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Abstract Transparent, inorganic composite materials are of broad interest, from structural components in astronomical telescopes and mirror supports to solid-state lasers, smart window devices, and gravitational wave detectors. Despite great progress in material synthesis, it remains a standing challenge to fabricate such transparent glass composites with high crystallinity (HC-TGC). Here, we demonstrate the co-solidification of a mixture of melts with a stark contrast in crystallization habit as an approach for preparing HC-TGC materials. The melts used in this approach are selected so that glass formation and crystal precipitation occur simultaneously and synergistically, avoiding the formation of interfacial cracks, residual pores, and delamination effects. Using this method, various unusual hybridized HC-TGC materials such as oxychloride, oxybromide, and oxyiodide composite systems were fabricated in dense, bulk shapes. These materials exhibit intriguing optical properties and neutron response-ability. Using such HC-TGC materials, we develop a neutron detector and demonstrate the application for efficient neutron monitoring and even single neutron detection. We expect that these findings may help to bring about a generation of fully inorganic, transparent composites with synergistic combinations of conventionally incompatible materials.

Abstract Although an increased risk of myocarditis has been observed after vaccination with mRNA encoding severe acute respiratory syndrome coronavirus 2 spike protein, its underlying mechanism has not been elucidated. This study investigated the direct effects of spike receptor-binding domain (S-RBD) on human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs). Immunostaining experiments using ACE2 wild-type (WT) and knockout (KO) iPSC-CMs treated with purified S-RBD demonstrated that S-RBD was bound to ACE2 and internalized into the subcellular space in the iPSC-CMs, depending on ACE2. Immunostaining combined with live cell imaging using a recombinant S-RBD fused to the superfolder GFP (S-RBD-sfGFP) demonstrated that S-RBD was bound to the cell membrane, co-localized with RAB5A, and then delivered from the endosomes to the lysosomes in iPSC-CMs. Quantitative PCR array analysis followed by single cell RNA sequence analysis clarified that S-RBD-sfGFP treatment significantly upregulated the NF-kβ pathway-related gene (CXCL1) in the differentiated non-cardiomyocytes, while upregulated interferon (IFN)-responsive genes (IFI6, ISG15, and IFITM3) in the matured cardiomyocytes. S-RBD-sfGFP treatment promoted protein ISGylation, an ISG15-mediated post-translational modification in ACE2-WT-iPSC-CMs, which was suppressed in ACE2-KO-iPSC-CMs. Our experimental study demonstrates that S-RBD is internalized through the endolysosomal pathway, which upregulates IFN-responsive genes and promotes ISGylation in the iPSC-CMs.

Abstract Background Combination therapy with tazobactam/ceftolozane (TAZ/CTLZ) and high-dose aminoglycosides has been reported to be efficacious in extensively drug-resistant (XDR)-Pseudomonas aeruginosa infection. However, there are no reports of efficacy in XDR-P. aeruginosa infection for combination therapy with low-dose aminoglycosides and TAZ/CTLZ. Herein, we describe a rare case of severe burn injury patients with persistent bacteremia due to XDR-P. aeruginosa, which was successfully treated with TAZ/CTLZ and low-dose tobramycin (TOB). Case presentation A 31-year-old man was admitted to the intensive care unit with severe burn injury involving 52% of the total body surface area and a prognostic burn index of 79.5. The patient had recurrent bacterial infections since admission, and blood cultures collected on the 37th day of admission revealed the presence of P. aeruginosa strains that were resistant to all β-lactams and amikacin (AMK). The results of the antimicrobial synergistic study showed no synergistic effect of low-dose meropenem (MEPM) and AMK combination therapy. The patient had acute renal failure, and it was difficult to increase the dose of MEPM and AMK, respectively. Thus, we initiated TAZ/CTLZ 1.5 g/8 h instead of the AMK and MEPM combination therapy on the 43rd day of hospitalization. Low-dose TAZ/CTLZ was continued because of prolonged renal dysfunction and resulted in a transient clinical improvement. However, the dosage of TAZ/CTLZ could be increased as the renal function improved, but despite an increased TAZ/CTLZ dose, bacteremia persisted, and the blood cultures remained positive. Thus, TOB was added to TAZ/CTLZ at low doses for synergistic effect against Gram-negative bacteria. Blood cultures collected after initiation of combination therapy with TAZ/CTLZ and low-dose TOB were negative on two consecutive follow-up evaluations. Thereafter, although the patient had several episodes of fever and increased inflammatory response, blood cultures consistently tested negative, and all of the wounds healed. On the 93rd day, due to the good healing progress, the patient was transferred to another hospital. Conclusions TAZ/CTLZ and low-dose TOB combination therapy showed the potential for synergistic effects. Our present report suggests a novel synergistic treatment strategy for rare cases that are refractory to the treatment of infections, such as XDR-P. aeruginosa infection.

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Innovative treatment is required to improve overall survival rates for advanced NSCLC. Oncolytic virotherapy using enteroviruses has emerged as a promising anticancer strategy. To identify a novel, potent virotherapy with an improved safety profile, we assessed the oncolytic activity of 28 enteroviral strains and focused on coxsackievirus A11 (CVA11). CVA11 infection caused extensive oncolytic activity in all three of the examined human NSCLC cell lines, with high intercellular adhesion molecule-1 (ICAM-1) expression associated with greater CVA11-induced cytotoxicity. In vitro inhibition analysis using a pan-caspase inhibitor and western blot detection of cleaved poly (ADP-ribose) polymerase (PARP) indicated that apoptosis partly contributed to CVA11-driven cytotoxicity. CVA11 infection-induced immunogenic cell death in vitro was strongly suggested by substantial calreticulin expression and release of high mobility group box-1 protein (HMGB1). Moreover, in vivo treatment of human NSCLC xenografts with intratumoral CVA11 injection caused complete tumor regression in all treated mice, without significant weight loss. Our findings indicate that novel oncolytic virotherapy utilizing CVA11 may be less toxic and more effective than current treatments for human NSCLC, thus warranting further investigation in clinical trial settings, especially in combination with immunotherapy.

Connected and Autonomous Vehicles (CAVs) offer improved efficiency and convenience through innovative embedded devices. However, the development of these technologies has often neglected security measures, leading to vulnerabilities that can be exploited by hackers. Conceding that a CAV system is compromised, it can result in unsafe driving conditions and pose a threat to human safety. Prioritizing both security measures and functional enhancements on development of CAVs is essential to ensure their safety and reliability and enhance consumer trust in the technology. CAVs use artificial intelligence to control their driving behavior, which can be easily influenced by small changes in the model that can significantly impact and potentially mislead the system. To address this issue, this study proposed a defense mechanism that uses an autoencoder and a compressive memory module to store normal image features and prevent unexpected generalization on adversarial inputs. The proposed solution was studied against Hijacking, Vanishing, Fabrication, and Mislabeling attacks using FGSM and AdvGAN against the Nvidia Dave-2 driving model, and was found to be effective, with success rates of $$93.8\% $$ and $$91.2\% $$ in a Whitebox setup, and $$74.1\% $$ and $$64.4\% $$ in a Blackbox setup for FGSM and AdvGAN, respectively. That improves the results by $$24.7\% $$ in Whitebox setup $$21.5\% $$ in Blackbox setup.

Abstract Background Recently, there has been an increase in the number of reports of needle tract seeding (NTS) of tumor cells after a biopsy as one of the adverse events related to endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). In most of the previously reported cases of NTS in pancreatic cancer, distal pancreatectomy was performed as the initial surgery, following which metachronous metastasis was discovered in the gastric wall, whose localization matched the puncture route of the EUS-FNA. We report a case of early metastasis from pancreatic cancer in the gastric wall, which was postulated to be caused by NTS. Our patient underwent a total pancreatectomy (TP), and the NTS was resected synchronously. Case presentation A 70-year-old woman with a diagnosis of pancreatic head-body-tail cancer presented to our department for surgery. Transgastric EUS-FNA and biopsy established the histological diagnosis in her case. We administered neoadjuvant chemotherapy (NAC) to the patient and performed a TP. Histopathological and immunohistochemical examination subsequently confirmed the diagnosis of pT3N1aM1 pancreatic adenocarcinoma and its gastric metastasis, which was caused by NTS. It is postulated that the tumor cells of NTS had progressed to develop the metastatic lesion in the gastric wall during the NAC period. This was also resected during the initial surgery. The patient developed an early postoperative recurrence in the peritoneum 8 months after the surgery. Conclusion In pancreatic head cancer cases, the puncture route is often included in the resection area of radical surgery, and NTS is seldom considered as a potential clinical problem. However, NTS can progress rapidly and may be associated with early recurrence of malignancy. Therefore, when transgastrointestinal puncture is performed for the diagnosis of pancreatic cancer, the treatment strategy should be established considering the potential development of NTS.

In recent years, legislation and standardization of cyber security management for cyber-physical systems such as automotive systems have been progressing steadily. ISO/SAE 21434, published in 2021, addresses the management and analysis of electrical systems within road vehicles from a cybersecurity perspective. It also recommends some methods for the threat analysis and risk assessment (TARA) process. However, there are two problems in the evaluation methods derived from conventional security analysis approaches. One problem is related to the insufficient evaluation of attack feasibilities for cyber-physical systems by the CVSS-based approach. Another problem is the unclear relationship between damage factors in analyzing the impact of damage to each asset. In this paper, we focus on the TARA process, and apply an “asset container” method for threat classification, proposed by the authors at DECSoS 2017, and a CWSS-based risk quantification method. Moreover, we can also add some perspective to improve risk evaluation suitable for automotive systems. Following our past studies on methodologies to evaluate the risk of such special cyber-physical systems, we can quantify risks limited to some cyber-physical systems, such as direct access attacks to in-vehicle networks.

Abstract Background In patients with severe coronavirus disease (COVID-19), the use of acrylonitrile hemofilters can reduce cytokine concentrations. However, acrylonitrile hemofilters can easily coagulate, and the effect of hemofilters on improvement in patient prognosis remains unclear. Therefore, we aimed to investigate the changes in serum cytokine concentrations, alleviation of organ damage, and improvement in patient prognosis with continuous renal replacement therapy (CRRT) using a cellulose triacetate (CTA) filter with excellent anticoagulation property in patients with severe COVID-19. Methods This was a retrospective, single-center study conducted by the Advanced Critical Care Center in Sapporo Medical University Hospital, Japan. Seven patients with severe COVID-19 between March 01 and June 30, 2020, were included. The patients were under mechanical ventilation and received continuous blood purification therapy with a CTA filter. We summarized the CRRT status and patient prognosis and measured their serum cytokine (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ) and serum marker levels, before and after CRRT. In addition, we evaluated the changes in their respiratory status, hemodynamics, and organ dysfunction scores. The average age of the patients was 61.5 years, and five patients were male. Extracorporeal membrane oxygenation was used in five patients. The treatment outcome included three deaths. Results The median CRRT duration was 7 days. The hemofilter was replaced once a day. After CRRT, the IL-6 concentration decreased from 393 to 85 pg/mL (p = 0.016), the Krebs von den Lungen-6 concentration decreased from 554 to 350 U/mL, and the PaO2/FiO2 ratio increased significantly from 90 to 248, and therefore, oxygenation improved. In addition, the norepinephrine dose and lactate level decreased, and the circulation tended to improve; however, the renal function and Sequential Organ Failure Assessment score did not change. Conclusions The serum IL-6 level decreased, and the respiratory status improved upon CRRT using a CTA filter in patients with severe COVID-19.

Abstract Purpose A distal femoral trial component was manufactured, and flexion gap size and inclination were evaluated with or without the distal femoral trial component in total knee arthroplasty (TKA). This study aimed to evaluate the effect of the distal femoral trial component on flexion gap size and joint inclination in posterior-stabilized (PS)-TKA. Materials and methods A total of 84 patients with medial osteoarthritis who underwent mobile-bearing PS-TKA using modified gap techniques were included in this retrospective study. The flexion gap size and inclination before and after setting the distal femoral trial component were evaluated and compared with the final gap size and inclination. Results The joint gap size and inclination were significantly lower in those with than in those without the distal femoral trial component (P = 0.005, P

The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes. Particular focus has been placed on “gene-environment interactions” in the development of a reduced pancreatic β-cell mass, as well as type 1 and type 2 diabetes mellitus. Changes in the intrauterine environment, such as intrauterine growth restriction, contribute to alterations of gene expression in pancreatic β-cells, ultimately resulting in the development of pancreatic β-cell failure and diabetes. As a molecular mechanism underlying the effect of the intrauterine environment, epigenetic modifications have been widely investigated. The association of diabetes susceptibility genes or dietary habits with gene-environment interactions has been reported. In this review, we provide an overview of the role of gene-environment interactions in pancreatic β-cell failure as revealed by previous reports and data from experiments.

Abstract Background Pulmonary vein (PV) reconnection is the main cause of atrial fibrillation (AF) recurrence. This study aimed to examine the effect of first‐pass PV isolation (PVI) on PV reconnection frequency during the procedure and on AF ablation outcomes. Methods This retrospective study included 446 patients with drug‐refractory AF (370 men, aged 64 ± 10 years) who underwent initial PVI using an open‐irrigated contact force catheter between January 2015 and October 2016. We investigated the effect of first‐pass PVI on PV reconnection during spontaneous PV reconnection and dormant conduction after an adenosine triphosphate challenge. Results First‐pass PVI was achieved in 69% (617/892) of ipsilateral PVs, of which we observed PV reconnection during the procedure in 134 (22%) PVs. This value was significantly lower than that observed in those without first‐pass PVI (50%, 138/275) (P

Abstract A 72‐year‐old man, diagnosed with advanced lung squamous cell carcinoma, was administered of cisplatin plus gemcitabine with necitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), as a sixth‐line treatment. Tumor shrinkage was observed, but asymptomatic grade 4 hypomagnesemia occurred on day 8 of the second cycle. He received magnesium replenishment and hypomagnesemia recovered on day 40, but tumor progression was observed during the period of magnesium correction. Hypomagnesemia is known as a major adverse event of treatment with anti‐EGFR antibodies, but there have been no case reports of severe hypomagnesemia or its clinical course.

Abstract Background Since inflammation and the immune system contribute to the development and progression of malignancies, parameters that reflect a host’s immune-inflammatory status may be useful prognostic indicators of gastric cancer (GC). The present study examined the clinical significance of a preoperative systemic immune-inflammation index (SII) for predicting postoperative survival outcomes in GC. Methods A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. SII was calculated as platelet count × neutrophil count/lymphocyte count. The prognostic impact of preoperative SII was examined using univariate and multivariate analyses. Results Preoperative SII ranged between 105 and 4455 (median 474), and the optimal cutoff value for predicting overall survival (OS) was 395 based on a receiver operating characteristic curve. The 5-year OS rate of the SII ≥ 395 group was 80.0%, which was significantly worse than that (92.7%) of the SII < 395 group (p < 0.001). The multivariate analysis identified SII ≥ 395 (hazard ratio [HR] 2.95; 95% confidence interval [CI] 1.49–6.39; p = 0.001), heart disease (HR 2.14, 95% CI 1.07–4.07), C-reactive protein ≥ 0.5 (HR 2.45, 95% CI 1.15–4.94), pT4 (HR 4.46, 95% CI 2.44–8.14), and pN+ (HR 4.02, 95% CI 2.10–7.93) as independent predictors of worse OS. Peritoneal recurrence was more frequent in the high SII group than in the low SII group (p = 0.028). Conclusion Preoperative SII may be a useful predictor of postoperative survival outcomes in GC. The meticulous surveillance of GC relapse, particularly peritoneal dissemination, is necessary for patients with SII ≥ 395 even after curative gastrectomy.

Abstract Background In total knee arthroplasty (TKA) using the modified gap technique, the soft-tissue balance is measured after osteotomy of the distal femur and proximal tibia (conventional bone gap). However, after osteotomy, the flexion gap size during 90° knee flexion may be larger than that observed after implantation. The tension of the lateral compartment during 90° flexion may also be reduced after osteotomy of the distal femur. We manufactured a distal femoral trial component to reproduce the condition after implantation and prior to posterior condyle osteotomy. This study aimed to evaluate the effect of the trial component on the flexion gap. Methods This prospective study included 21 consecutive patients aged 78 years with medial osteoarthritis who underwent cruciate-retaining TKA between February 2017 and March 2018. The postoperative flexion gap size and inclination during 90° flexion were compared between cases with and without the trial component. Results The mean joint gap size with the trial component (13.4 ± 0.80 mm) was significantly smaller than that without the trial component (14.7 ± 0.84 mm). The mean gap inclination angle with the trial component (3.7° ± 0.62°) was significantly smaller than that without the trial component (5.5° ± 0.78°). Conclusions In the present study, the joint gap size and medial tension were significantly reduced after the trial component had been set. Accurate measurement of the soft-tissue balance is an important factor in the modified gap technique, and this method using a distal femoral trial component can offer better outcomes than those achieved with conventional methods.

In this study, we anodized a TiNbSn alloy with low Young’s modulus in an electrolyte of sodium tartrate with and without hydrogen peroxide (H2O2). The photo-induced characteristics of the anodized alloy were analyzed for crystallinity and electrochemical conditions with comparisons to the effect with the addition of H2O2. The antibacterial activity was evaluated using methicillin-resistant Staphylococcus aureus and other pathogenic bacteria according to ISO 27447, and time decay antibacterial tests were also conducted. The anodized oxide had a porous microstructure with anatase- and rutile-structured titanium dioxide (TiO2). In contrast, the peaks of rutile-structured TiO2 were accelerated in the anodized TiNbSn alloy with H2O2. The formation of hydroxyl radicals and methylene blue breaching performance under ultraviolet irradiation was confirmed in the anodic oxide on TiNbSn alloy with and without H2O2. The anodic oxide on TiNbSn alloy had a robust antibacterial activity, and no significant difference was detected with or without H2O2. We conclude that anodized TiNbSn alloy with sodium tartrate electrolyte may be a functional biomaterial with a low Young’s modulus and an antibacterial function.

Abstract Crustal earthquake ruptures tend to initiate near fluid-rich zones. However, it is relatively unknown whether fluid-rich zones can further promote or arrest these ruptures. We image the electrical resistivity structure around the focal area of the 2016 Kumamoto earthquake sequence by using 200 sites broadband magnetotelluric data, and discuss its quantitative relationship to earthquake initiation, growth, and arrest processes. The ruptures that initiated along the outer edge of the low-resistivity fluid-rich zones ( 400 °C) fluid-rich zones, whereas shallower low-temperature (200–400 °C) fluid-rich zones either promoted or arrested the ruptures. These results suggest that the distribution of mid-crustal fluids contributes to the initiation, growth, and arrest of crustal earthquakes. The pre-failure pressure/temperature gradient (spatial difference) of the pore fluids may contribute to the rupture initiation, propagation, and arrest.

TiNbSn alloy is a high-performance titanium alloy which is biosafe, strong, and has a low Young’s modulus. TiNbSn alloy has been clinically applied as a material for orthopedic prosthesis. Anodized TiNbSn alloys with acetic and sulfuric acid electrolytes have excellent biocompatibility for osseointegration. Herein, TiNbSn alloy was anodized in a sulfuric acid electrolyte to determine the antimicrobial activity. The photocatalytic activities of the anodic oxide alloys were investigated based on their electronic band structure and crystallinity. In addition, the cytotoxicity of the anodized TiNbSn alloy was evaluated using cell lines of the osteoblast and fibroblast lineages. The antimicrobial activity of the anodic oxide alloy was assessed according to the ISO 27447 using methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. The anodic oxide comprised rutile and anatase titanium dioxide (TiO2) and exhibited a porous microstructure. A well-crystallized rutile TiO2 phase was observed in the anodized TiNbSn alloy. The methylene blue degradation tests under ultraviolet illumination exhibited photocatalytic activity. In antimicrobial tests, the anodized TiNbSn alloy exhibited robust antimicrobial activities under ultraviolet illumination for all bacterial species, regardless of drug resistance. Therefore, the anodized TiNbSn alloy can be used as a functional biomaterial with low Young’s modulus and excellent antimicrobial activity.

Background Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non‐small cell lung cancer (NSCLC) to prognosis. Methods We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay. Results Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease‐free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for disease‐free survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively. Conclusions Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells. Key points Significant findings of the study We found that high MOB1 expression in surgical specimens of lung adenocarcinoma was associated with poor disease‐free survival and with intratumoral vascular invasion. MOB1 expression also promoted the invasiveness of NSCLC cells in vitro. What this study adds Our results thus suggest that high MOB1 expression is a risk factor for early postoperative recurrence in lung adenocarcinoma.

A new low-temperature magnetic Bi2O3-CoO-Fe2O3-B2O3 (BCFB) glass was designed to acquire magnetic yttrium iron garnet (YIG/YIG) joint. This paper investigated the thermal behavior of BCFB glass and its wettability on YIG. The microstructural evolution, mechanical and electromagnetic properties of YIG/YIG joint were systematically studied. CoFe2O4 nuclei were gradually formed, growing up into nano-scale CoFe2O4 crystals in the glass seam. Meanwhile, some CoFe2O4 crystals grew up excessively by swallowing nano CoFe2O4, reaching microns. YBO3 reaction layer was formed and grew into YBO3 whiskers at the interface of YIG/glass with the brazing temperature increasing. The joint shear strength increased, reaching a maximum of 85.2 MPa at 775 °C under the collaborative reinforcement of well-integrated interface and glass-ceramic seam, then declined due to the aggravative reaction. The dielectric constant of YIG/YIG joints decreased with the brazing temperature increasing, varying from 18.5 to 16.6 at the frequency of 10 MHz. AFM/MFM and VSM analyses indicate that the glass seam performed magnetic property. The saturation magnetization of BCFB glass reached about 4.2 emu/g and 5.0 emu/g heat-treated at 750 °C and 775 °C, respectively, which could effectively enhance the magnetism of the glass seam.

Abstract Aims/Introduction Mean platelet volume (MPV) is a widely used biological marker of platelet function and activity. Increased MPV is associated with accelerated thrombopoiesis and an elevated risk of cardiovascular disease. However, it is not known whether higher MPV is related to the pathogenesis of type 2 diabetes and diabetic macrovascular complications in Japanese patients. Therefore, we analyzed MPV and its correlation with atherosclerosis in Japanese patients with type 2 diabetes and those who had prediabetes. Materials and Methods We divided the patients into three groups: normoglycemic patients (n = 56), prediabetes patients (n = 44) and type 2 diabetes patients group, (n = 115). We measured platelet parameters and evaluated arterial stiffness in the three groups. Results Significantly higher MPV was found in the type 2 diabetes mellitus and prediabetes patients compared with normoglycemic patients. MPV was significantly correlated with fasting blood glucose and glycated hemoglobin levels. Multiple linear regression analysis showed that MPV was positively correlated with HbA1c, even after adjustment for confounding factors. In the evaluation of arterial stiffness by measuring the cardio‐ankle vascular index and maximum intima‐media thickness, MPV showed a positive correlation with these parameters. Conclusions These findings suggest that MPV was significantly increased in the early stage of type 2 diabetes. We showed positive correlations between MPV and HbA1c levels, and between MPV and arterial stiffness in Japanese patients with type 2 diabetes.

Abstract Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.

Xylanase B, a member of subfamily 7 of the GH30 (glycoside hydrolase family 30) from Talaromyces cellulolyticus (TcXyn30B), is a bifunctional enzyme with glucuronoxylanase and xylobiohydrolase activities. In the present study, crystal structures of the native enzyme and the enzyme–product complex of TcXyn30B expressed in Pichia pastoris were determined at resolutions of 1.60 and 1.65 Å, respectively. The enzyme complexed with 22‐(4‐O‐methyl‐α‐d‐glucuronyl)‐xylobiose (U4m2X) revealed that TcXyn30B strictly recognizes both the C‐6 carboxyl group and the 4‐O‐methyl group of the 4‐O‐methyl‐α‐d‐glucuronyl side chain by the conserved residues in GH30‐7 endoxylanases. The crystal structure and site‐directed mutagenesis indicated that Asn‐93 on the β2‐α2‐loop interacts with the non‐reducing end of the xylose residue at subsite‐2 and is likely to be involved in xylobiohydrolase activity. These findings provide structural insight into the mechanisms of substrate recognition of GH30‐7 glucuronoxylanase and xylobiohydrolase.

Controller Area Network (CAN) is a de facto standard of in-vehicle networks. Since CAN employs broadcast communication and a slower network than other general networks (e.g. Ethernet, IEEE802.11), it is inherently vulnerable to Denial-of-Service (DoS) attacks. As a countermeasure against DoS attacks on CAN, a method for detecting a DoS attack using the entropy in a sliding window has been proposed. This method has a good advantage in terms of effectiveness and the small computational overhead. However, this method may only be effective against DoS attacks under naive conditions such as some higher priority messages. In addition, if an adversary can adjust the entropy of the DoS attack to its normal value, the conventional method cannot detect a DoS attack in which the adversary manipulates the entropy. We found this type of DoS attack, which is called an entropy-manipulated attack. In this paper, we propose a method that can detect an entropy-manipulated attack by using the similarity of two sliding windows. We confirmed that the proposed method detected the DoS attack in 100% of the cases in our experiment, and we showed that the detection time is up to 93% (14 μs) shorter than the conventional method.

The modern automobile is a complex piece of technology that uses the Controller Area Network (CAN) bus system as a central system for managing the communication between the electronic control units (ECUs). Despite its central importance, the CAN bus system does not support authentication and authorization mechanisms, i.e., CAN messages are broadcast without basic security features. As a result, it is easy for attackers to launch attacks at the CAN bus network system. Attackers can compromise the CAN bus system in several ways including Denial of Service (DoS), Fuzzing and Spoofing attacks. It is imperative to devise methodologies to protect modern cars against the aforementioned attacks. In this paper, we propose a Long Short-Term Memory (LSTM)-based Intrusion Detection System (IDS) to detect and mitigate the CAN bus network attacks. We generate our own dataset by first extracting attack-free data from our experimental car and by injecting attacks into the latter and collecting the dataset. We use the dataset for testing and training our model. With our selected hyper-parameter values, our results demonstrate that our classifier is efficient in detecting the CAN bus network attacks, we achieved an overall detection accuracy of 99.995%. We also compare the proposed LSTM method with the Survival Analysis for automobile IDS dataset which is developed by the Hacking and Countermeasure Research Lab, Korea. Our proposed LSTM model achieves a higher detection rate than the Survival Analysis method.

Summary: The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

BackgroundPancreatic cancer is associated with high mortality and its rates of detection are very low; as such, the disease is typically diagnosed at an advanced stage. A number of risk factors for pancreatic cancer have been reported and may be used to identify individuals at high risk for the development of this disease. ObjectiveThe aim of this prospective, observational trial is to evaluate a scoring metric for systematic early detection of pancreatic cancer in Mie Prefecture, Japan. MethodsEligible patients aged 20 years and older will be referred from participating clinics in the Tsu City area to the Faculty of Medicine, Gastroenterology, and Hepatology at Mie University Graduate School, until September 30, 2022. Participants will undergo a detailed examination for pancreatic cancer. Data collection will include diagnostic and follow-up imaging data and disease staging information. ResultsThe study was initiated in September 2020 and aims to recruit at least 150 patients in a 2-year period. Recruitment of patients is currently still underway. Final data analysis is expected to be complete by March 2025. ConclusionsThis study will provide insights into the feasibility of using a scoring system for the early detection of pancreatic cancer, thus potentially improving the survival outcomes of diagnosed patients. Trial RegistrationUMIN-CTR Clinical Trials Registry UMIN000041624; https://tinyurl.com/94tbbn3s International Registered Report Identifier (IRRID)DERR1-10.2196/26898

Background: Pemetrexed is a key drug in chemotherapy for nonsquamous non-small-cell lung cancer (nonsq NSCLC). Several studies have reported thyroid transcription factor-1 (TTF-1) as a biomarker of the efficacy in chemotherapy regimens, including pemetrexed in non-Asian people. Objective: We aimed to examine the impact of the results of the TTF-1 immunostaining of tumor cells on the therapeutic effect of chemotherapy in Japanese patients with nonsq NSCLC. Methods: We examined the results of TTF-1 immunostaining and the clinical background of Japanese patients with nonsq NSCLC who received platinum-doublet chemotherapy at our hospital, from April 2009 to April 2021, and the correlation between regimens with or without pemetrexed in progression-free survival (PFS) and overall survival (OS). The efficacy of each regimen was then compared between TTF-1-positive and TTF-1-negative tumors. Results: TTF-1 immunostaining was performed in 145 patients during the study period: 92 were positive, and 53 were negative. A total of 24 patients presented with EGFR/ALK gene abnormality (16.6%). The PFS and OS of patients who were TTF-1-positive tended to be longer than those of the patients who were TTF-1-negative under either regimen. In other words, patients who were TTF-1-negative were frequently resistant to numerous chemotherapy drugs and experienced a poor prognosis under both regimens. The OS of patients who were TTF-1-positive and treated with the pemetrexed regimen was significantly longer than those on regimens without pemetrexed (963 vs. 412 days, HR = 0.73; 95% CI 0.55–0.96, p = 0.022), whereas there was no difference in PFS. Conclusions: The positivity of TTF-1 immunostaining in tumors could be a predominant prognostic marker for patients who have advanced nonsq NSCLC. Our analysis examined the possibility of a pemetrexed regimen leading to a longer prognosis in Asian patients who were TTF-1-positive for nonsq NSCLC, as shown in previous studies.

Introduction Neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NAC/NACRT) for resectable/borderline resectable pancreatic cancers was recently performed to improve clinical outcomes and led to good results, although it remains controversial whether NAC/NACRT is beneficial for resectable pancreatic cancer. A few recent studies revealed longer patency and lower cost related to the stent occlusion of a metal stent than those of a plastic stent during NAC/NACRT. It also remains controversial which type of self-expandable metal stent (SEMS) is the most suitable for patients with resectable/borderline resectable pancreatic cancer during NAC/NACRT: an uncovered SEMS (USEMS), a fully covered SEMS (FCSEMS) or a partially covered SEMS (PCSEMS). So far, two randomised controlled trials indicated that a USEMS and an FCSEMS were similar in preoperative stent dysfunction and adverse event rate. Thus, we aimed to verify the non-inferiority of a PCSEMS to a USEMS in this multicentre randomised controlled trial.Methods and analysis We designed a multicentre randomised controlled trial, for which we will recruit 100 patients with resectable/borderline resectable pancreatic cancer and distal biliary obstruction scheduled for NAC/NACRT from 13 high-volume institutions. Patients will be randomly allocated to the PCSEMS group or USEMS group. The primary outcome measure is the preoperative biliary event rate. Data will be analysed after completion of the study. We will calculate the 95% CIs of the incidence of preoperative biliary events in each group and analyse whether the difference between them is within the non-inferiority margin (10%).Ethics and dissemination This study has been approved by the institutional review board of Hokkaido University Hospital. The results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal.Trial registration number UMIN000041737; jRCT1012200002.

Abstract During the past two decades, studies of the Aso volcano in Japan have improved our understanding of the shallow hydrothermal system that exists beneath the active crater of this volcano. Detailed knowledge of the subsurface structure of this volcanic edifice is essential for developing a better understanding of the behavior of the volcanic fluids and of the triggering mechanism of volcanic eruptions. Here, we report a three-dimensional (3-D) electrical resistivity model for the active crater of the Nakadake central cone of Aso volcano using audio-frequency magnetotelluric (AMT) data obtained during 2004–2005. The AMT data were collected at 43 sites on a grid (distance between grid points: ~ 300 m) around the crater. However, as yet, only two-dimensional sectional resistivity models have been generated for this survey area. Using 3-D inversion, we obtain a resistivity model that shows similar characteristics to those of the 2-D models. A highly conductive zone is observed beneath the active crater down to a depth of approximately 300 m. Based on the recent findings regarding the shallow hydrothermal system of the volcano, we interpret this conductive zone to have been formed by highly conductive acidic fluids filling a fractured region. This view modifies the past interpretation made on the 2-D models and promotes understanding of fluid behavior beneath the active crater.

Abstract Strombolian explosions are one of the most studied eruptive styles and are characterized by intermittent explosions. The mechanism of a Strombolian explosion is modeled as a large gas pocket (slug) migrating through the magma conduit and then bursting at the air–magma interface. These ascending and bursting processes of the slug induce characteristic seismo-acoustic signals during each explosion: very-long-period (VLP) seismic signals, eruption earthquake signals, and infrasound signals. However, at Stromboli volcano, it has been reported that the ascent velocity estimated from the time differences between observed signals is nearly an order of magnitude higher than that expected from laboratory experiments simulating slug ascent. This discrepancy between observation-based and experiment-based velocities has not yet been fully explained and strongly suggests that the conventional model of Strombolian explosions should be partially revised. In this study, we attempted to validate the model of Strombolian explosions by estimating the gas phase velocity in the conduit in the case of Aso volcano. We recorded seismo-acoustic signals accompanying Strombolian events at Aso volcano, Japan, in late April 2015 via our monitoring network, and the ascent velocity of the gas phase was determined from the difference in arrival times between the VLP signals and the infrasound signals. Our estimated velocity exceeded 100 m/s, which is much faster than the experimental value of 7.5 m/s predicted for Aso volcano. To explain this rapid ascent velocity, we propose a revised model describing the migration of the gas phase via a more complicated mechanism, such as annular flow. In this model, we assumed that the gas phase ascends in the conduit at high velocity while making a pathway leading to the magma surface, most likely due to a temporary increase in the gas flux. Our model will help to deepen the understanding of the complicated dynamics in the magma conduit during a Strombolian explosion.

Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes.

Abstract Background In cases of severe accidental hypothermia, it was recommended that resuscitation should be continued until the patient has rewarmed, as hypothermia itself can preserve cerebral function, and hypothermic cardiac arrest is reversible. During cardiopulmonary resuscitation for normothermic patients, muscle rigidity suggests the initiation of postmortem changes such as rigor mortis and can lead to the termination of resuscitation. Currently, the prognosis of cardiac arrest due to severe accidental hypothermia accompanied by rigidity is unknown. Case presentation A 29-year-old woman was found unresponsive near a snowy mountain trail. Upon discovery, she was found to be in cardiac arrest with an initial asystole rhythm and exhibited mandibular rigidity. On admission, her core temperature was 22 °C. Although cardiac arrest continued, and she showed no response to normal resuscitation, blood gas analysis revealed that her initial serum potassium level was 5.4 mmol/L. Extracorporeal membrane oxygenation (ECMO) for systemic perfusion and rewarming was initiated. After ECMO was introduced, return of spontaneous circulation was achieved. She showed no neurological impairments at discharge. Conclusions Muscle rigidity does not rule out the possibility of resuscitation in patients with severe accidental hypothermia under cardiac arrest. Serum potassium levels may assist in deciding whether ECMO should be introduced, even if a patient is in asystole. This knowledge may help emergency physicians to save the lives of such patients.

Abstract Imaging the shallow velocity structures beneath Aso caldera is necessary to further understand volcanism at the volcano and in the region. The network for monitoring Aso volcano has been progressively renewed and upgraded with denser and more modern instruments. We used approximately 4 years of seismic data recorded by a network of 25 seismic stations to image S-wave velocity (Vs) structures beneath Aso caldera with seismic noise interferometry. We calculated daily cross-correlation functions (CCFs) of broadband and short-period station pairs separately and then stacked CCFs monthly, to obtain the time-domain empirical Green’s functions and corresponding Rayleigh-wave phase-velocity dispersion curves. Finally, we constructed 1–5-s phase-velocity maps interpolated from nodes spaced 0.05° grid. The maps allow investigating crustal Vs structures between the surface and a depth of 6 km, likely related to shallow volcanic reservoirs and pathways. High velocities are found within the first kilometer of the crust beneath post-caldera central cones. Low velocities in the center of the post-caldera central cones extend from the surface to a depth of 1–2.5 km; we infer that the anomalies mark shallow hydrothermal reservoirs likely replenished by precipitation and hydrographic networks. The prevalence of high velocities below 3 km can be considered as consolidated igneous rock. Low-velocity anomalies identified at depths of 5–6 km beneath the post-caldera central cones could be a manifestation of magma accumulation. The low-velocity belts situated at 2.5–5 km depths are likely pathways for the transfer of hydrothermal fluids, volcanic gases, or melting magma to the surface. The northern part of the caldera shows relevant lateral velocity variations, with low velocities and high velocities predominant in the east and west, respectively. Other low-Vs anomalies appear near the surface to the west and northwest of Aso caldera.

A first-principles molecular dynamics simulation study was carried out to investigate the structural features of Ti4+ in aqueous sulfuric acid. Ti4+ forms several stoichiometric compounds in aqueous sulfuric acid, the identity and structural information details of which have been the subject of numerous studies. Three stoichiometric compounds of Ti4+ in aqueous sulfuric acid were found in the simulations, namely, [Ti=O(OH)2(H2O)3], [Ti(OH)2(H2O)2SO4], and [Ti2O2(H2O)5(OH)2SO4]. The results indicated that HSO4− formed a complex with the Ti ion by releasing its proton, which implies that such a coordination increases the proton concentration in the solution. The multinuclear complex was formed in our simulation conditions (concentration: 1M Ti4+ and temperature: 353 K); the result supports the interpretation of a previous experimental study.

Abstract During the last magmatic eruption period of Aso volcano (November 2014 to May 2015), a controlled-source electromagnetic volcano monitoring experiment (ACTIVE) was conducted. Here, we interpret the temporal variations in the electromagnetic responses. The ACTIVE system installed at the first Nakadake crater, the only active crater of Aso, consisted of a transmitter located northwest of the crater and four (before the eruptions) or three (after the eruptions) vertical induction coil receiver stations. The ACTIVE system succeeded in detecting temporal variations in the resistivity structure during the latest magmatic eruption period. The response amplitude started to increase in November 2014, peaked in February 2015, and decreased slightly in August 2015. An unstructured tetrahedral finite element three-dimensional inversion that accounted for topographic effects was used to interpret temporal variations in the ACTIVE response. The 3-D inversion results revealed that temporal variations in the ACTIVE response are attributed mainly to (1) a broad increase in resistivity at elevations from 750 to 850 m, not only directly beneath the crater bottom but also outside the crater, and (2) a thin layer of decrease in resistivity at the elevation of ~ 1000 m on the western side of the crater. The increase in resistivity can be ascribed to a decrease in the amount of conductive groundwater in the upper part of an aquifer located below the elevation of 800 m, while the decrease in resistivity implies that enhanced fluid temperature and pressure changed the subsurface hydrothermal system and formed a temporal fluid reservoir at the shallow level during the magmatic eruption period.

Abstract Volcanic tremor is often observed to be associated with an increase in volcanic activity and during periods approaching eruptions. It is therefore of crucial importance to study this phenomenon. The opening of a new vent and subsequent ash–gas emissions was observed in the active crater (Nakadake crater) of Aso volcano, Japan, in January 2014. These events were considered to be associated with phreatomagmatic activity similar to the small events of 2003–2005. During the period from December 2013 to January 2014, a significant variation in the amplitude of continuous seismic tremors was observed corresponding to surficial volcanic activity. We estimated the tremor source locations for this two-month period by a three-dimensional grid search using the tremor amplitude ratio of 5–10 Hz band-pass filtered waveforms. The estimated source locations were distributed in a roughly cylindrical region (100–150 m in diameter) ranging from the ground surface to a depth of 400 m. Migration of the estimated source location was also identified and was associated with changes in volcanic activity. We assumed that the source locations coincided with a conduit system of the volcano, consisting of networks of fractures. This area is likely situated above the crack-like conduit proposed in previous studies. Before the 2014 event, an increase in gas-dominated volcanic fluid first caused an enlargement of the conduit zone, followed by the migration of further magmatic fluid through other pathways, which resulted in a subsequent ash–gas emission. Although we do not have sufficient information to discuss the causal relationship between these processes, it seems reasonable that continuous tremors might change the conduit conditions.

The ionotropic P2X receptor, P2X7, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X7 receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X7 receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X7 receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X7 receptor antagonists, while only the second component was inhibited by P2X1, 3, and 4 receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X7-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area.

Background: The role of Helicobacter pylori in the pathogenesis of reflux esophagitis is controversial. This study investigated the frequency of reflux esophagitis before and after H. pylori eradication in patients having endoscopic submucosal dissection for early gastric cancer. Methods: This study included 160 patients that fulfilled the study’s criteria. Endoscopy was performed before and after H. pylori eradication, and reflux esophagitis was evaluated during the follow-up period. Results: Seropositivity for H. pylori in patients with early gastric cancer was 68.8%, 101 of them received eradication therapy. During the follow-up period, the incidence of reflux esophagitis increased from 3.1% to 18.8% in the successful eradication group but no case of reflux esophagitis was observed in the failed eradication group. The univariate and multivariate analyses showed a significant correlation between successful H. pylori eradication rate and the development of reflux esophagitis. Conclusions: This study demonstrated that a successful H. pylori eradication therapy is a risk factor for newly developed reflux esophagitis in patients with endoscopic submucosal dissection for early gastric cancer.

Abstract Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

The non-catalytic hydrothermal pretreatment of softwood is generally less effective for subsequent enzymatic hydrolysis. In this study, the efficacy of hot-compressed water (HCW) treatment of Douglas fir was investigated between 180 °C and 260 °C, allowing solubilization of the cellulose components. The enzymatic digestibility of cellulosic residues increased significantly under HCW conditions > 250 °C, and the enhanced glucan digestibility was closely related to the decomposition of the cellulose component. Combination of the first-stage HCW treatment (220 °C, 5 min) to recover hemicellulosic sugars with the second-stage HCW treatment (260 °C, 5 min) to improve cellulose digestibility gave a total sugar recovery of 56.2% based on the dried raw materials. This yield was 1.4 times higher than that from the one-step HCW-treated sample (260 °C, 5 min). Additionally, an enzymatic hydrolysate from the two-step HCW-treated sample exceeded 90% of the ethanol fermentation yield based on the total sugars present in the hydrolysates. These results suggest the potential of the two-step HCW treatment of softwood as a pretreatment technology for efficient total sugar recovery and ethanol production.

The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.

Small cell lung cancer (SCLC) is a severe malignancy associated with early and widespread metastasis. To study SCLC metastasis, we previously developed an orthotopic transplantation model using the human SCLC cell line DMS273. In the model, metastatic foci were found in distant tissues such as bone and the adrenal gland, similarly as observed in patients with SCLC. In this study, we evaluated the differentially expressed genes between orthotopic and metastatic tumors in the model. We isolated tumor cells from orthotopic and metastatic sites, and the tumor cell RNA was analyzed using DNA microarray analysis. We found that 19 genes in metastatic tumors were upregulated by more than 4-fold compared with their expression in orthotopic tumors. One of these genes encodes a transmembrane protein, interferon (IFN)-induced transmembrane protein 1 (IFITM1), and immunohistochemical analysis confirmed the higher expression of the protein in metastatic sites than in orthotopic sites. IFITM1 was also detected in some SCLC cell lines and lung tumors from patients with SCLC. The overexpression of IFITM1 in DMS273 cells increased their metastatic formation in the orthotopic model and in an experimental metastasis model. Conversely, the silencing of IFITM1 suppressed metastatic formation by DMS273 cells. We also found that IFITM1 overexpression promoted the metastatic formation of NCI-H69 human SCLC cells. These results demonstrate that IFITM1 promotes distant metastasis in xenograft models of human SCLC.

Pyruvate, a potential precursor of various chemicals, is one of the fundamental chemicals produced by the fermentation process. We previously reported a pyruvate-producing Escherichia coli strain LAFCPCPt-accBC-aceE (PYR) that has the potential to be applied to the industrial production of pyruvate. In this study, the availability of the PYR strain for the production of pyruvate-derivative chemicals was evaluated using a d-lactate-producing strain (LAC) based on the PYR strain. The LAC strain expresses a d-lactate dehydrogenase-encoding gene from Lactobacillus bulgaricus under the control of a T7 expression system. The d-lactate productivity of the LAC strain was further improved by limiting aeration and changing the induction period for the expression of d-lactate dehydrogenase-encoding gene expression. Under combined conditions, the LAC strain produced d-lactate at 21.7 ± 1.4 g·L−1, which was compatible with the pyruvate production by the PYR strain (26.1 ± 0.9 g·L−1). These results suggest that we have succeeded in the effective conversion of pyruvate to d-lactate in the LAC strain, demonstrating the wide versatility of the parental PYR strain as basal strain for various chemicals production.

The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.

To investigate the link between the genomic landscape of cancer cells and immune microenvironment in tumor tissues, we characterized somatic mutations and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM), including mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells and TILs (T-cell receptor β (TCRβ) repertoire), and expression profiles of immune-related genes using specimens of three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. Integrated analysis identified the distinct patterns of somatic mutations and the immune microenvironment signatures both intratumorally and interindividually. MPM cases showed intratumoral heterogeneity in somatic mutations with unique TCRβ clonotypes of TILs that were restricted to each tumor site, suggesting the presence of a neoantigen-related immune response. Correlation analyses showed that higher neoantigen load was significantly correlated with stronger clonal expansion of TILs (p = 0.048) and a higher expression level of an immune-associated cytolytic factor (PRF1 (p = 0.0041) in tumor tissues), suggesting that high neoantigen loads in tumor cells might promote expansion of functional tumor-specific T cells in the tumor bed. Our results collectively indicate that MPM tumors constitute a diverse heterogeneity in both the genomic landscape and immune microenvironment, and that mutation/neoantigen load may affect the immune microenvironment in MPM tissues.

A 48-year-old woman presented to our hospital with a 1-year history of a continuous high fever. She was diagnosed with metastatic pancreatic adenocarcinoma accompanied by leukocytosis without infection. Her serum concentration of granulocyte colony-stimulating factor was highly elevated. Forty-five days after initiating chemotherapy, she was readmitted because of a neuropsychiatric disturbance and hypercalcemia. Her serum concentration of parathyroid hormone-related protein (PTH-rP) was elevated. A pretreatment biopsy specimen showed strong cytoplasmic immunoreactivity to anti-PTH-rP antibody, suggesting that overproduction of PTH-rP accounted for the hypercalcemia. Although the patient regained consciousness after treatment, she died of progressive disease 60 days after chemotherapy.

Glasses with the composition xBaO–(99.9 − x)SiO2–0.1ErO3/2 (0 ≤x ≤ 34.9) were fabricated by a levitation technique. The glasses in the immiscibility region were opaque due to chemical inhomogeneity, while the other glasses were colorless and transparent. The scanning electron microscope observations and electron probe microanalysis scan profiles revealed that more Er3+ ions were preferentially distributed in the regions where more Ba2+ ions existed in the chemically inhomogeneous glasses. The synchronicity of the spatial distributions of the two ions initially increased with increasing x and then decreased when the Ba2+ concentration exceeded a certain value. The peak shape and lifetime of the fluorescence at 1.55 μm depended on x as well as the spatial distribution of both ions. These results indicate that although ErOn polyhedra are preferentially coordinated with Ba2+ ions and their local structure is affected by the coordination of Ba2+, there is a maximum in the amount of Ba2+ ions that can coordinate ErOn polyhedra since the available space for Ba2+ ions is limited. These findings provide us with efficient ways to design the chemical composition of glasses with superior Er3+ fluorescence properties for optical communication network systems.

The present work aimed to investigate the pretreatment of oil palm mesocarp fiber (OPMF) in subcritical H2O-CO2 at a temperature range from 150–200 °C and 20–180 min with CO2 pressure from 3–5 MPa. The pretreated solids and liquids from this process were separated by filtration and characterized. Xylooligosaccharides (XOs), sugar monomers, acids, furans and phenols in the pretreated liquids were analyzed by using HPLC. XOs with a degree of polymerization X2–X4 comprising xylobiose, xylotriose, xylotetraose were analyzed by using HPAEC-PAD. Enzymatic hydrolysis was performed on cellulose-rich pretreated solids to observe xylose and glucose production. An optimal condition for XOs production was achieved at 180 °C, 60 min, 3 MPa and the highest XOs obtained was 81.60 mg/g which corresponded to 36.59% of XOs yield from total xylan of OPMF. The highest xylose and glucose yields obtained from pretreated solids were 29.96% and 84.65%, respectively at cellulase loading of 10 FPU/g-substrate.

We recently demonstrated that SA13353, a transient receptor potential vanilloid 1 (TRPV1) agonist, reduced the severity of the symptoms of kidney injury, arthritis, and encephalomyelitis in disease models. Here, we investigated the effects of orally administered SA13353 on leukocyte infiltration in lipopolysaccharide (LPS)-induced acute lung injury and ovalbumin-induced allergic airway inflammation. In LPS-induced lung injury, SA13353 attenuated neutrophil infiltration and the increase of TNF-α and CINC-1 levels. In allergic airway inflammation, SA13353 tended to inhibit leukocyte infiltration and attenuated the increase of IL-4 and IL-12p40. These results suggest that somatosensory TRPV1 may play an anti-inflammatory role in lung inflammation. Keywords:: SA13353, transient receptor potential vanilloid 1, lung inflammation

Since papillary thyroid carcinoma (PTC) with tracheal invasion shows a worse prognosis, aggressive surgical treatment including airway resection has been recommended. However, little is known about local recurrence of PTC with minimal tracheal invasion after shaving or laminated resection of the tracheal cartilage. In this study, we investigated the local prognosis of patients who were intra-operatively diagnosed as having minimal tracheal invasion. Methods: Of 6,015 patients who underwent initial surgery for PTC between 1987 and 2004, 127 (2.1%) were intra-operatively suspected of having minimal invasion to the trachea and underwent shaving or laminated resection of the tracheal cartilage. These 127 patients were enrolled in this study. Results: Of 127 patients, 107 were intra-operatively regarded as having received macroscopically curative treatment (curative group), whereas minimal carcinoma remnants were suspected in the remaining 20 patients (suspicious group). To date, six patients (4.6%) (one patient in the curative group and five in the suspicious group) showed local recurrence at the tracheal edge. The local disease-free survival of patients in the curative group was better than that of those in the suspicious group (p = 0.0007), although the cause-specific survival of patients in the two groups did not differ. Cut surfaces of resected carcinoma were also pathologically examined for 119 patients and 58 (48.7%) were diagnosed as carcinoma-positive, but the cut surface status was not related to macroscopic curative treatment. Of six patients showing local recurrence, only one died of lung metastasis of carcinoma. Conclusion: The incidence of local recurrence of PTC with minimal tracheal invasion is low at 4.6%. Although this event might not be immediately life-threatening for patients, to improve local prognosis, local curative treatment should be pursued. In cases that are suspected of persistent carcinoma remnants, further shaving or laminated dissection should be performed, and if the carcinoma remnant cannot be eliminated, tracheal fenestration should be considered, although such high-risk tumours may be likely to recur regardless of surgical radicality.