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The purpose of the present study was to identify histological biomarkers that could be used to predict adipose tissue invasion by oral squamous cell carcinoma (OSCC). The medical records and preoperative computed tomography scans of patients with primary OSCC with suspected buccal fat pad invasion were retrospectively reviewed, and an immunohistochemical study of candidate predictive biomarkers of adipose tissue invasion (α-SMA, E-cadherin, N-cadherin, FABP4, Col VI, and MMP-11) was carried out. Thirty OSCC patients whose tumors were suspected to be in contact with the buccal fat pad based on preoperative imaging were included in this study. Of these, infiltrative adipose tissue invasion was histopathologically confirmed in 6 patients (20.0 %). The significant higher immunoreactivity of candidate predictive biomarkers was detected in the tumor-buccal fat pad contact area compared to in the tumor surface area.(Pearson’s correlation coefficient test: α-SMA: 0.422, p

Salivary dysfunction, such as reduced salivary flow and an altered salivary composition, is caused by several diseases, medical conditions, and medications. The purpose of the present study was to clarify the relationship between hypertension and morphological changes in the submandibular glands. An epidemiological study was conducted to elucidate the relationship between hypertension and dry mouth. The effects of hypertension on morphological changes and the intima thickness of arteries in the submandibular glands were histopathologically investigated. Among 1933 subjects in the epidemiological study, 155 (8.0%) had dry mouth. A multivariate analysis revealed that dry mouth correlated with age (p

The accurate preoperative determination of the extent of mandibular resection remains a challenge for the surgeons. The purpose of the present study was to immunohistochemically investigate predictive markers for histological bone invasion of oral squamous cell carcinoma (OSCC). The medical records of primary OSCC patients with mandibular bone contact in preoperative computed tomography scans between January 2003 and December 2017 were retrospectively reviewed and an immunohistochemical investigation was performed. Forty-five OSCC patients with mandibular bone contact radiographically were included in this study. Histopathologically, infiltrative bone invasion was observed in 19 patients (42.2%) and compressive bone invasion in 15 (33.3%). A correlation was noted between the histological pattern of bone invasion and mode of invasion (chi-squared test, p

The impact of host systemic conditions/diseases on the prosperity of oral Candida colonies remains unclear. The aim of the present study was to investigate whether a relationship exists between the quantity of oral Candida and the systemic condition/diseases of the host. The cross-sectional relationship between Candida mannan concentrations and health check-up results was analyzed in consideration of local conditions that influence the prevalence of oral Candida. Candida mannan concentrations correlated with age, the number of untreated decayed teeth, number of prosthetic teeth, salivary pH, HbA1c, and the red blood cell count in a univariate analysis. In a multivariate analysis, Candida mannan concentrations correlated with age, the number of untreated decayed teeth, number of prosthetic teeth, salivary pH, and the red blood cell count. Candida mannan concentrations were higher in subjects older than 80 years, with a higher number of either untreated or prosthetic teeth, with a lower salivary pH, and with a decreased red blood cell count. Mannan concentrations were slightly higher in subjects with elevated HbA1c. The present results suggest a close relationship between the quantity of oral Candida and the systemic condition/diseases of the host. Oral Candida may increase in immunocompromised hosts.

A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.

The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK 1 receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24 h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK2 receptor (NK2-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK2-R agonist, βAla8-neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK2-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK2-R antagonists in dose- and/or plasma concentration–dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r2 = 0.61). Furthermore, the minimum effective doses on the VMR and ID50 values calculated in the PD model were highly correlated (r2 = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK2-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK2-R with in vivo therapeutic efficacy. Keywords:: NK2-receptor antagonist, colonic contraction, pharmacodynamic (PD) marker, pharmacokinetic (PK) / pharmacodynamic (PD), colorectal distension

On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7 , we prepared several five-membered heterocyclic analogues ( 8 ) and evaluated their H + ,K + -ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H + ,K + -ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.

A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.

In this study, we attempted to clarify the mechanism of tachykinin-induced motor response in isolated smooth muscle preparations of the human colon. Fresh specimens of normal colon were obtained from patients suffering from colonic cancer. Using mucosa-free smooth muscle strips, smooth muscle tension with circular direction was monitored isometrically. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) produced marked contraction. All of these contractions were inhibited by saredutant, a selective NK2-R antagonist, but not by CP122721, a selective NK1-R antagonist or talnetant, a selective NK3-R antagonist. βAla8-NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar9-Met11-SP and Met-Phe7-NKB did not cause marked contraction. Colonic contraction induced by βAla8-NKA(4-10) was completely blocked by saredutant, but not by atropine. Tetrodotoxin or NG-nitro-l-arginine methyl ester pretreatment significantly enhanced βAla8-NKA(4-10)–induced contraction. Immunohistochemical analysis showed that the NK2-R was expressed on the smooth muscle layers and myenteric plexus where it was also co-expressed with neuronal nitric oxide synthase in the myenteric plexus. These results suggest that the NK2-R is a major contributor to tachykinin-induced smooth muscle contraction in human colon and that the NK2-R–mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons. Keywords:: NK1 receptor, NK2 receptor, NK3 receptor, human colon, smooth muscle

H(+),K(+)-ATPase is a key enzyme in the process of gastric acid secretion, and proton pump inhibitors (PPIs) have been accepted as one of the most effective treatments for peptic ulcer and gastroesophageal reflux disease. To discover a novel class of PPIs, the authors screened a low-molecular-weight compound library and identified two prospective acid blockers that were pyrrole derivatives. Both compounds inhibited H(+),K(+)-ATPase in a reversible and potassium-competitive manner. These compounds led to the development of TAK-438 (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate), which is currently undergoing clinical trials as a novel potassium-competitive acid blocker for the treatment of acid-related diseases.

We synthesized a series of novel 3-phenyl-4-benzylaminopiperidine derivatives that were identified as potent tachykinin NK(1) receptor antagonists by structural modification of the 3-benzhydrylpiperidone derivative through high-throughput screening. N-{2-[(3R,4S)-4-({2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}amino)-3-phenyl-1-piperidinyl]-2-oxoethyl}acetamide ((+)-39) was found to be one of the most potent tachykinin NK(1) receptor antagonists with high metabolic stability. Highly efficient asymmetric synthesis of (+)-39 was achieved via dynamic kinetic resolution.

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

There have been two types of Web visualization techniques: visualization of Web sites themselves based on such as link structures or lexical contents, and visualization of browsers’ behaviors. We think that integration of such two visualization techniques is very useful for Web site management, and therefore we are currently studying on visualization of access pattern and link structure on a single screen. This paper presents a Web visualization technique using our own multiple-category-embedded graph visualization technique. The presented technique constructs link structures using crawler software, and access patterns from access log files. It then integrates them and visualizes by our graph visualization technique. We expect that users can visually understand the relationship between access patterns and link structures, and utilize the knowledge for design and management of Web sites. This paper shows our case study and discusses typical access patterns we observed by the technique.