Acetic acid-indigo carmine chromoendoscopy for delineating early gastric cancers: its usefulness according to histological type

<p>Abstract</p> <p>Background</p> <p>Endoscopic treatments, such as endoscopic submucosal dissection (ESD) and laparoscopic gastrectomy, are increasingly used to treat a subset of patients with early gastric cancer (EGC). To achieve successful outcomes, it is very important to accurately determine the lateral extent of the tumor. Therefore, we investigated the diagnostic performance of chromoendoscopy using indigo carmine dye added to acetic acid (AI chromoendoscopy) in delineating differentiated or undifferentiated adenocarcinomas in patients with EGC.</p> <p>Methods</p> <p>We prospectively included 151 lesions of 141 patients that had an endoscopic diagnosis of EGC. All the lesions were examined by conventional endoscopy and AI chromoendoscopy before ESD or laparoscopic gastrectomy. The border clarification between the lesion and the normal mucosa was classified as distinct or indistinct before and after AI chromoendoscopy.</p> <p>Results</p> <p>The borders of the lesions were distinct in 66.9% (101/151) with conventional endoscopy and in 84.1% (127/151) with AI chromoendoscopy (<it>P </it>< 0.001). Compared with conventional endoscopy, AI chromoendoscopy clarified the border in a significantly higher percentage of differentiated adenocarcinomas (74/108 [68.5%] vs 97/108 [89.8%], respectively, <it>P </it>< 0.001). However, the border clarification rate for undifferentiated adenocarcinomas did not differ between conventional endoscopy and AI chromoendoscopy (27/43 [62.8%] vs 30/43 [70.0%], respectively, <it>P </it>= 0.494).</p> <p>Conclusions</p> <p>AI chromoendoscopy is useful in determining the lateral extent of EGCs. However, its usefulness is reduced in undifferentiated adenocarcinomas.</p

Cilostazol Prevents Tumor Necrosis Factor-␣-Induced Cell Death by Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Activation of Akt/Cyclic AMP Response Element-Binding Protein Phosphorylation

ABSTRACT This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol (ϳ0.1-100 M) prevented tumor necrosis factor-␣ (TNF-␣)-induced decrease in viability of SK-N-SH and HCN-1A cells, which was antagonized by 1 M iberiotoxin, a maxi-K channel blocker. TNF-␣ did not suppress the viability of the U87-MG cell, a phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioblastoma cell, but it did decrease viability of U87-MG cells transfected with expression vectors for the sense PTEN, and this decrease was also prevented by cilostazol. Cilostazol as well as 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)-(ϩ)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS 204352), maxi-K channel openers, prevented increased DNA fragmentation evoked by TNF-␣, which were antagonizable by iberiotoxin. TNF-␣-induced increased PTEN phosphorylation and decreased Akt/ cyclic AMP response element-binding protein (CREB) phosphorylation were significantly prevented by cilostazol, those of which were antagonized by both iberiotoxin and paxilline, maxi-K channel blockers. The same results were evident in U87-MG cells transfected with expression vectors for sense PTEN. Cilostazol increases the K ϩ current in SK-N-SH cells by activating maxi-K channels without affecting the ATP-sensitive K ϩ channel. Thus, our results for the first time provide evidence that cilostazol prevents TNF-␣-induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening. Recent research has shown that the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is implicated in the regulation of several cellular functions, including cell viability from apoptosi

Recent developments in protein–ligand affinity mass spectrometry

This review provides an overview of direct and indirect technologies to screen protein–ligand interactions with mass spectrometry. These technologies have as a key feature the selection or affinity purification of ligands in mixtures prior to detection. Specific fields of interest for these technologies are metabolic profiling of bioactive metabolites, natural extract screening, and the screening of libraries for bioactives, such as parallel synthesis libraries and small combichem libraries. The review addresses the principles of each of the methods discussed, with a focus on developments in recent years, and the applicability of the methods to lead generation and development in drug discovery

An Essential Regulatory Role of Downstream of Kinase-1 in the Ovalbumin-Induced Murine Model of Asthma

The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases

Effect of meal timing on pharmacokinetics and pharmacodynamics of tegoprazan in healthy male volunteers

Abstract Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open‐label, single‐dose, three‐treatment, three‐period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high‐fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24‐h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high‐fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high‐fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high‐fat meal compared with fasting the condition and when administered 30 min before a high‐fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study showed that delayed absorption of tegoprazan was observed at “after meal condition,” however, the amount of systemic exposure of “after meal condition” was similar to “fasting condition” and “before meal condition.” In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan