Cancer stem cells induced by chronic stimulation with prostaglandin E2 exhibited constitutively activated PI3K axis

Previously, our group has demonstrated establishment of Cancer Stem Cell (CSC) models from stem cells in the presence of conditioned medium of cancer cell lines. In this study, we tried to identify the factors responsible for the induction of CSCs. Since we found the lipid composition could be traced to arachidonic acid cascade in the CSC model, we assessed prostaglandin E2 (PGE2) as a candidate for the ability to induce CSCs from induced pluripotent stem cells (iPSCs). Mouse iPSCs acquired the characteristics of CSCs in the presence of 10 ng/mL of PGE2 after 4 weeks. Since constitutive Akt activation and pik3cg overexpression were found in the resultant CSCs, of which growth was found independent of PGE2, chronic stimulation of the receptors EP-2/4 by PGE2 was supposed to induce CSCs from iPSCs through epigenetic effect. The bioinformatics analysis of the next generation sequence data of the obtained CSCs proposed not only receptor tyrosine kinase activation by growth factors but also extracellular matrix and focal adhesion enhanced PI3K pathway. Collectively, chronic stimulation of stem cells with PGE2 was implied responsible for cancer initiation enhancing PI3K/Akt axis

Development of an improved method for quantitative analysis of skin blotting: Increasing reliability and applicability for skin assessment

Objective: A novel skin assessment tool named \u27skin blotting\u27 has been recently developed, which can easily predict the skin status to avoid its deterioration. The aim of this study was to propose a normalization method for skin blotting to compensate for individual differences that can hamper the quantitative comparisons and clinical applications. Methods: To normalize individual differences, we utilized a total protein as a \u27normalizer\u27 with calibration curves. For evaluation, we performed a simple simulation experiment, in which the same concentration of a protein of interest [tumour necrosis factor (TNF)-α] was applied at different volumes as a virtual individual difference. Moreover, to demonstrate the applicability of this normalization, male volunteers were recruited for skin blotting followed by the estimation of TNF-α with normalization. Results: We obtained good calibration curves for total protein (R2 = 0.995) and TNF-α (R2 = 0.997), both of which were necessary for an exact quantification. In the simulation experiment, we estimated the exact concentration of TNF-α regardless of the applied volume, demonstrating the applicability of this normalization method in skin blotting. Further, skin blotting on human subjects showed a wide range of variation in the total protein content, although the normalization was thought to reduce such individual variations. Conclusion: This study has proposed total protein normalization for skin blotting with calibration curves. This method may strengthen the quantitative performance of skin blotting, which may expand the applicability of this method as a skin assessment tool in broader fields, such as nursing and cosmetology. Résumé: Objectif: Un nouvel outil d\u27évaluation de la peau nommé "skin blotting" a été récemment mis au point, qui peut facilement prédire l\u27état de la peau pour éviter sa détérioration. Le but de cette étude est de proposer une méthode de normalisation pour la "peau buvard" pour compenser les différences individuelles qui peuvent entraver les comparaisons quantitatives et applications cliniques. Méthodes: Pour normaliser les différences individuelles, nous avons utilisé le paramètre protéine totale comme «normalisateur» avec des courbes d\u27étalonnage. Pour l\u27évaluation, nous avons réalisé une expérience de simulation simple, dans lequel la même concentration d\u27une protéine d\u27intérêt [facteur de nécrose tumorale (TNF) -α] a été appliqué à des volumes différents en tant que différence individuelle virtuel. En outre, pour démontrer l\u27applicabilité de cette normalisation, les volontaires masculins ont été recrutés pour le skin blotting suivi par l\u27estimation de TNF-α avec la normalisation. Resultats: Nous avons obtenu de bonnes courbes d\u27étalonnage pour les protéines totales (R2 = 0.995) et le TNF-α (R2 = 0.997), qui étaient tous deux nécessaires pour une quantification exacte. Dans l\u27expérience de simulation, nous avons estimé la concentration exacte de TNF-α quel que soit le volume appliqué, ce qui démontre l\u27applicabilité de cette méthode de normalisation de la "peau buvard". En outre, le skin blotting sur sujets humains a montré une large gamme de variation de la teneur totale en protéines, bien que la normalisation ait dû réduire ces variations individuelles. Conclusion: Cette étude a proposé une normalisation de protéines pour le skin blotting avec des courbes d\u27étalonnage. Cette méthode peut augmenter la performance quantitative de la technique, ce qui peut élargir l\u27applicabilité de cette méthode comme un outil d\u27évaluation de la peau dans des domaines plus larges, comme les soins infirmiers et de la cosmétologie. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.発行後1年より全文公

Increased level of tumour necrosis factor-alpha (TNF-α) on the skin of Japanese obese males: Measured by quantitative skin blotting

Objective: A state of chronic inflammation, characterized by an increased level of tumour necrosis factor-alpha (TNF-α), is often found in the obese population. The negative effects of elevated TNF-α are not limited to systemic metabolism. It also reportedly affects skin integrity. Recently, the relationship between obesity and skin fragility was reported; however, there has been little insight into how the level of TNF-α in the skin in situ is related to the severity of obesity. In this study, we aimed to measure the level of TNF-α on the skin and to find the relationship between obesity and the level of TNF-α detected on the skin. Methods: We used a novel, non-invasive method called quantitative skin blotting. Fifty-nine healthy (but some were classified as being overweight or obese) Japanese males were enrolled as subjects. The levels of TNF-α detected on the abdominal and thigh skin along with the body composition were measured, followed by a correlation analysis. Results: Significant positive correlations were found between the levels of TNF-α detected on the skin and the severity of obesity such as body mass index (BMI), body fat weight and visceral fat rating. Conclusion: We found that high levels of TNF-α were detected on the skin of Japanese obese males, which implied the higher TNF-α in the skin. The elevation of skin TNF-α may be one factor related to skin fragility that is often found in obese individuals. © 2016 John Wiley & Sons Ltd.Embargo Period 12 month

Analysis of comorbid factors that increase the COPD assessment test scores

Background: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores. Methods: An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients’ reports, physicians’ records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed. Results: The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients. Conclusions: Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognize

Title page Involvement of Human Organic Cation Transporter 1 (OCT1) in the Hepatic Uptake of YM155 Monobromide, 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide, a Novel, Small Molecule Survivi

Abstract YM155 monobromide, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide, which is a hydrophilic and cationic compound, exhibits anti-tumor activity in experimental human hormone refractory prostate carcinoma models. Urinary excretion was 18.3% to 28.6% of the dose in the clinical phase I study, and non-renal elimination may be explained by the biliary excretion of YM155 in its unchanged form. As the penetration through the sinusoidal membrane of the hepatocytes is the first step and an important part of biliary excretion, we evaluated the uptake o

Esophageal Squamous Cell Carcinoma with Marked Eosinophil Infiltration

We report a case of esophageal squamous cell carcinoma (SCC) with marked eosinophil infiltration which was identified postoperatively in the esophageal wall in areas not surrounding the SCC. The eosinophil infiltration was seen in the submucosa, muscle and adventitia, but not in the mucosa. Eosinophilic esophagitis (EoE) is a pathological condition defined as eosinophil infiltration within the esophageal mucosa. Eosinophil infiltration at the invasion front of esophageal SCC is termed tumor-associated tissue eosinophilia (TATE). However, the eosinophil infiltration in this case may be pathologically different from both EoE and TATE. To our knowledge, this is the first report of esophageal SCC with eosinophil infiltration

Trick or Tweak: On the (In)security of OTR’s Tweaks

Tweakable blockcipher (TBC) is a powerful tool to design authenticated encryption schemes as illustrated by Minematsu\u27s Offset Two Rounds (OTR) construction. It considers an additional input, called tweak, to a standard blockcipher which adds some variability to this primitive. More specifically, each tweak is expected to define a different, independent pseudo-random permutation. In this work we focus on OTR\u27s way to instantiate a TBC and show that it does not achieve such a property for a large amount of parameters. We indeed describe collisions between the input masks derived from the tweaks and explain how they result in practical attacks against this scheme, breaking privacy, authenticity, or both, using a single encryption query, with advantage at least 1/4. We stress however that our results do not invalidate the OTR construction as a whole but simply prove that the TBC\u27s input masks should be designed differently

ZMAC: A Fast Tweakable Block Cipher Mode for Highly Secure Message Authentication

We propose a new mode of operation called ZMAC allowing to construct a (stateless and deterministic) message authentication code (MAC) from a tweakable block cipher (TBC). When using a TBC with $n$-bit blocks and $t$-bit tweaks, our construction provides security (as a variable-input-length PRF) beyond the birthday bound with respect to the block-length $n$ and allows to process $n+t$ bits of inputs per TBC call. In comparison, previous TBC-based modes such as PMAC1, the TBC-based generalization of the seminal PMAC mode (Black and Rogaway, EUROCRYPT 2002) or PMAC_TBC1k (Naito, ProvSec 2015) only process $n$ bits of input per TBC call. Since an $n$-bit block, $t$-bit tweak TBC can process at most $n+t$ bits of input per call, the efficiency of our construction is essentially optimal, while achieving beyond-birthday-bound security. The ZMAC mode is fully parallelizable and can be directly instantiated with several concrete TBC proposals, such as Deoxys and SKINNY. We also use ZMAC to construct a stateless and deterministic Authenticated Encryption scheme called ZAE which is very efficient and secure beyond the birthday bound

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

<p>Abstract</p> <p>Background</p> <p>Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart.</p> <p>Methods</p> <p>The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects.</p> <p>Results</p> <p>Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC₅₀values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine.</p> <p>Conclusions</p> <p>In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.</p