combined with hoof trimming, and may prevent a relapse of dermatitis and a re-infection of Treponema-like spirochetes.

A hollow fiber degassing membrane (DM) was applied to enhance organic matter degradation and methane gas production of anaerobic granular sludge process by reducing the dissolved hydrogen gas (D-H2) concentration in the liquid phase. DM was installed in the bench-scale anaerobic granular sludge reactors and D-H2 was removed through DM using a vacuum pump. Degasification improved the organic matter degradation efficiency to 79% while the efficiency was 62% without degasification at 12,000 mg L-1 of the influent T-COD concentration. Measurement of D-H2 concentrations in the liquid phase confirmed that D-H2 was removed by degasification. Furthermore, the effect of acetate concentrations on the organic matter degradation efficiency was investigated. At acetate concentrations above 3 g L−1, organic matter degradation deteriorated. Degasification enhanced the propionate and acetate degradation. These results suggest that degasification reduced D-H2 concentration and volatile fatty acids concentrations, prevented pH drop, and subsequent enhanced organic matter degradation.

An ionophore-doped sensing membrane phosphate (PO4) microsensor based on bis(dibromophenylstannyl)methane (Bis microsensor) is described. The Bis microsensor showed a Nernstian response. The response of the Bis microsensor was log-linear down to a monohydrogen phosphate ion (HPO42-) concentration of 0.5 μM (corresponding to 1.0 μM of orthophosphate at pH 7.2), whereas the detection limit of PO4-microsensors based on trialkyl/aryltin chloride was 50 μM of HPO42-. The Bis microsensor showed excellent selectivity for HPO42- against nitrite, nitrate, chloride, bicarbonate and sulfate, as compared with PO4 microsensors based on trialkyl/aryltin chloride. Dissolved oxygen, which is known to interfere with the response of a previously developed cobalt-based potentiometric solid-state PO4 microsensor, had no effect on the response of the ionophore-doped sensing membrane-type microsensors described herein. Only OH- (i.e., pH) interfered with the ionophore-doped sensing membrane-type microsensors.

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 &mu, g/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1&beta, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

This study aimed to investigate the effect of low prostate-specific antigen (PSA) on prognosis, as the association of initial PSA level with prognosis in patients with metastatic castration-naive prostate cancer (mCNPC) remains unclear.We evaluated 575 patients with mCNPC from 10 hospitals. Patients were stratified into 2 groups according to their initial PSA: PSA 100 and PSA ≥ 100 groups. We compared castration-resistant prostate cancer (CRPC)-free survival, overall survival (OS), and OS from the CRPC diagnosis between the groups. Multivariate Cox regression analysis was performed to evaluate the effect of initial PSA level on prognosis.Of the 575 patients, 196 (34%) patients belonged to the PSA 100 group. No significant difference was found in patients' backgrounds except for PSA, the extent of disease, and high tumor burden between the groups. CRPC-free survival was significantly shorter in the PSA ≥ 100 group than in the PSA 100 group. However, the OS after CRPC diagnosis was significantly shorter in the PSA 100 group than that of the PSA ≥ 100 group. Multivariate analyses showed that PSA 100 ng/mL was an independent factor for OS after CRPC, whereas no significant association was observed in the CRPC-free survival and OS.A significant effect of initial PSA 100 ng/mL on OS after CRPC was observed. PSA 100 ng/mL might be a poor prognostic factor in patients with mCNPC after CRPC.

Scaling of Si MOSFETs has proceeded based on scaling law reported by R. H. Dennard in 1974[1], and technologies scaled down to 5 nm node are currently incorporated in ICs in production. Meanwhile, according to an IEEE semiconductor roadmap[2], the 5-nm node device has a gate length of 18 nm, suggesting that scaling is reaching its limit. FETs using crystalline oxide semiconductor (OS), especially, c-axis-aligned crystalline (CAAC)-IGZO, are highly compatible with BEOL process of CMOS because OSFETs can be fabricated at 450°C or lower. Unlike bulk Si, OSFETs can adopt a trench-gate-self-aligned (TGSA) structure[3] enabling isolation from the substrate and accommodating chip bonding technologies. Crystalline oxide semiconductor process contributes to vertical integration required in the future technology. FETs using CAAC-IGZO is preferred to have a charge accumulation structure such as n-i(n-)-n junction (FIG. 1) in which its channel region, especially the region direct below the gate, has to be adjusted to have an i(n-)-type conductivity. Such a junction structure enables threshold voltage control and a reduction in leakage current of the FET. The leakage current of the CAAC-IGZO FET is extremely low, yA (10-24 A)/mm measured at the transistor level at 85°C, which is lower by 10 digits than that of a CMOS device[3]. A variety of applications using crystalline OS have been studied, including AI accelerators, high-resolution displays, nonvolatile memories and combination with sensors. Among them, an AI accelerator using crystalline OS has attracted attention[4]. Using crystalline OS enables memory to be placed near compute units. It can also be driven with low current; accordingly, improvement in computational efficiency is expected. Crystalline oxide semiconductor process is a promising technology enabling both high integration and lower power consumption of ICs with CMOS devices. ＜ Reference ＞ [1] R. H. Dennard et al., “Design of Ion-Implanted MOSFET’s with Very Small Physical Dimensions,” IEEE Journal of Solid-State Circuits, vol 9, Issue 5, pp.256-268, 1974. [2] International Roadmap for Devices and Systems (IRDS™) 2020 Edition, 2020. [3] H. Kunitake et al., “A c -Axis-Aligned Crystalline In-Ga-Zn Oxide FET With a Gate Length of 21 nm Suitable for Memory Applications,” IEEE J-EDS, vol. 7, pp. 495-502, 2019. Yamazaki et al., “Crystalline IGZO ceramics (crystalline oxide semiconductor)–based devices for artificial intelligence,” Ceramic Engineering & Science, vol. 1, Issue 1, pp.6-20, 2019. [4] D. Saito et al., “IGZO-Based Compute Cell for Analog In-Memory Computing—DTCO Analysis to Enable Ultralow-Power AI at Edge,” IEEE Transactions on Electron Devices, vol. 67, Issue 11, pp.4616-4620, 2020. FIG. 1: Electron holography analysis result of sample using crystalline OS. Figure 1

A 60-year-old woman was admitted to a medical clinic because of epigastric pain. Esophagogastroduodenoscopy revealed a submucosal tumor in the upper gastric corpus and, the tumor was subsequently resected using partial gastrectomy. The pathological findings revealed that the tumor was a gastrointestinal stromal tumor. After 4 months of observation without any adjuvant treatment, the patient was found to have liver metastasis and she was admitted to our hospital for treatment. We successfully treated the patient through sequential drug therapies, including imatinib, nilotinib, sunitinib, and regorafenib, and maintaining disease control for more than 5 years.

To analyze the relationship of blood metabolite concentrations and body condition score (BCS) with persistent bacterial uterine infection, specifically that caused by Trueperella pyogenes and anaerobic bacteria, uterine bacteriological swabs (n = 128) were collected from 64 Holstein cows at 5 (W5) and 7 (W7) weeks postpartum, and the percentage of neutrophils in the endometrium was evaluated. Blood glucose, total cholesterol (T-cho), blood urea nitrogen (BUN), non-esterified fatty acid (NEFA), and β-hydroxybutyric acid concentrations were analyzed at 3 weeks (W-3) and 1 week (W-1) prepartum and W3, W5, and W7 postpartum. BCS were evaluated at W-3, W3, and W7. Blood glucose concentrations at W-3 and W-1 in cows with persistent bacterial infection were lower (P = 0.05) than in the rest of the cows. Total BUN concentrations in cows with persistent bacterial infection were lower (P < 0.01) than those in other cows, although the association between the pre or postpartum time and status of infection was not significant. Total NEFA concentrations in cows with persistent bacterial infection were similar to those in uninfected cows and cows positive for infection at W5 but not W7. Total BCS in cows with persistent bacterial infection were lower (P < 0.01) than those in cows positive for infection at both W5 but not W7 and W7 but not W5; however, the association between the pre or postpartum time and status of infection was not significant. Glucose concentrations at W-3 and W-1 negatively correlated with persistent bacterial infection at W5 and W7 (P < 0.01). BUN concentrations at W3 (P < 0.01), W5 (P < 0.05), and W7 (P < 0.05) and BCS at W3 (P < 0.01) negatively correlated with persistent postpartum bacterial infection. Decreased prepartum blood glucose concentrations might be an important risk factor for persistent postpartum bacterial uterine infection in dairy cows.

Background: Incomplete cross-resistances between paclitaxel (PTX) and docetaxel (DTX) has been demonstrated in several types of cancer. The objective of the present study was to assess the existence of cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Methods: Patients in the PTX group received PTX without DTX pretreatment, patients in the prior DTX (Pr-DTX) group received PTX after the development of resistance to DTX, and patients in the DTX group received DTX without subsequent PTX treatment. Results: A total of 73 patients were enrolled. The response rates to PTX in the PTX and Pr-DTX groups were 22.7 and 20.0%, respectively. The median progression-free survival times from the first day of PTX treatment in the PTX and Pr-DTX groups were 113 (95% CI 56-154) and 97 days (95% CI 36-189), respectively. The median overall survival times from the first day of DTX treatment in the Pr-DTX and DTX groups were 315 (95% CI 124-453) and 148 days (95% CI 139-177), respectively. Conclusions: There is no or incomplete clinical cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Replacement of DTX with PTX is a suitable treatment option for patients with DTX-resistant esophageal squamous cell carcinoma.

Magnesium (Mg) ion implantation into gallium nitride (GaN) at 1000 °C is proposed. Since ion implantation and annealing occur simultaneously in high-temperature implantation, it is considered that Mg ions can be introduced at an appropriate position upon their implantation. GaN vertical diodes implanted with Mg ions were fabricated and current–voltage measurements were performed. As a result, clear rectifying properties were confirmed in a sample that was implanted with Mg ions at 1000 °C and annealed after implantation. However, the sample subjected to Mg ion implantation at RT and annealed after implantation showed no clear rectification. These results show that high-temperature implantation of Mg ions at 1000 °C reduces Mg ion implantation-induced damage and simultaneously activates Mg ions upon their implantation.

Hiroo Imai, Ken Saijo, Keigo Komine, Yoshifumi Kawamura, Sakura Hiraide, Sho Umegaki, Yoshinari Okada, Kota Ohuchi, Yuko Sato, Masahiro Takahashi, Shin Takahashi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan Purpose: Research has revealed that some patients who develop resistance to the first taxane treatment exhibit a moderate response to the second taxane treatment (incomplete cross-resistance between paclitaxel and docetaxel). However, which patients are most likely to respond to the second treatment remains unclear. The aim of this study was to determine the predictive factors for the efficacy of the second taxane treatment in patients resistant to the first.Patients and methods: We enrolled patients treated with paclitaxel and docetaxel (n=31) in this study. Using univariate and multivariate analyses, we determined the predictive factors for the efficacy of the second taxane treatment. Then, we assigned patients to one of the three groups: 1) those with a partial response (PR) to the first taxane treatment who subsequently became refractory (PR group); 2) those whose response was stable disease (SD) and subsequently became refractory (SD group); and 3) those whose response was the progression of the disease with the first taxane treatment (progression disease [PD] group). Furthermore, the response rates were assessed for each group. All statistical analyses were performed using JMP 11.Results: Responses to the first taxane treatment considerably correlated with the efficacy of the second treatment in patients with a PR to the first taxane treatment (P=0.0061, univariate analysis; P=0.0056, multivariate analysis). In addition, response rates to the second taxane treatment in the PR, SD, and PD groups were 33.3%, 0%, and 0%, respectively.Conclusion: The response to the first taxane treatment was a predictive factor for the efficacy of the second taxane treatment in patients with a PR to the first. Thus, the second treatment is highly recommended for patients who exhibit tumor shrinkage (a PR) by the first treatment. Keywords: taxane, predictive factor, univariate analysis, multivariate analysis

Background There has been growth in the treatment options for castration-sensitive metastatic prostate cancer (mPCa), but without clear guidance for risk stratification. Objective To identify clinical parameters associated with overall survival (OS) and establish a prognostic model for use with treatment-naive castration-sensitive mPCa. Design, setting, and participants A retrospective review of 304 patients treated at Kyoto University Hospital was performed. A prognostic model was created using clinical parameters associated with OS. The model was externally validated in an independent cohort of 520 patients. Outcome measurements and statistical analysis Multivariable analysis was performed to identify the clinical parameters associated with OS. Risk scores were calculated using Cox proportional hazards analysis for each combination of risk factors, and patients were grouped into categories based on those scores. Results and limitations Over 80% of the cohort had a Gleason sum score ≥8. The median OS was 53 mo among patients with CHAARTED high-volume PCa (n = 172) and 131 mo among those with low-volume PCa (n = 100). Independent factors associated with OS were extent of disease score ≥2 or the presence of liver metastasis; lactate dehydrogenase >250 U/L; and a primary Gleason score of 5. The median OS for the high-, intermediate-, and low-risk groups according to the new model were 28 mo, 59 mo, and not reached, respectively; the corresponding values in the validation cohort were 41 mo, 63 mo, and not reached. Harrell's C-index was 0.649. Conclusions Our simple and reproducible prognostic model for treatment-naive castration-sensitive mPCa could aid in risk stratification and treatment selection. Patient summary We identified clinical parameters associated with prognosis in castration-sensitive metastatic prostate cancer and established a reproducible prognostic model that could be used to guide treatment decisions.

Although the mechanical properties and compositions of lipid bilayer membranes can change upon deformation, the fundamental relations between the composition, membrane tension and fluidity of membranes with little curvature have not yet been studied. In the current study, the membrane tension and the diffusion coefficients of free-standing black lipid membranes (BLMs), based on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), were observed by systematic control of the cholesterol concentration and the osmotic pressure with the laser-induced surface deformation (LISD) and fluorescence recovery after photobleaching (FRAP) techniques. When the osmotic pressure was raised and, therefore, the curvature became larger, both the membrane tension and the diffusion coefficients increased as well. On the other hand, when the cholesterol concentration was raised, the membrane tension increased whereas the diffusion coefficient decreased. The importance of the present results goes beyond this quantitative evaluation of the relation between the membrane tension and the fluidity, as it clarifies the changes in the fundamental properties of lipid bilayers upon natural fluctuations and perturbative deformation that were hitherto unknown.

We developed an asymmetric fluorescent sensor 1 for Cu2+, based on 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY), by introducing 4-carboxyphenyl and bis(pyridin-2-ylmethyl)amine groups at the 5- and 3-positions, respectively, of the BODIPY core. We then investigated the photophysical and cation-sensing properties of the sensor. BODIPY 1 showed large absorption and fluorescence spectral shifts on binding to Cu2+. The fluorescence peak at 580 nm red-shifted to 620 nm. The binding stoichiometry of BODIPY 1 and Cu2+ was 1:3. The ratio of the fluorescence intensity at 620 nm to that at 580 nm (F620/F580) increased with increasing concentration of Cu2+ (3–10 equiv); this enabled ratiometric determination of Cu2+. Although BODIPY 1 showed good selectivity for Cu2+, there was an interfering effect of Fe3+. BODIPY 1 could be used for the naked-eye detection of Cu2+ in a water-containing sample.

Piezoluminescence and liquid crystallinity of anthracene-based bispyridinium salts were investigated in stimulus-responsive luminescent organic crystals and luminescent ionic liquid crystals. The salts possess an anthracene moiety as a fluorophore in their center, and the pyridiniums attached to the anthracene moiety are substituted with trialkoxybenzyl groups. Single crystals of the salts bearing two trimethoxybenzyl groups were obtained as solvates. Ethyl acetate, acetone, and dioxane solvates of the chlorides have almost the same crystal structures with one-dimensional channels. Grinding of the solvated crystals caused the extrusion of the included solvent molecules, which resulted in the red shifts of their fluorescence in the solid state. The dimethyl sulfoxide solvate of the hexafluorophosphate also showed piezoluminescene by grinding. Tris(octyloxy)benzyl and tris(dodecyloxy)benzyl derivatives exhibited rectangular columnar liquid crystals upon being heated for their bromide and tetrafluoroborate s...

Anthracene derivatives possessing a carbamate group and an ester group at their 9- and 10-positions, respectively, were prepared to furnish pairwise packing of anthracene fluorophores in their crystal structures. They were nonluminescent in ethanol solution and showed AIE (aggregation-induced emission) in aqueous ethanol solution and in solid state. Crystal structure analysis of them showed that the H-bonding networks involved in their crystal structures could be classified into four patterns, H-bonding between the carbamate and the ester carbonyl (motif A), H-bonding between the carbamate and the ester oxygen atom (motif B), H-bonded cyclic dimer of carbamate moieties (motif C), and H-bonded chain among carbamate moieties (motif D). Compounds with pairwisely packed anthracene fluorophores showed dimer emission with the longer fluorescence wavelength than others without the pair formation. Fluorescence maximum wavelengths and lifetimes become longer proportional to the degree of overlapping of two facing ...

Blood samples were obtained sequentially from 10 dairy cows around the time of parturition to assess plasma fluctuations in estradiol-17β (E2) levels in association with those of several bone resorption markers. Plasma E2 concentration increased sharply a few days prepartum and decreased quickly after parturition. In terms of bone resorption markers, the plasma level of tartrate-resistant acid phosphatase isoform 5b (TRAP5b) rose significantly, commencing 1 week prepartum, and was maintained at this level to a few days postpartum. The plasma concentration of carboxyterminal collagen cross-links of type-I collagen (CTx) increased significantly after parturition. These observations suggest that osteoclast-mediated bone resorption was activated after parturition when plasma E2 concentrations decreased.

Biaxial smectic A (SmAb) and biaxial nematic (Nb) liquid crystal (LC) phases using achiral straight-rod molecules were realized through perfluoroarene–arene (PFA–A) and CH/F interactions. Compounds 1a, 1b and 1c, 4,4′-bis(2,3,4-trifluorobenzoyloxy)biphenyl, 4,4′-bis(2,3-difluorobenzoyloxy)biphenyl and 4,4′-bis(2-fluorobenzoyloxy)biphenyl, were synthesized. The liquid crystallinity of these compounds was investigated using polarized light optical microscopy (POM) and differential scanning calorimetry (DSC). Furthermore, the ferroelectric switching behaviors of 1a in the nematic (N) and smectic A (SmA) LC phases and 1b in the N phase were confirmed by applying a triangular wave voltage in electro-optic experiments. Then, the values of spontaneous polarization (Ps) in the LC phases of 1a were investigated as functions of frequency, voltage, and temperature. It was strongly hypothesized that the semiperfluorinated phenyl (SFP) groups rotate around the molecular long axes and change pairs in the CH/F interacting sites, and this cooperative movement of the SFP groups is repeated during the switching process.

We report a histologically pure stage 1 seminoma with an elevated human chorionic gonadotropin (hCG). A 38 year-old man was referred for the evaluation of the left testicular swelling. He showed an elevated serum hCG level of 25,265 mIU/ml with normal a fetoprotein and lactate dehydrogenase. Imaging showed heterogeneous tumor without any metastatic lesions. We conducted 4 courses of chemotherapy before detecting hCG nadir. The final pathological report showed pure seminoma with syncytiotrophoblastic cells but no choriocarcinoma components. The patient remains disease free until present time. The case raised several questions regarding diagnosis and treatment strategy for bulky testicular seminoma.

The basal stem/progenitor cell maintains homeostasis of the epidermis. Progressive disturbance of this homeostasis has been implicated as a possible cause in the pathogenesis of epithelial disease, such as middle ear cholesteatoma. In many cases of stem/progenitor cell regulation, the importance of extracellular signals provided by the surrounding cells is well-recognized. Keratinocyte growth factor (KGF) is a mesenchymal-cell-derived paracrine growth factor that specifically participates in skin homeostasis; however, the overexpression of KGF induces middle ear cholesteatoma. In this study, two kinds of thymidine analogs were transferred at different time points and we investigated the effects of overexpressed KGF on the cell kinetics of stem/progenitor cells in vivo. As a result, BrdU(+)EdU(+) cells (stem/progenitor cells) were detected in the thickened epithelium of KGF-transfected specimens. The use of a high-resolution microscope enabled us to analyze the phosphorylated level of p63 in individual nuclei, and the results clearly demonstrated that BrdU(+)EdU(+) cells are regarded as progenitor cells. In the overexpression of KGF, the stimulation of progenitor cell proliferation was inhibited by SU5402, an inhibitor for tyrosine kinase of KGFR. These findings indicate that KGF overexpression may increase stem/progenitor cell proliferation and block terminal differentiation, resulting in epithelial hyperplasia, which is typical in middle ear cholesteatoma.

Phenylenediurea dibenzoic acid derivatives 1, 2, 3, and 5 and an amide derivative 4 were synthesized, and their molecular structures were elucidated to be an S-shape by single crystal X-ray analysis. Crystals of 1 were obtained as a DMF solvate, while those of 2 and 3 were not. Sheet and ladder structures were created in the crystal packing of 1 and 3, and 2, respectively. Unlike the para-substituted diureas 1–3 which possessed meso-conformation, the meta-substituted diurea 5 exhibited helical-conformation in its crystal structure. The way of crystal packing of 4 is analogous to that of the corresponding dicarboxylic acid derivative 2. A water cluster of a chair-shaped hexagonal array of water molecules was created in the crystal structure of 4. Diureas 1 and 2 gave cocrystals with melamine recrystallized from DMF/ethyl acetate and DMF/H2O, respectively. Unusual zigzag tapes of a H-bonding network of melamine were created in both cocrystals. The zigzag tapes were connected with S-shaped diureas by H-bondi...

The purpose of the study is to review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the hypopharynx and to evaluate the factors affecting survival and larynx preservation. Retrospective study. The records of 102 patients with Stage III or IV resectable SCC of the hypopharynx treated with CCRT between January 1998 and August 2010 were reviewed. Of the 102 patients, 62 were treated with high-dose regimens including cisplatin, 5-fluorouracil, methotrexate, leucovorin or docetaxel, cisplatin, and 5-fluorouracil. The remaining 40 were treated with low-dose regimens including carboplatin and uracil-tegafur, weekly docetaxel, or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray (Gy), to a total dose of 64.8–70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan–Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for OS, DSS, and DSS with larynx preservation. The 5-year OS and DSS for all patients treated with CCRT were 51.3 and 64.3 %, respectively. The 5-year DSS with larynx preservation was 55.5 %. On multivariate analysis, the content of chemotherapy was a significant predictor of OS and DSS for patients undergoing CCRT; N stage was a significant prognostic factor for DSS and larynx preservation. The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the N stages of SCC of the hypopharynx.

We have fabricated a back-channel-etched TFT using the CAAC-IGZO film that we developed. As a factor of success in manufacturing stable back-channel-etched TFTs, it is considered that CAAC-IGZO has a strong structure because of its crystallinity. For verification, we have compared the cohesive energy of c-IGZO and that of a-IGZO.

Two novel asymmetric BODIPY fluoroionophores with dipicolylamine (BDP-DPA, dipicolylamine: bis(pyridylmethyl)) and terpyridine (BDP-TPY) are described. These fluoroionophores display opposite wavelength responses on complexation with heavy metal ions. Furthermore, the fluorescence spectra vary depending on the ionic species. In particular, BDP-DPA shows a high affinity toward Cr3+ and upon complexation, the fluorescence spectrum blue-shifts from 591 to 566 nm. In contrast, BDP-TPY preferentially binds to Zn2+ and the fluorescence spectra red-shifts from 539 to 567 nm. BDP-TPY is the first example of asymmetric BODIPY with a pyridyl receptor at the 3 position showing redshifted fluorescence by complexation with metal ions. The concentration of each metal ion was successfully determined by ratiometric measurement. The wavelength-responses characteristics of these fluoroionophores could be very useful in the development of novel ratiometric fluoroionophores for metal ions.

Because the role of bone turnover during early to peak lactation in dairy cows is unclear, plasma levels of osteoclast- or collagen-specific bone resorption and osteoblast-specific bone formation markers from postpartum week 3 (W+3) to W+7 were compared with prepartum W-3 levels in multiparous (n = 15) and primiparous (n = 13) Holstein cows. The multiparous group showed a consistently low level of osteoclast-specific bone resorption markers, while collagen-specific resorption and osteoblast-specific formation markers decreased at postpartum W+7 and from W+5, respectively. In the primiparous group, the plasma levels of all three markers decreased from postpartum W+3. These results suggest that the calcium demand during the transition from early to peak lactation in dairy cows is less affected by bone turnover.

Feeding rumen bypass polyunsaturated fatty acids (PUFA) affects to Japanese Black cows affects their reproduction, though its influence on superovulatory response in donor cows and conception in recipient cattle has not been well studied. Here, we investigated the effects of feeding PUFA to Japanese Black cows on blood biochemistry, the numbers of ova and embryos or transferable embryos and pregnancy rate following embryo transfer (ET) to recipient Holstein heifers. PUFA (40% linoleic acid) was fed at 300 g/day in the experimental group from the last day of estrus until the day of artificial insemination for superovulatory treatment. Blood was collected on the first day of follicle-stimulating hormone administration. Total cholesterol level was significantly higher in the 15- to 19-day feeding group (117.4 mg/dl) than in the control group (95.0 mg/dl). The numbers of ova and embryos or transferable embryos were significantly higher in the 15- to 19-day feeding group than in the control group. The numbers of transferable embryos in the 15- to 19-day feeding group were significantly higher than in the 10- to 14-day feeding group. The pregnancy rate at day 60 was significantly higher in the experimental group (66.7 and 57.1%) than in the control group (51.1 and 44.0%) after transfer of fresh and frozen-thawed embryos, respectively. In conclusion, the numbers of ova and embryos or transferable embryos after superovulatory treatment increased, and the pregnancy rate after ET was higher in Japanese Black cows fed PUFA than in the control group.

2-Hydroxytryptanthrin (T2OH) and its sodium salt (sodium tryptanthrin-2-olate, T2ONa) were synthesized as near-infrared (NIR) dyes for fluorescent imaging. The absorption maxima (λ(a,max)) of T2OH under a pH range from 1.3 to 7.2 and from 8.5 to 10.6 were ca. 410 nm and ca. 495 nm, respectively. Moreover, the fluorescence maxima (λ(f,max)) were ca. 660 nm regardless of the pH range. T2ONa was water soluble and the λf,max were ca. 660 nm in both aprotic and protic solvents.

Single crystal X-ray structures of cocrystals, 1·2 and 1·3, derived from U-shaped ureadicarboxylic acid (1) with 2-aminopyrimidine (2) and melamine (3), respectively, were examined. Cocrystals were obtained as a 1:1 mixture of 1 and the corresponding base. Two molecules of 1 and two molecules of the base were combined together via intermolecular H-bonding creating a supramolecularly assembled cyclic heterotetramer motif of rhombus shape. In the case of cocrystal 1·3, the cyclic heterotetramers were connected via H-bonding by utilizing a remaining amino group of melamine resulting in the formation of a tape of cyclic heterotetramer.

Storage of natural gas (NG) is required for a range of applications. In this study, we succeeded to maintain NG within water cages of anomalously preserved NG hydrate crystal for more than three weeks under thermodynamically unstable conditions at 253 K and atmospheric pressure. This anomalous preservation phenomenon of NG hydrate pellet was measured quantitatively by powder X-ray diffraction and gas chromatography as well as measuring the change in weight caused by hydrate dissociation. In addition, two different types of phase contrast X-ray imaging techniques, X-ray interferometric imaging and diffraction enhanced imaging, also revealed that the NG hydrate was maintained inside the pellet. Also, scanning electron microscopy showed that the outer ice layer formed contained many pores while the internal microstructure of NG hydrate pellet was dense without pores. These experimental results suggest that formation of the outer ice layer may not be related to anomalous preservation of NG hydrate, but format...

Crystal structures of three zwitterionic bisimidazolium salts 1–3 in which imidazolium sulfonate moieties were connected with aromatic linkers, p-xylylene, 4,4′-dimethylenebiphenyl, and phenylene, respectively, were examined. The latter two were obtained as hydrates. An S-shaped molecular structure in which the sulfonate moiety was placed on the imidazolium ring was observed for 1. A helical array of hydrated water molecules was obtained for 2 while a linear array of hydrated water molecules was observed for 3.

In order to examine versatility of ureadicarboxylic acids as U-shaped building blocks for crystal engineering, their crystal structures and cocrystals with pyridine derivatives were investigated. H-bonding networks created by a sequential linking of H-bonded carboxylic acid dimers resulted in the formation of ladder-type networks in the crystals of N,N′-diethyl-N,N′-diphenylureadicarboxylic acid (2) and N,N′-diallyl-N,N′-diphenylureadicarboxylic acid (3). A zigzag type H-bonding network with wedging of water molecules into carboxy–carboxy H-bonding was observed for N,N′-dibenzyl-N,N′-diphenylureadicarboxylic acid (4). Cocrystals of N,N′-dimethyl-N,N′-diphenylureadicarboxylic acid (1) with 2,5-di(pyridine-4-yl)thiazolo[5,4-d]thiazole (5) and 2 with 4,4′-dipyridyl (6) afforded zigzag-type assembled structures. Two types of channel structures were created in the cocrystals of 1 and dipyridylurea (7) by inclusion of water molecules together with either methanol or ethanol. The former afforded a straight-type ...

Improved synthesis and reinvestigation of the magnetic properties of triphenylamine bearing three nitronylnitroxide radicals (1) were carried out. Single crystal X-ray crystallographic analysis of 1 established that its molecular shape had a C3-symmetry. Our newly prepared 1 showed different physical properties from those of reported. SQUID measurements of 1 showed that each of the three spins of 1 behaved independently at room temperature. In contrast, the three spins coupled antiferromagnetically at lower temperature as low as ca. 1.8 K. These spin behaviors can be explained by a regular triangular antiferromagnetic model (J/kB = −3.3 K) and interpreted as a spin frustration system.

Nondestructive observation of anomalously preserved methane (CH4) hydrate stored outside its thermodynamically stable zone below the melting point of ice was performed at 193 K. By use of two different types of phase contrast X-ray imaging techniques, X-ray interferometric imaging and diffraction enhanced imaging, it was shown that CH4 hydrate stored under anomalous preservation conditions was completely enveloped and stabilized by a thin layer of ice. The thickness of the ice layer was inhomogeneous, with an average thickness of about 100 μm after storage for 24 h at 253 K. These results obtained were consistent with quantitative analysis by means of powder X-ray diffraction and Raman spectroscopy. It was revealed that the interior of CH4 hydrate retained a high CH4 gas storage capacity even after one month under thermodynamically unstable conditions.

Organic crystals containing several types of water channels are generated by clipping water molecules with biszwitterionic imidazolium carboxylates as hydrogen-bonding acceptors. The types of water channels to be generated depend on the size and the shape of the aromatic spacers tethered with two imidazolium carboxylates moieties. Clusters of water tetramers and dimers were obtained from imidazolium carboxylates with phenylene (1) and naphthalene (2) linkers, respectively. The latter showed pseudopolymorphism, affording layers of water hexamers. Imidazolium carboxylate possessing biphenylene linker (3) afforded channels of discrete water tetramers.

Single crystal X-ray structures of three imidazolium salts were examined. In contrast to imidazolium salt 1 possessing an ester group which created a network of C H⋯halide–anion interactions with a linear array of imidazolium and the corresponding counter anions, unique network structures were observed in imidazolium salts 2 and 3 with long alkyl chains and with carboxy moieties, respectively. Water molecules were incorporated in their H-bonding networks. Water molecules were wedged into the two neighboring halide anions to create square units which acted as a bridge to connect the two adjacent C H⋯halide–anion networks of imidazolium moieties and counter anions.

Recent studies have been supporting that the generation of Aβ42 oligomers is responsible for Alzheimer's disease. Therefore, those peptides which bind to Aβ42 are scientifically interesting and can be possible candidates for the diagnosis and therapy of Alzheimer's disease. A systemic in vitro evolution, developed recently and the designated progressive library method (PLM), was applied to obtain Ab42-binding aptamers peptides. As a result, high affinity peptide aptamers made of 8 or 9 amino acids could be identified by this approach, endorsing the methodological effectiveness. Namely, the selection products from the secondary library of diversified peptides, which was constructed based on the information obtained from the primary library selection, were confirmed to be superior to those selected from the primary library as had been reported previously. The affinities of those peptides measured by SPR (surface plasmon resonance) were comparable to or higher than that of those peptides so far reported (K(d) of 10⁻⁷). The other peptides selected were confirmed of their binding by a novel mode of gel shift assay (fluorescence enhancement caused by the binding). Thus, novel Aβ42-binding peptides with high affinity were provided for the future Alzheimer's disease study. The demonstration of the effectiveness of the systemic in vitro evolution of PLM is very encouraging for the study of identifying novel functional peptides.