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Abstract Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad‐spectrum anti‐inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART‐648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole‐blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART‐648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide‐induced TNFα release in ex vivo whole‐blood assay. In the single rising dose study, ART‐648 was safe and well tolerated with a dose‐proportional increase in exposures up to 4 mg. Single doses of ART‐648 demonstrated dose‐dependent PD response, indicating target engagement at 2‐8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART‐648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

Abstract A 61‐year‐old woman, who had a history of total thyroidectomy for follicular variant of papillary thyroid carcinoma (PTC), visited our hospital for assessment of an enlarging nodule which appeared in the lung with multiple metastatic lesions of PTC which had been stable for 17 years. Wedge resection of the lung was performed. Miliary nodules were confirmed to be metastatic PTCs based on their morphological as well as immunohistochemical findings. As for the main nodule, its morphological features suggested a diagnosis of metastatic PTC, while its immunohistochemical findings were identical with primary lung adenocarcinoma. Further genetic analysis provided no definitive information for the diagnosis of the main nodule. The present case shows the need of comprehensive analyses for differentiation between primary lung adenocarcinoma and metastatic PTCs.

Abstract ART‐001 is an orally available selective PI3Kα inhibitor currently being developed for the treatment of slow‐flow vascular malformations (SFVMs). ART‐001 used to be developed for advanced solid tumors, but was suspended largely due to significant pharmacokinetic (PK) variability in its phase I studies. This phase I, randomized, double‐blinded, placebo‐controlled study evaluated safety, tolerability and PK of ART‐001 with a newly developed dry syrup formulation, which was designed to optimize PK properties of ART‐001 and to be compliant with the pediatric population. Single and multiple doses of ART‐001 were administered to healthy male adults. ART‐001 was rapidly absorbed after the single and repeated doses, and the exposure of ART‐001 increased with increased dose. The dry syrup formulation substantially improved the intersubject PK variability. Food decreased area under the concentration‐time curve (AUC) and maximum plasma concentration by 12% and 36%, respectively. The plasma concentration had reached a steady‐state on day 5 of the repeated doses of 100 mg and AUC accumulation ratio was 1.9. There were no deaths or serious adverse events. The most frequent adverse event was hyperglycemia. All cases of hyperglycemia were mild to moderate and transient, and required no medical interventions. Serum creatinine increase was observed in 300 mg once daily dosing group leading to dose discontinuation on day 5. In conclusion, it was demonstrated that the single doses and repeated doses of the ART‐001 dry syrup formulation, at up to 400 and 100 mg, respectively, were safe and tolerated with favorable PK profile, supporting further clinical development for the treatment of SFVMs.

To investigate the regulation of soluble very low-density lipoprotein receptor (sVLDL-R), which is cleaved mostly from the extracellular domain of VLDL-R II, we generated two rat monoclonal antibodies (mAbs) against human sVLDL-R, and used them to develop a sandwich enzyme-linked immunosorbent assay (ELISA) to measure sVLDL-R levels in human serum or plasma. The ELISA had a linear range from 0.20 ng/mL to 13.02 ng/mL and allowed for the quantification of sVLDL-R in serum and culture cell medium. The coefficient of variation (CV) was less than 10% for both the intra- and inter-assays. The bililubin F, and C, triglyceride (TG), and hemoglobin levels did not affect assay precision. The sVLDL-R concentration was negatively associated with body fat percentage, TG, and HbA1c, suggesting the possibility of obesity and diabetes in middle-aged Japanese women.

Background: Regarding changes in muscle mass, differences due to types of exercise and/or nutritional interventions, and associations with nutrient balances are still unclear. Methods: To estimate changes in muscle mass during a body weight loss program using either a diet or exercise regimen, we investigated levels of muscle mass-related indices, and body contents of nitrogen, sodium, and potassium as measured by the balance method. Six healthy young adult male volunteers participated in two 10-day crossover experiments (20 days total). The first 5 days comprised an adjustment period (energy intake, 2656 ± 367 kcal/day (mean ± standard deviation)). During the second 5-day period, the participants either reduced their energy intake to 1770 ± 244 kcal/day (diet regimen) or exercised on a bicycle ergometer to expend 886 ± 122 kcal/day (exercise regimen). Results: The nitrogen, sodium, and potassium balances were significantly more positive during the exercise regimen than during the diet regimen. The urinary excretion levels of creatinine, 3-methylhistidine (3-MH), aldosterone, and catecholamines, and the 3-MH/creatinine ratio were significantly increased only during the exercise regimen. Conclusions: The exercise regimen suppresses the decrease in muscle mass-related indices during body weight loss compared to the diet regimen with a relatively positive state of whole-body protein, sodium, and potassium balances, accompanied by an increase in sympathetic/adrenal cortical functions.

Heart fibrosis involves a feedback loop where stiffening increases fibrosis-related gene expression in myofibroblasts. Here authors reveal the mechanosensitive nuclear translocation of VGLL3, where it phase separates and promotes collagen production, and show that its knock-out is protective after myocardial infarction.

Adversaries perform port scanning to discover accessible and vulnerable hosts as a prelude to cyber havoc. A darknet is a cyberattack observation network to capture these scanning activities through reachable yet unused IP addresses. However, the enormous amount of packets and superposition of diverse scanning strategies prevent extracting significant insights from the aggregate traffic. Some coordinated scanners disperse probe packets whose TCP/IP header follows a unique pattern to determine whether the received packets are valid responses to their probes or are part of other background traffic. We call such a pattern a fingerprint. For example, a probe packet from a Mirai-infected host satisfies a pattern whereby the destination IP address equals the sequence number. A fingerprint indicates that the source host has been involved in a particular scanning campaign. Although some fingerprints have been discovered and known to the public, there are and will be more undiscovered ones. We intend to unveil these fingerprints. Our preliminary work automatically identified flexible fingerprints but overlooked low-rate and coordinated scanners. In this work, we improved the fingerprint identifier, enabling it to detect these stealth scans. Moreover, we revealed the scans’ objectives by investigating destination port sets. We associated fingerprints with threat intelligence and verified their reliability. Our approach identified all well-known and eight unknown fingerprints on one month’s worth of darknet data collected from about three-hundred thousand unused IP addresses. We disclosed the fingerprints of the Mozi botnet and destination port sets that were previously unreported.

Key Clinical Message Poor personal hygiene wearing the same unwashed briefs, and prolonged sitting have led to the development of chronic perianal pyoderma. This can be confused with hidradenitis suppurativa and must be differentiated as their treatments are different. Abstract There are potential risks of persistent inflammation resulting from poor personal hygiene. This comprises wearing the same unwashed briefs and prolonged sitting posture that led to developing chronic perianal pyoderma (CPP) in a smoking man. CPP can be confused with hidradenitis suppurativa, requiring differentiation as their treatment strategies distinctly differ.

Introduction In early-stage oral tongue squamous cell carcinoma (OTSCC), elective neck dissection (END) is recommended when occult lymph node metastasis is suspected; however, there is no unanimous consensus on the risks and benefits of END in such cases. The management of clinically node-negative (cN0) OTSCC remains controversial. This study, therefore, aimed to evaluate the efficacy of END and its impact on the quality of life (QoL) of patients with cN0 OTSCC.Methods and analysis This is a prospective, multicentre, nonrandomised observational study. The choice of whether to perform END at the same time as resection of the primary tumour is based on institutional policy and patient preference. The primary endpoint of this study is 3-year overall survival. The secondary endpoints are 3-year disease-specific survival, 3-year relapse-free survival and the impact on patient QoL. Propensity score-matching analysis will be performed to reduce selection bias.Ethics and dissemination This study was approved by the Clinical Research Review Board of the Nagasaki University. The protocol of this study was registered at the University Hospital Medical Information Network Clinical Trials Registry. The datasets generated during the current study will be available from the corresponding author on reasonable request. The results will be disseminated internationally, through scientific and professional conferences and in peer-reviewed medical journals.Trial registration number UMIN000027875.

Background: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs. Methods: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016–2017. Responses were collected from 70 patients (57.9%) and subjected to analysis. Results: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min–max, 0–53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3–73) and at diagnosis 32.8 years (0–73). Patients reported an average of 15.7 (0–100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0–200) before diagnosis, but these declined to 4.3 (0–50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect. Conclusions: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.

Background/purpose: The prevalence of oral adverse events and dental treatments related complications during the molecular targeted drugs therapy remains unclear. The purpose of this study was to investigate the contents of dental treatment-related complications in Japanese patients during molecular targeted therapy. Materials and methods: The nation-wide survey of dental treatment related complications was performed by the Japanese Society of Dentistry for Medically Compromised Patient as retrospective cohort study. Results: Among 212 dentists, 87.3% recognized the possibility of dental treatments related complications in patients with angiogenesis inhibitors. The oral adverse events including dental treatment-related complications associated with angiogenesis inhibitors were 79 cases. In patients with angiogenesis inhibitors, 73.4% of patients were administrated with bevacizumab. The average administration period of angiogenesis inhibitors was 14.0 ± 10.0 months. As the dental treatment related complications, delayed wound healing was most commonly seen in 45 patients (57.0%), followed by osteonecrosis of the jaw in 25 (31.6%). The triggered factor of complications was tooth extraction in 51 cases (96.2%). Conclusion: The extraction of the tooth with pre-existing inflammation may be suggested as one of risk factors for angiogenesis inhibitor-related dental treatment complications.

Abstract The studies of browsing behavior have gained increasing attention in web analysis for providing better service. Most of the conventional approaches focus on simple indices such as average dwell time and conversion rate. These indices make similar evaluations to websites even if their features are significantly different. Moreover, such statistical indices are not sensitive to the dynamics of users’ interests. In this paper, we propose a new framework for measuring a website’s attractiveness that takes into account both the distribution and dynamics of users’ interests. Within the framework, we define a new index for the website, called Attractiveness Factor, which evaluates the degree of users’ attention. It consists of three procedures: First, we capture the transition of users’ interests during browsing by solving a nonnegative matrix factorization and constrained network flow problems. To accommodate multiple types of interests of a user, we applied a soft clustering as opposed to a hard clustering to model attributes of users and websites. Second, for each website, the feature of each cluster is obtained by fitting the dwell time distribution with Weibull distribution. Finally, we calculate Attractiveness Factor of a website by applying the results of clustering and fitting. Attractiveness Factor depends on the distribution of the dwell time of users interested in the website, which reflects the change of interest of users. Numerical experiments with real web access data of Yahoo Japan News are conducted by solving extremely large-scale optimization problems. They show that Attractiveness Factor captures more exceptional information about browsing behavior more effectively than well-used indices. Attractive factors give low ratings to category pages; however, it can assign high ratings to websites that attract many people, such as hot topic news about the 2018 FIFA World Cup, Japan’s new imperial era’ REIWA,’ and North Korea—the United States Hanoi Summit. Moreover, we demonstrate that Attractiveness Factor can detect the tendency of users’ attention to each website at a given time interval of the day.

It is well established that nuclear factor κB (NF‐κB) acts as one of the most important transcription factors for tumor initiation and progression, as it both protects cells from apoptotic/necrotic signals and accelerates angiogenesis and tumor metastasis, which is mediated via the expression of target genes. However, it has not yet been clarified how oncogenic signals accelerate the activation of NF‐κB. In the current study, we utilized untransformed NIH‐3T3 cells stably harboring a κB‐driven luciferase gene to show that an oncogenic mutant of Ras GTPase augmented TNFα‐induced NF‐κB activation. Notably, enforced expression of cyclin‐dependent kinase inhibitors, such as p27Kip1 and p21Cip1, effectively canceled the accelerated activation of NF‐κB, suggesting that oncogenic Ras‐induced cell cycle progression is essential for the hyperactivation of NF‐κB. Furthermore, we found that Ras (G12V) augmented the transcriptional activation of NF‐κB, and this activation required the p38 MAP kinase. We observed that a downstream kinase of p38 MAP kinase, MSK1, was activated by Ras (G12V) and catalyzed the phosphorylation of p65/RelA at Ser‐276, which is critical for its transcriptional activation. Significantly, phosphorylation of the p65/RelA subunit at Ser‐276 was elevated in patient samples of colorectal cancer harboring oncogenic mutations of the K‐Ras gene, and the expression levels of NF‐κB target genes were drastically enhanced in several cancer tissues. These observations strongly suggest that oncogenic signal‐induced acceleration of NF‐κB activation is caused by activation of the p38 MAP kinase–MSK1 signaling axis and by cell cycle progression in cancer cells.

Abstract Background Laparoscopic abdominal surgery is considered superior to open surgery. However, efficacy and safety outcomes of laparoscopic surgery in colorectal cancer (CRC) are unclear, particularly in patients undergoing antiplatelet therapy (APT). The aim of this study was to evaluate safety of antiplatelet agents, especially aspirin, in peri-operative management of patients undergoing laparoscopic colorectal resection for CRC. Methods A total of 578 radical laparoscopic colorectal surgeries in CRC patients performed between January 2005 and December 2015 at the Kokura Memorial Hospital were retrospectively reviewed. Patients were divided into three groups based on the risk for thromboembolism: a high-risk group receiving APT (APT-HR), a low-risk group receiving APT (APT-LR), and a low-risk group not receiving APT (non-APT). Bleeding complications (BC) and thromboembolic complications (TC) were assessed. Perioperative and outcome variables in groups receiving APT were compared with those in the non-APT group. Results APT-HR, APT-LR, and non-APT groups included 54 (9.3%), 114 (19.7%), and 410 (70.9%) patients, respectively. Blood loss during operation (p = 0.304), operative time (p = 0.956), hospitalisation after surgery (p = 0.307), and Clavien–Dindo classification of surgery-related complications (p = 0.467) were not significantly different in the three groups. Occurrence of intra-operative BC (blood loss ≥ 200 ml) (p = 0.864), post-operative BC (p = 0.630), and TC (p = 0.287) were also not significantly different in the three groups. Results of our analysis indicated that APT and non-interrupted APT were not associated with BC or TC. Conclusions Analysis of laparoscopic colorectal resection in CRC showed that APT was not a major factor for fatal BC or TC. In patients with high thromboembolic risk, continuing aspirin may inhibit the increase in TC without increasing BC in the peri-operative period.

Abstract Background We previously reported that the consumption of 8 g of protein per day in the form of lactic-fermented egg white (LAFEW) improves visceral fat obesity. In this study, we investigated the minimum effective intake of LAFEW for visceral fat reduction in the Japanese males with mild obesity. Methods Twenty-two Japanese adult males with a Body mass index (BMI) ≥24 and a waist circumference ≥ 85 cm were included in this study. The subjects were divided into three groups, that is, control group, LAFEW 6 g group, and LAFEW 8 g group. The LAFEW 6 and 8 g groups consumed 6 and 8 g, respectively, of egg white protein (EWP) in a drink at breakfast for 8 weeks, whereas the control group consumed a drink containing 8 g of milk whey protein. Body weight, body fat percentage, abdominal circumference, and visceral fat (VF) area around the navel were measured at 0 and 8 weeks after initiating the consumption. Results No changes in body weight or body fat percentage were observed in any of the groups. No significant differences between the pre- and posttreatment measurements were found in the VF area around the navel in the control group and the LAFEW 6 g group. In the LAFEW 8 g group, the VF area had decreased significantly after 8 weeks of consumption, when compared to that before consumption, and the average observed decrease (Δcm2) was 13.2 ± 4.7 cm2. Among the subjects with an initial BMI > 25, the VF area was significantly smaller in the LAFEW 8 group, when compared to the week 0 values and those in the control group. Visceral fat/subcutaneous fat values in the LAFEW 8 group were also significantly smaller than those in the control group or at week 0. Conclusion The results suggested that the minimum effective intake of EWP in the LAFEW to reduce the VF area in the Japanese men is 8 g. Trial registration This clinical trial was retrospectively registered with the University hospital Medical Information Network (UMIN) Center, (UMIN000031681; registered on 12/03/2018).

Objectives: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method. Design: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 ​mmol/L (1000 ​mg/dL). Results: For LDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.991x + 0.009 ​mmol/L; r ​= ​0.999; and Sy/x ​= ​0.025 ​mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y ​= ​0.988x + 0.041 ​mmol/L, r ​= ​0.999, and Sy/x ​= ​0.019 ​mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method. Conclusions: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.

Introduction We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity.Research design and methods The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2).Results Acetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue.Conclusions The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.

Abstract Background It was reported that egg white protein (EWP) reduced body fat in rats. We developed a lactic-fermented egg white (LE) that facilitates the consumption of egg whites by fermenting them with lactobacillus, and were able to study their intake in humans. In this double-blind, placebo-controlled design, we evaluated the effect of LE on visceral fat area (VFA). Methods Participants included 37 adult males and females aged ≥40 years (VFA at navel ≥100 cm2). They were divided into two groups: the control group and the LE group. The control and LE groups consumed drinks containing whey and LE, respectively, for 12 weeks (providing 8 g protein/day). VFA was measured at baseline and at week 12 of intake. Abdominal girth was measured at baseline and at weeks 6 and 12. Results LE intake decreased VFA significantly compared with baseline (−8.89 cm2, p

Abstract Anatomical variations of hepatic arteries may be problematic in pancreaticoduodenectomy (PD). We experienced pancreatic head cancer in a patient with rare variation of hepatic artery and performed PD successfully with the resection of this artery. A 75-year-old woman showed pancreatic head tumor on CT. Preoperative CT detected rare variation of hepatic artery; posterior segmental branch of right hepatic artery (RHA-PB) originating from posterior inferior pancreaticoduodenal artery. The image also demonstrated that there was a junction between RHA-PB and anterior branch of right hepatic artery (RHA-AB). We performed PD for suspected pancreatic head cancer. We divided RHA-PB for complete resection of cancer because we preoperatively knew that there was the junction between RHA-PB and RHA-AB. She was discharged uneventfully, and there was no evidence of local recurrence throughout the whole course. Careful preoperative assessment of hepatic blood supply is the key to perform successful PD even in this troublesome situation.

Abstract Background Lowering cholesterol levels decreases the risk of atherosclerotic diseases. Effective ways to stably reduce LDL-C level are warranted in type 2 diabetic patients, a high-risk population for CVD, with various anti-diabetic therapeutic background. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles. We evaluated long-term ezetimibe add-on therapy in T2DM patients with hypercholesterolemia. Methods In a randomized, multicenter, open-label, prospective study, a total of 109 T2DM patients not attaining LDL-C target value despite first-line dose statin (10 mg of atorvastatin or 1 mg of pitavastatin) therapy in Japan were recruited. We investigated the difference in cholesterol lowering effect between ezetimibe (10 mg) add-on statin (EAT) group and double-dose statin (DST) group. Changes of parameters related to atherosclerotic event risks were assessed. Results The reduction of LDL-C was larger in the EAT group (28.3%) than in the DST group (9.2%) at 52 weeks as well as the primary endpoint of 12 weeks. EAT achieved significant lower levels of TC and apo B, respectively. Both treatments attained significant reduction in sd-LDL-C or hsCRP on this long-term basis. Notably, sd-LDL-C in EAT reduced as low as 36.1 ± 14.9 mg/dl to reach near the threshold (35.0 mg/dl) for atherosclerosis with significantly higher achievement rate (55.6%) than DST treatment. Simultaneously, hsCRP reduction by EAT attained as low value as 0.52 ± 0.43 mg/l. Conclusions In the present 52-week long-term period, ezetimibe add-on therapy showed a robust advantage in lowering LDL-C and in attaining target LDL-C values compared with the doubling of statin dose. Moreover, it’s meaningful that sd-LDL, powerfully atherogenic lipoprotein, exhibited prominent decrease consistently prominently by ezetimibe add-on therapy. DM patients with hypercholesterolemia are at high risk for CAD, and adding ezetimibe onto usual-dose statin treatment in Japan has been suggested as the first-line therapy for those DM patients who failed to attain the target LDL-C value (UMIN000002593).

The physiological importance of reactive sulfur species (RSS) such as cysteine hydropersulfide (CysSSH) has been increasingly recognized in recent years. We have established a reactive sulfur metabolomics analysis by using RSS metabolic profiling, which revealed appreciable amounts of RSS generated endogenously and ubiquitously in both prokaryotic and eukaryotic organisms. The chemical nature of these polysulfides is not fully understood, however, because of their reactive or complicated redox-active properties. In our study here, we determined that tyrosine and a hydroxyphenyl-containing derivative, β-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAM), had potent stabilizing effects on diverse polysulfide residues formed in CysSSH-related low-molecular-weight species, e.g., glutathione polysulfides (oxidized glutathione trisulfide and oxidized glutathione tetrasulfide). The protective effect against degradation was likely caused by the inhibitory activity of hydroxyphenyl residues of tyrosine and HPE-IAM against alkaline hydrolysis of polysulfides. This hydrolysis occurred via heterolytic scission triggered by the hydroxyl anion acting on polysulfides that are cleaved into thiolates and sulfenic acids, with the hydrolysis being enhanced by alkylating reagents (e.g. IAM) and dimedone. Moreover, tyrosine prevented electrophilic degradation occurring in alkaline pH. The polysulfide stabilization induced by tyrosine or the hydroxyphenyl moiety of HPE-IAM will greatly improve our understanding of the chemical properties of polysulfides and may benefit the sulfur metabolomics analysis if it can be applied successfully to any kind of biological samples, including clinical specimens. Keywords: Reactive sulfur species, β-(4-Hydroxyphenyl)ethyl iodoacetamide, Tyrosine, Reactive sulfur metabolomics analysis, Reactive sulfur signaling, Redox signaling

Introduction. We herein present three cases of locally advanced colon cancer (LACC) invading the urinary bladder, in whom combined neoadjuvant chemotherapy with surgical intervention was effective in disease control and preserving urinary function. Case Presentation. Before neoadjuvant chemotherapy, all three cases underwent loop transverse colostomy for symptomatic colonic obstruction. Case 1: after 6 courses of capecitabine plus oxaliplatin (CAPOX), we performed sigmoid colectomy and partial resection of the bladder. The histological examination revealed pathological complete response (pCR). The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 2: after 13 courses of CAPOX plus bevacizumab, we performed Hartmann’s operation with partial resection of the bladder. The histological examination revealed pCR. The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 3: after 6 courses of chemotherapy with CAPOX plus bevacizumab, we performed sigmoid colectomy and partial resection of the bladder. The pathological response was grade 1a according to the Japanese Classification of Colorectal Carcinoma. The final diagnosis was ypStage IIC (ypT4bypN0M0). All three cases underwent capecitabine-based adjuvant chemotherapy after radical surgery and patients are alive without recurrence. Conclusion. Neoadjuvant chemotherapy with CAPOX with or without bevacizumab followed by radical surgery could be an effective treatment option for LACC invading the urinary bladder.

We experienced the giant seminoma with 18 × 10 × 10 cm sized and about 2.6 kg weight of 25 year old patient. We intensively examined the histological tissue type distributions in this giant seminoma. Most of the tumor consisted of seminoma components. In addition, the tumor included the very small fragments of yolk sac tumor and embryonal carcinoma component at the root part of the seminoma mass. This shows that intensive histological examination may contribute to the finding of other embryonic component of the large seminoma. This may show that leaving the seminoma growing may generate the other embryonic tumor component, not always big enough to find out in a routine procedure, during the growth, in the different way from the original mixed cell germ tumor.

The boundary zone between two different hydrological regimes is often a biologically enriched environment with distinct planktonic communities. In the center of the Amazon River basin, muddy white water of the Amazon River meets with black water of the Negro River, creating a conspicuous visible boundary spanning over 10 km along the Amazon River. Here, we tested the hypothesis that the confluence boundary between the white and black water rivers concentrates prey and is used as a feeding habitat for consumers by investigating the density, biomass and distribution of mesozooplankton and ichthyoplankton communities across the two rivers during the rainy season. Our results show that mean mesozooplankton density (2,730 inds. m−3) and biomass (4.8 mg m−3) were higher in the black-water river compared to the white-water river (959 inds. m−3; 2.4 mg m−3); however an exceptionally high mesozooplankton density was not observed in the confluence boundary. Nonetheless we found the highest density of ichthyoplankton in the confluence boundary (9.7 inds. m−3), being up to 9-fold higher than in adjacent rivers. The confluence between white and black waters is sandwiched by both environments with low (white water) and high (black water) zooplankton concentrations and by both environments with low (white water) and high (black water) predation pressures for fish larvae, and may function as a boundary layer that offers benefits of both high prey concentrations and low predation risk. This forms a plausible explanation for the high density of ichthyoplankton in the confluence zone of black and white water rivers.

α-Lipoic acid (ALA) has a chiral center at the C6 position, and exists as two enantiomers, R(+)-ALA (RALA) and S(−)-ALA (SALA). RALA is naturally occurring, and is a cofactor for mitochondrial enzymes, therefore playing a major role in energy metabolism. However, RALA cannot be used for pharmaceuticals or nutraceuticals because it readily polymerizes via a 1,2-dithiolane ring-opening when exposed to light or heat. So, it is highly desired to find out the method to stabilize RALA. The purpose of this study is to provide the spectroscopic information of stabilized RALA and SALA through complexation with cyclodextrins (CDs), α-CD, β-CD and γ-CD and to examine the physical characteristics of the resultant complexes in the solid state. The RALA-CD structures were elucidated based on the micro fourier transform infrared (FT-IR) and Raman analyses. The FT-IR results showed that the C=O stretching vibration of RALA appeared at 1717 cm−1 and then shifted on formation of the RALA-CD complexes. The Raman spectra showed that the S–S and C–S stretching vibrations for RALA at 511 cm−1 (S–S), 631 cm−1 (C–S) and 675 cm−1 (C–S) drastically weakened and almost disappeared upon complexation with CDs. Several peaks indicative of O–H vibrations also shifted or changed in intensity. These results indicate that RALA and CDs form host-guest complexes by interacting with one another.

In trichothecene-producing fusaria, isotrichodermol (ITDol) is the first intermediate with a trichothecene skeleton. In the biosynthetic pathway of trichothecene, a 3-O-acetyltransferase, encoded by Tri101, acetylates ITDol to a less-toxic intermediate, isotrichodermin (ITD). Although trichothecene resistance has been conferred to microbes and plants transformed with Tri101, there are no reports of resistance in cultured mammalian cells. In this study, we found that a 3-O-acetyl group of trichothecenes is liable to hydrolysis by esterases in fetal bovine serum and FM3A cells. We transfected the cells with Tri101 under the control of the MMTV-LTR promoter and obtained a cell line G3 with the highest level of C-3 acetylase activity. While the wild-type FM3A cells hardly grew in the medium containing 0.40 μM ITDol, many G3 cells survived at this concentration. The IC50 values of ITDol and ITD in G3 cells were 1.0 and 9.6 μM, respectively, which were higher than the values of 0.23 and 3.0 μM in the wild-type FM3A cells. A similar, but more modest, tendency was observed in deoxynivalenol and 3-acetyldeoxynivalenol. Our findings indicate that the expression of Tri101 conferred trichothecene resistance in cultured mammalian cells.

The distribution of burden layers is a vital factor that affects the production of a blast furnace. Radars are advanced instruments that can provide the detection results of the burden surface shape inside a blast furnace in real time. To better estimate the burden layer thicknesses through improving the prediction accuracy of the burden descent during charging periods, an innovative data-driven model for predicting the distribution of the burden surface descent speed is proposed. The data adopted were from the detection results of an operating blast furnace, collected using a mechanical swing radar system. Under a kinematic continuum modeling mechanism, the proposed model adopts a linear combination of Gaussian radial basis functions to approximate the equivalent field of burden descent speed along the burden surface radius. A proof of the existence and uniqueness of the prediction solution is given to guarantee that the predicted radial profile of the burden surface can always be calculated numerically. Compared with the plain data-driven descriptive model, the proposed model has the ability to better characterize the variability in the radial distribution of burden descent speed. In addition, the proposed model provides prediction results of higher accuracy for both the future surface shape and descent speed distribution.

Background: The aim of this study was to clarify whether some environmental and genetic factors (food allergy, older siblings, early day-care attendance and parents' allergy history) are related to the development of allergic symptoms (wheezing in the previous 12 months [WP], eczema symptoms in the previous 12 months [EP], and rhinoconjunctivitis symptoms in the previous 12 months [RP]) in Japanese children. Methods: Using the modified version of the International Study on Asthma and Allergies in Childhood (ISSAC) questionnaire, we studied the prevalence of WP, EP and RP among six-year-old children attending 72 primary schools throughout Himeji City, Japan, during the two years from 2005 to 2006. Results: Food allergy and parents' history of allergy showed a significant relationship with the prevalence of WP, EP and RP. Day-care attendance in the first two years of life and presence of older siblings showed a significant inverse relationship with the prevalence of RP. However, neither day-care attendance nor presence of older siblings was related to the development of W and ER. Conclusions: Among Japanese children, food allergy and parents' history of allergy are risk factors for WP, ES or RS. However, early day-care attendance and presence of older siblings might be protective factors against RS. Infections in early life may affect the prevalence of rhinoconjunctivitis in six-year-old children.

Micrometeorological parameters were measured in a closed forest (CF) and at a tree-fall gap (LG) near Novo Aripuanã, AM, along the Madeira River in dry season (August to September 2003) and rainy season (March 2004), and were compared to the number of species per family and the number of seedlings obtained from forest inventory. The daily averages of net radiation (W/m2) between CF and LG were 9.5:168.0 during dry season and 3.6:125.9 during rainy season, and these averages were influenced by the difference in shortwave radiation between the sites (CFPourouma, Parkia, Tachigalia, and Orbignya, meanwhile genera peculiar to closed forests (Protium, Chrysophyllum, Micropholis) were also found.

Micrometeorological parameters were measured in a closed forest (CF) and at a tree-fall gap (LG) near Novo Aripuanã, AM, along the Madeira River in dry season (August to September 2003) and rainy season (March 2004), and were compared to the number of species per family and the number of seedlings obtained from forest inventory. The daily averages of net radiation (W/m2) between CF and LG were 9.5:168.0 during dry season and 3.6:125.9 during rainy season, and these averages were influenced by the difference in shortwave radiation between the sites (CF

There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.The UMIN Clinical Trials Registry UMIN000002593.

Forest inventory, stem core sampling, and meteorological observations were carried out in a dense tropical forest in Novo Aripuanã, Amazonas. In the research quadrat (1.9 ha), 210 woody species belonging to over 38 botanical families, and 14 palm species were identified. The aboveground biomass, which was estimated to be 202.72 t/ha, was standard for Amazonia, but the forest was considered to repeat regeneration by tree-fall gaps because early succession species such as Iryanthera ssp. (Myristicaceae), Croton sp. (Euphorbiaceae), and palms were large in number. The relationship between tree height and percentage of vessel area in stem cross sections in the 2001 and 2002 growth rings had a positive correlation coefficient. The enlargement of vessel area was to improve the efficiency for absorbing sap against gravity, which means that the increase in pore zone leads to weakening the resistance of stems against squalls. From meteorological measurements, it was found that diurnal downward short-wave radiation at forest canopy was a few times to several dozen times as large as that at forest floor, and in consequence, net radiation surpassed 600 w/m2 in the canopy, while it was about 30 w/m2 on the floor. The radiation balance in tree-fall gaps was similar to that of forest canopy, but the gaps were characterized to have a large temperature difference between day and night (12 to 13 oC). Radiative cooling easily condensed humid air when temperatures decreased to 27-28 oC, and the condensation each night amounted to 5-7 g/m3, about double that of closed forests.

A autoecologia das três espécies florestais em linhas de enriquecimento foi avaliada junto com o monitoramento do microclima e fertilidade do solo na floresta primária de terra-firme da Amazônia brasileira. A área situa-se no município de Novo Aripuanã Amazonas - Brasil (5º18'S, 60º04'W.). Nas três diferentes larguras de linhas (3, 5 e 7m) foram monitoradas os parâmetros de radiação com fotografias hemisféricas e sensor RFA. As linhas de 5 e 7m classificam-se como grande abertura de dossel (19,77-20,78%), a de 3m mostrou maior variação na radiação RFA. Quanto à análise química do solo observou-se, uma redução significativa de K e Ca em relação ao aumento das larguras das linhas. Também foram monitorados os crescimentos em altura e diâmetro, índice de ganho foliar e o teor de clorofila nas plântulas das três espécies estidadas: Astronium lecointei Ducke, Cordia goeldiana Huber e Scleronema micranthum Ducke. Todas espécies sofreram devido à alta radiação e ao estresse hídrico. Astronium lecointei apresentou uma maior resistência tanto durante forte seca, como também ao excesso de chuva. Scleronema micranthum apresentou diferenças de crescimento entre linhas, principalmente na estação chuvosa. Beneficiou-se positivamente com a radiação direta nas linhas largas de enriquecimento. As duas apresentaram alta amplitude de nicho entre tolerante à sombra a intermediária. Já C.goeldiana apresentou maior variação em seu crescimento (CV: Cordia goeldiana: 113> Astronium lecointei: 60,6> Scleronema micranthum: 59,7). A largura de linha de 5m na floresta primária de terra-firme foi suficiente para estabelecimento de espécies tolerante à sombra e intermediária.In this study, autoecological traits of three Amazonian terra-firme tree species grown in enrichment plantation lines were evaluated. The microclimatological parameters also were assessed in these lines. The study site is located in Novo Aripuanã, Amazonas State, Brazil (5(0)18'S, 60(0)04'W). Light condition in the three width lines (3, 5 and 7m) were assessed using hemispherical photographs and PAR sensor focusing radiation parameters. Although lines of 5 and 7m widths can be classified as large canopy opening (19,77-20,78%), lines of 3m represented major PAR variation. For soil chemical analysis, a significant reduction of K ans Ca was observed. Three tree species seedlings, Astronium lecointei Ducke, Cordia goeldiana Huber and Scleronema micranthum Ducke were set in the enrichment plantation lines. The relative growth rate (stem diameter+height) and chlorophyll contents were monitored in these plants. All species were subjected to high direct and diffuse radiation, low levels of nutrients and water stress. Astronium lecointei Ducke showed high drought resistance. Scleronema micranthum in the rainy season also benefited in the wider enrichment lines, showing positive responses to direct radiation. These two species showed features of intermediate to shade tolerant species (broad niche) when growth patterns were compared. On the other hand, C.goeldiana showed greater growth fluctuation than others (VC: Cordia goeldiana: 113> Astronium lecointei: 60,6> Scleronema micranthum: 59,7). Lines with five meters widths of primary terra-firme forests should be sufficient to establish shade tolerant and intermediate species.

Background: The importance of peanut allergy has not been well recognized in Japanese society. IgE antibody to peanut can be, however, detected in patients without clinical peanut allergy. Methods: Clinical characteristics of 14 patients (aged 1–8 years) with peanut allergy were evaluated. IgE antibodies to peanut from patients with and without clinical peanut allergy were compared with those to soybean and other nuts. To examine the role of cross-reactive carbohydrate determinant (CCD) on the clinically false positive detection of peanut IgE, horseradish peroxidase (HRP) and bromelain specific IgE were measured by Uni CAP IgE kit. Inhibition of peanut IgE by HRP was also examined. Results: The patients repeatedly experienced potentially life-threatening symptoms, including anaphylaxis. Sera from patients with peanut allergy had negative or relatively low IgE antibodies to other nuts. However, clinically false positive peanut IgE showed significant correlation-coefficients with soybean, almond, chestnut, pistachio, macadamia and cashew (r = 0.61–1.00). Anti-HRP and anti-bromelain IgE antibodies were detected in the clinically false positive sera, but not in the sera from patients with peanut allergy. Two out of four clinically false positive peanut IgE antibodies were significantly inhibited by HRP. Conclusions: Social education about the features of peanut allergy is needed in Japan. Anti-CCD IgE antibody was suggested to be one of the mechanisms contributing to the false positive detection of peanut IgE. Detection of anti-HRP or anti-bromelain IgE can be a useful tool to recognize the presence of anti-CCD antibodies.

Certain triglyceride-rich lipoproteins (TRLs), specifically chylomicrons, dyslipemic VLDLs, and their remnants, are atherogenic and can induce monocyte-macrophage foam cell formation in vitro via the apolipoprotein B-48 receptor (apoB-48R). Human atherosclerotic lesion foam cells express the apoB-48R, as determined immunohistochemically, suggesting it can play a role in the conversion of macrophages into foam cells in vivo. The regulation of the apoB-48R in monocyte-macrophages is not fully understood, albeit previous studies indicated that cellular sterol levels and state of differentiation do not affect apoB-48R expression. Since peroxisome proliferator-activated receptors (PPARs) regulate some aspects of cellular lipid metabolism and may be protective in atherogenesis by up-regulation of liver X-activated receptor α and ATP-binding cassette transporter A1, we examined the regulation of apoB-48R by PPAR ligands in human monocyte-macrophages. Using real-time PCR, Northern, Western, and functional cellular lipid accumulation assays, we show that PPARα and PPARγ activators significantly suppress the expression of apoB-48R mRNA in human THP-1 and blood-borne monocyte-macrophages. Moreover, PPAR activators inhibit the expression of the apoB-48R protein and, notably, the apoB-48R-mediated lipid accumulation of TRL by THP-1 monocytes in vitro.If PPAR activators also suppress the apoB-48R pathway in vivo, diminished apoB-48R-mediated monocyte-macrophage lipid accumulation may be yet another antiatherogenic effect of the action of PPAR ligands.

The appropriate proportions of macronutritional intake have been controversial in medical nutritional therapy for diabetes, and evidence of the effects of carbohydrate consumption on diabetes complications in prospective settings is sparse. We investigated the relationships between proportions of carbohydrate intake as the % of total energy and diabetes complications in a nationwide cohort of Japanese patients with type 2 diabetes aged 40–70 years with hemoglobin A1c ≥6.5%. The analysis was of 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to overt nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) after 8 years. Hazard ratios (HRs) for proportions of carbohydrate intake were estimated by Cox regression adjusted for confounders. High carbohydrate intake was significantly related to higher intakes of grain, fruits, and sweets/snacks and lower intakes of soybean and soy products, vegetables, seaweed, meat and processed meat, fish and processed fish, eggs, milk and dairy products, oil, and alcoholic beverages. During the eight-year follow-up, there were 81, 275, and 129 events of overt nephropathy, diabetic retinopathy, and CVD, respectively. After adjustment for confounders, HRs for complications in patients with carbohydrate intake in the second or third tertiles (51.0%–56.4% and ≥56.5%, respectively) compared with carbohydrate intake in the first tertile (

Aconite contains four highly toxic diester-diterpene alkaloids, including aconitine, mesaconitine, hypaconitine, and jesaconitine, in all plant parts. Aconite has been used as for suicide, murder, and as an arrow poison since ancient Greek and Roman times. Ventricular tachyarrhythmias are the most common cause of death in aconite poisoning, and antiarrhythmic drugs and cardioversion are ineffective. A 61-year-old woman ingested the crushed raw roots of a single aconite plant. An ambulance brought her to the Tottori University Hospital 30 min after ingestion. She had a history of chronic stage 5 kidney disease but was not on dialysis. Her heart rate (HR) was 120 bpm upon arrival. The patient developed sustained supraventricular tachycardia (SVT) at an HR of 165 bpm with frequent premature ventricular contractions (PVCs) 15 min after arrival. She then developed sustained monomorphic ventricular tachycardia (VT) at an HR of 200 bpm 20 min after arrival, which progressed to pulseless polymorphic VT. Cardioversion was unsuccessful. External cardiac massage restored spontaneous circulation; however, her underlying rhythm remained sustained SVT with frequent PVCs. These arrhythmias repeatedly led to circulatory arrest. She was administered six intravenous boluses of 2 g of MgSO4 in the emergency department, which prevented her from going into sustained pulseless VT. Hemoperfusion (HP) with activated charcoal was performed 1.5 h after arrival. The aconitine, mesaconitine, and hypaconitine plasma concentrations were high at 8.9, 23.5, and 5.5 ng/mL, respectively, before the start of HP but decreased to 1.7, 4.0, and 2.7 ng/mL, respectively, after 7 h of HP. She returned to sinus rhythm on the second day of hospitalization; however, the patient required maintenance hemodialysis. We concluded that high-dose IV MgSO4 is an effective treatment for fatal tachyarrhythmias due to aconite poisoning, and that in cases of renal failure, HP may be required to remove aconite toxins from the body. [ABSTRACT FROM AUTHOR]