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Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues. [ABSTRACT FROM AUTHOR]

Optical and microphysical properties of the upper clouds at an altitude range of 5-11 km were measured over Tsukuba, Japan, on 29-30 March 2004 using a ground-based Raman lidar and a balloon-borne hydrometeor videosonde (HYVIS). The Raman lidar measured the vertical distributions of the particle extinction coefficient, backscattering coefficients, depolarization ratio, and extinction-to-backscatter ratio (lidar ratio) at 532 nm; further, it measured the water vapor mixing ratio. The HYVIS measured the vertical distributions of the particle size, shape, cross-sectional area, and number concentration of the cloud particles by taking microscopic images. The HYVIS measurement showed that the cloud particles were ice crystals whose shapes were columnar, bulletlike, platelike, and irregular, and 7-400 [micro]m in size. The Raman lidar measurement showed that the depolarization ratio ranged from 0% to 35% and the lidar ranged from 0.3 to 30 sr for the clouds in ice-saturated air. The comparison between the measured data and theoretical calculations of the cloud optical properties suggests that the observed variations in the depolarization ratio and lidar ratio were primarily due to the variation in the proportion of the horizontally oriented ice crystals in the clouds. The optical thickness of the cloud obtained from the lidar was about 2 times lower than that calculated from the HYVIS data, and the maximum extinction coefficient was about 5 times lower than the HYVIS data. The most probable reason for the differences is the horizontal inhomogeneities of the cloud properties between the measurements sites for the two instruments.

Combined treatment of human oral squamous cell carcinoma (OSCCs) with DNA methyltransferase inhibitors (DNMTis), histone methyltransferase inhibitors (HMTis), and histone deacetylase inhibitors (HDACis), and the molecular mechanisms underlying their anticancer effects, have not been fully elucidated. Herein, we investigated the cytotoxic effects of combined DNMTis (5-Aza-deoxycytidine: 5-Aza-dC, RG108), HMTis (3-deazaneplanocin A: DZNep), and HDACis (trichostatin A: TSA) treatment on human OSCC cells and explored their molecular mechanisms. Combined 5-Aza-dC, or RG108, and TSA treatment significantly decreased HSC-2 and Ca9-22 cell viability. Combinatorial DZNep and TSA treatment also decreased Ca9-22 cell viability. Although caspase 3/7 activation was not observed in HSC-2 cells following combined treatment, caspase activity was significantly increased in Ca9-22 cells treated with DZNep and TSA. Moreover, combined treatment with 5-Aza-dC, RG108, and TSA increased the proportion of HSC-2 and Ca9-22 cells in the S and G2/M phases. Meanwhile, increased phosphorylation of the histone variant H2A.X, a marker of double-stranded DNA breaks, was observed in both cells after combination treatment. Hence, the decreased viability induced by combined treatment with epigenomic inhibitors results from apoptosis and cell cycle arrest in S and G2/M phases. Thus, epigenomic therapy comprising combined low concentrations of DNMTi, HMTi, and HDACi is effective against OSCC. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the alternatively activated M2 macrophages exhibit protumor functions that contribute to tumor development and progression. Although TAMs have been detected in oral squamous cell carcinoma (OSCC), little is known about their phenotype. In the present study, we performed an immunohistochemical analysis to identify TAMs in surgically resected specimens from 50 patients with OSCC and evaluated the relationship between infiltrated TAMs and the pathological grade of OSCC. Positive staining for CD163, which has been used as a marker for M2 macrophages, was observed in OSCC specimens, and the percentages of CD163+ cells were significantly increased based on the pathological grade. CD163+ cells were detected in the tumor stroma in grade I tumors, whereas an increase in the CD163+cells in the tumor nest was observed in higher grades of tumors. Although infiltrated CD4+ and CD8+ T cells were detected in all pathological grades of OSCC, no correlation between the infiltrated T cells and the CD163+ TAMs was observed. These results indicate that the infiltrated TAMs in OSCC have an M2 phenotype and that the M2 macrophages may participate in the development of OSCC. [ABSTRACT FROM AUTHOR]

This paper addresses the problem of the detection of speaker changes and clustering speakers when no information is available regarding speaker classes or even the total number of classes. This study provides preprocessing for a method which adapts speaker information based on incremental on-line speaker clustering. We assume that no previous information on speakers is available (no speaker model, no training phase) and that people do not speak simultaneously. The aim is to apply speaker grouping information to speaker adaptation for speech recognition. We use Vector Quantization (VQ) distortion as the criterion. A speaker model is created from successive utterances as a codebook by a VQ algorithm, and the VQ distortion is calculated between the model and an utterance. The results of an experiment on speaker detection and speaker clustering are presented. The speaker change detection experiment was compared with results of the Generalized Likelihood Ratio (GLR) and Bayesian Information Criterion (BIC). By using GLR and BIC, we obtained F-measures of 75.8 and 81.4, respectively. On the other hand, we obtained an F-measure of 84.4 by the proposed method. Furthermore, by a combination of the method with an acoustic back-off method, we obtained a measure of 93.1 and a classification rate of 97.7%. These results show the superiority of our proposed method. Finally, we demonstrate the validity of our proposed method by experiments on speech recognition using on-line speaker adaptation. © 2003 Wiley Periodicals, Inc. Syst Comp Jpn, 34(13): 25–35, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.10488 [ABSTRACT FROM AUTHOR]

The zona penetration test and triple stain technique were used to elucidate the blocking effects of carbohydrates on human fertilization and their mechanisms. In the presence of D-mannose or D-fructose (final concentration, 50 mmol/1), sperm penetration through the human zona pellucida was completely blocked. The triple stain technique revealed that D-fructose (50 mmol/1) significantly ( < 0.01) suppressed the acrosome reaction of human spermatozoa, while D-mannose did not show a suppressive effect on the acrosome reaction. These results reinforce our hypothesis proposed previously, that a mandatory step in human fertilization is the binding of a D-mannose-binding constituent of the sperm surface to a D-mannose residue in the sperm receptor site on the zona pellucida. In addition, D-fructose may play an important role as an acrosome stabilizing factor in seminal fluid. [ABSTRACT FROM PUBLISHER]

Simple Summary: Oral squamous cell carcinoma (OSCC), the most common oral malignancy, severely impacts patient quality of life because of oro-facial destruction. OSCC is preceded by oral premalignant lesions (OPLs). Moreover, lower T cell infiltration in OPLs is associated with OSCC, suggesting that T cell-mediated adaptive immunity protects against malignant transformation. In this study, we used the carcinogen 4NQO, which mimics tobacco-related carcinogenesis, in a mouse model to examine the gene expression kinetics of chemokines/cytokines during OPL and OSCC development. Our results demonstrate that both Th1- and Treg-associated chemokines were simultaneously expressed in 4NQO-induced OPL, with their expression correlating with the infiltration of CD8+ and Foxp3+ cells, respectively. These results indicate that antitumor immune responses and immunosuppression are simultaneously initiated during OLP development. Chemokines and cytokines in the tumor microenvironment influence immune cell infiltration and activation. To elucidate their role in immune cell recruitment during oral cancer development, we generated a mouse tongue cancer model using the carcinogen 4-nitroquinoline 1-oxide (4NQO) and investigated the carcinogenetic process and chemokine/cytokine gene expression kinetics in the mouse tongue. C57/BL6 mice were administered 4NQO in drinking water, after which tongues were dissected at 16 and 28 weeks and subjected to analysis using the RT2 Profiler PCR Array, qRT-PCR, and pathologic and immunohistochemical analyses. We found that Th1-associated chemokine/cytokine (Cxcl9, Cxcl10, Ccl5, and Ifng) and Treg-associated chemokine/cytokine (Ccl17, Ccl22, and Il10) mRNA levels were simultaneously increased in premalignant lesions of 4NQO-treated mice at 16 weeks. Additionally, although levels of Gata3, a Th2 marker, were not upregulated, those of Cxcr3, Ccr4, and Foxp3 were upregulated in the tongue tissue. Furthermore, immunohistochemical analysis confirmed the infiltration of CD4+, CD8+, and Foxp3+ cells in the tongue tissue of 4NQO-treated mice, as well as significant correlations between Th1- or Treg-associated chemokine/cytokine mRNA expression and T cell infiltration. These results indicate that CD4+, CD8+, and Foxp3+ cells were simultaneously recruited through the expression of Th1- and Treg-associated chemokines in premalignant lesions of 4NQO-induced mouse tongue tissue. [ABSTRACT FROM AUTHOR]

The present article reviews the research progress of three major polyphenols (tannins, flavonoids and lignin carbohydrate complexes), chromone (backbone structure of flavonoids) and herbal extracts. Chemical modified chromone derivatives showed highly specific toxicity against human oral squamous cell carcinoma cell lines, with much lower toxicity against human oral keratinocytes, as compared with various anticancer drugs. QSAR analysis suggests the possible correlation between their tumor-specificity and three-dimensional molecular shape. Condensed tannins in the tea extracts inactivated the glucosyltransferase enzymes, involved in the biofilm formation. Lignin-carbohydrate complexes (prepared by alkaline extraction and acid-precipitation) and crude alkaline extract of the leaves of Sasa species (SE, available as an over-the-counter drug) showed much higher anti-HIV activity, than tannins, flavonoids and Japanese traditional medicine (Kampo). Long-term treatment with SE and several Kampo medicines showed an anti-inflammatory and anti-oxidant effects in small size of clinical trials. Although the anti-periodontitis activity of synthetic angiotensin II blockers has been suggested in many papers, natural angiotensin II blockers has not yet been tested for their possible anti-periodontitis activity. There should be still many unknown substances that are useful for treating the oral diseases in the natural kingdom., Competing Interests: One of the authors (H.S.) has been donated from the research fund from Daiwa Biological Research Institute Co., Ltd., Kanagawa, Japan. The authors wish to confirm that such financial support has not influenced the outcome the experimental data.

Background: Tumor-associated macrophages (TAMs) are implicated in the growth, invasion and metastasis of various solid tumors. However, the phenotype of TAMs in premalignant lesions of solid tumors has not been clarified. In the present study, we identify the phenotype of TAMs in leukoplakia, an oral premalignant lesion, by immunohistochemical analysis and investigate the involvement of infiltrated T cells that participate in the polarization of TAMs., Methods: The subjects included 30 patients with oral leukoplakia and 10 individuals with normal mucosa. Hematoxylin and eosin slides were examined for the histological grades, and immunohistochemical analysis was carried out using antibodies against CD68 (pan-MΦ), CD80 (M1 MΦ), CD163 (M2 MΦ), CD4 (helper T cells: Th), CD8 (cytotoxic T cells), CXCR3, CCR5 (Th1), CCR4 (Th2), signal transducer and activator of transcription (STAT1), phosphorylated STAT1 (pSTAT1) and chemokine CXCL9. The differences in the numbers of positively stained cells among the different histological grades were tested for statistical significance using the Kruskal-Wallis test. Correlations between different types of immune cells were determined using Spearman's rank analysis., Results: An increase in the rate of CD163(+) TAM infiltration was observed in mild and moderate epithelial dysplasia, which positively correlated with the rate of intraepithelial CD4(+) Th cell infiltration. Although CCR4(+) cells rarely infiltrated, CXCR3(+) and CCR5(+) cells were observed in these lesions. Cells positive for STAT1 and chemokine CXCL9, interferon- (IFN)-induced gene products, and pSTAT1 were also observed in the same lesions. Double immunofluorescence staining demonstrated that the cells that were positive for CD163 were also positive for STAT1., Conclusions: CD163(+) TAMs in oral premalignant lesions coexpress CD163 and STAT1, suggesting that the TAMs in oral premalignant lesions possess an M1 phenotype in a Th1-dominated micromilieu.

Patients admitted to the hospital with heart failure (HF) include those with new-onset of acute HF and those with acute exacerbation of chronic HF (CHF). In therapy for new-onset acute HF associated with acute myocardial infarction, therapy to inhibit left ventricular (LV) remodeling in the convalescent phase is required in addition to that needed to overcome the acute phase. Hitherto, CHF therapy was aimed at improving LV contractability, whereas more recently the aim has shifted to resting the heart. Most patients with HF should be routinely managed with a combination of 3 types of drugs: a diuretic; an angiotensin converting enzyme inhibitor and/or an angiotensin II receptor blocker; and a beta-blocker. The administration of beta-blockers is of particular importance. For HF unresponsive to medical therapy, non-pharmacological therapies are considered. When a HF patient fails to respond to all available therapies, heart transplantation becomes necessary. Of the 1,000 HF patients admitted to our hospital, two cases received heart transplants. 11 cases were indicated for heart transplantation but died before registration. It should be remembered that although in Japan the possibility of receiving a heart transplant is very low, it is by no means entirely impossible.

Background: Left ventricle diastolic dysfunction is attracting increasing attention of one of the etiologies of chronic heart failure (CHF)., Methods and Results: The study sample included 560 patients with CHF who were hospitalized during the 5-year period. They were classified into 2 groups according to the left ventricular ejection fraction (LVEF): reduced group (LVEF <50%, n=431); or preserved group (LVEF >or=50%, n=129). The degree of cardiac symptoms did not differ between the 2 groups; however, no difference was found between the 2 groups in the mortality rate (P=0.898), and readmission rates (P=0.674). The results of a multivariate analysis using a Cox proportional hazards model to identify predictors of the prognosis of heart failure revealed no difference in prognosis according to the presence/absence of decreased LVEF, whereas renal dysfunction and anemia were identified as significant prognostic determinants. Also, in the reduced group, the administration of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARB), beta-blockers reduced mortality. In the preserved group, ACE-I and/or ARB administration reduced mortality, whereas beta-blockers did not., Conclusion: In the present study, the likelihood of LVEF influencing prognosis was considered to be low, with the contribution of non-cardiac factors such as renal function and anemia concluded to be greater.

Background: It has been proposed that 0.5-mm-slice multislice computed tomography (MSCT) is a noninvasive tool for the detection of atherosclerotic plaque, but the validity of such an assessment has not been demonstrated by an invasive investigation. The present study was performed to compare the 0.5-mm-slice MSCT density of plaques with intravascular ultrasound (IVUS) findings., Methods and Results: Atherosclerotic plaques were characterized in 37 consecutive patients undergoing percutaneous interventions. Based on the IVUS echogenecity, the plaques were classified as soft (n=18), fibrous (n=40) or calcified (n=40). In these 98 plaques, 0.5-mm-slice MSCT plaque density was calculated in 443 regions-of-interest, including 331 lesional foci and 112 luminal cross-sections, and represented as Hounsfield units (HU). MSCT density of the 3 types of plaque was 11+/-12 HU, 78+/-21 HU, and 516 +/-198 HU respectively. Computed tomography density of the (contrast-filled) lumen was 258+/-43 HU. There were statistically highly significant differences in the densitometric characteristics among the 4 groups (soft, fibrous, calcified plaque and lumen) by nonparametric Kruskal-Wallis test (p<0.0001)., Conclusions: The IVUS-based coronary plaque configuration can be accurately identified by 0.5-mm slice MSCT. Noninvasive assessment of plaque characterization will ensure emphasis on the vessel wall beyond the vascular lumen.

Several trifluoromethyl ketones (TF1-4) and related non-fluorinated ketones (TF5 and 6) were tested for their relative cytotoxicity on four human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, HSC-4 and promyelocytic leukemia HL-60) and three normal human cells [gingival fibroblasts (HGF), pulp cells (HPC) and periodontal ligament fibroblasts (HPLF)]. Trifluoromethylated a-diketone (TF1, CF3COCOPh) and alpha-hydroxy ketones (TF2, CF3CH(OH)COPh; TF3, CF3CH(OH)COCH2Ph) showed higher tumor-specific cytotoxic activity than the corresponding non-fluorinated analogs (TF5, CH3COCOPh; TF6, CH3CH(OH)COPh), while the anti-tumor potency of trifluoromethyl ketone (TF4, CF3COCH2Ph) was lower. Among four tumor cell lines, HL-60 cells were the most sensitive to TF1-4, followed by HSC-2 and HSC-3 cells. HSC-4 cells were the most resistant in most cases. Agarose gel electrophoresis showed that TF1-3 did not induce intemucleosomal DNA fragmentation nor activated caspase-3. The cytotoxic activities of TF1-3 were not significantly affected by FeCl3. Electron microscopy of TF2- or 3-treated HL-60 cells showed the development of autophagosomes in HL-60 cells, without the production of an apoptotic body, or affecting the mitochondria and cell surface microvilli. The autophagy inhibitor, 3-methyladenine (3-MA), partially inhibited the TF2- or 3-induced cytotoxicity. These data suggest the induction of non-apoptotic cell death by TF2 or 3.

Most patients with acute myocarditis manifest particular clinical signs and symptoms, including marked cardiac failure and/or a high degree of atrioventricular block on admission. However, a 78-year-old man did not have symptoms and was hospitalized as a result of abnormalities observed on an incidentally obtained electrocardiogram (ECG). Several days later, he developed cardiogenic shock and fulminant myocarditis, which required percutaneous cardiopulmonary support; however, the cardiac failure persisted and he died approximately 4 months later. The ECG showed findings similar to those of acute inferior myocardial infarction, and on left ventriculography, diffuse hypokinesis was observed most prominently in the inferoposterior wall. During autopsy, interstitial fibrosis was marked in the inferoposterior wall, with small, round, cell infiltration prominent at the same site. Clustering of these cells is a characteristic feature of chronic myocarditis.