IntroductionHuman V␣24NKT cells are a subpopulation of T cells, highly conserved between mice (V␣14NKT cells) and humans (V␣24NKT cells), which can be stimulated by ␣-galactocylceramide (␣-GalCer, KRN7000) in a CD1d-dependent and a T-cell receptor (TCR)-mediated manner. [1][2][3] Most human peripheral blood V␣24NKT cells have a double-negative (DN; CD4 Ϫ CD8 Ϫ ) or CD4 ϩ phenotype and coexpress CD161. Other surface markers of natural killer (NK) cells (CD16, CD56, and CD57) and immunoglobulin (Ig)-type NK receptors such as p58.1, p58.2, and p70 are not expressed. Expression of CD94, a lectin-type NK receptor, varies probably depending on V␣24NKT cell subpopulations. [2][3][4] There is evidence for a role of these cells in preventing or controlling malignancy. Mice injected with ␣-GalCer were protected from experimentally induced tumors, and it is clear that V␣14NKT cells were responsible for these antitumor effects. [5][6][7] Similar antitumor effects were seen when murine V␣14NKT cells or human V␣24NKT cells were adoptively transferred into tumorbearing mice. 8 We have recently shown in vitro susceptibility of human malignant cell lines to cytotoxic activity of V␣24NKT cells. U937 (a cell line with monocytic characteristics), THP-1 (monocytic leukemia cell line), and Molt-4 (T-cell lymphoma) were sensitive to the cytotoxic activity of DNV␣24NKT cells, but neither K562 (chronic myelogeneous leukemia cell line) nor Daudi (Burkitt lymphoma cell line) were sensitive. 9 Among tumor cell lines we have tested, U937 was the most susceptible to the cytotoxic activity of both DN and CD4 ϩ V␣24NKT cells.These previous in vitro studies showing cytotoxic activity against human hematologic malignancies suggested that V␣24NKT cells, activated by ␣-GalCer, warranted further investigation for a possible immune therapeutic role in the treatment of acute myeloid leukemia (AML), particularly those of monocytic origin. AML encompasses a group of disorders characterized by clonal accumulation of immature and abnormal myeloid cells in the blood and marrow. Most adult patients with AML cannot be cured with current treatments involving maximum tolerated doses of chemotherapy; novel therapeutic strategies such as immune-based therapies are needed to sustain remission and increase the cure rate.Although antitumor activity of V␣24NKT has been clearly demonstrated in vitro, the mechanisms for selective killing of malignant cells have not been defined to date. Activation of V␣24NKT cells is dependent on the presentation of ␣-GalCer by CD1d, but neither is essential for their cytotoxic activity against some malignant cells. It is still unknown how V␣24NKT cells kill malignant targets. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a recently identified type II integral membrane protein belonging to the TNF family that selectively induces apoptosis of various tumor cell lines. [10][11][12][13][14] Lymphoid cells such as T cells and NK cells express TRAIL, and these TRAIL-expressing cells induce apoptotic cell death i...

Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

SummaryIn this study, no transgenic gentian (Gentiana triflora · Gentiana scabra) plants produced via Agrobacteriummediated transformation exhibited transgene (GtMADS, gentian-derived MADS-box genes or sGFP, green fluorescent protein) expression in their leaf tissues, despite the use of constitutive Cauliflower mosaic virus (CaMV) 35S promoter. Strikingly, no expression of the selectable marker gene (bar) used for bialaphos selection was observed. To investigate the possible cause of this drastic transgene silencing, methylation-specific sequences were analysed by bisulfite genomic sequencing using tobacco transformants as a control. Highly methylated cytosine residues of CpG and CpWpG (W contains A or T) sites were distinctively detected in the promoter and 5¢ coding regions of the transgenes 35S-bar and 35S-GtMADS in all gentian lines analysed. These lines also exhibited various degrees of cytosine methylation in asymmetrical sequences. The methylation frequencies in the other transgene, nopaline synthase (NOS) promoter-driven nptII, and the endogenous GtMADS gene coding region, were much lower and were variable compared with those in the 35S promoter regions. Transgene methylation was observed in the bialaphos-selected transgenic calluses expressing the transgenes, and methylation sequences were distributed preferentially around the as-1 element in the 35S promoter. Calluses derived from leaf tissues of silenced transgenic gentian also exhibited transgene suppression, but expression was recovered by treatment with the methylation inhibitor 5-aza-2¢-deoxycytidine (aza-dC). These results indicated that cytosine methylation occurs exclusively in the 35S promoter regions of the expressed transgenes during selection of gentian transformants, causing transcriptional gene silencing.

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Heme oxygenase-1 (HO-1) acts in cytoprotection against oxidants and aromatic hydrocarbons in cigarette smoke. A (GT)(n) dinucleotide repeat in the 5'-flanking region of the human HO-1 gene (alias HMOX1) reduces HO-1 inducibility and shows length polymorphism, which is grouped into three classes: class S (<27 GT), class M (27-32 GT), and class L (>/=33 GT) alleles. To investigate the correlation between the HO-1 gene polymorphism and the development of lung adenocarcinoma, we screened 151 Japanese patients with lung adenocarcinoma and 153 control subjects. Patients and control subjects were frequency-matched by age, gender, smoking history and proportion of chronic pulmonary emphysema. The proportion of class L allele frequencies, as well as that of genotypic frequencies in L allele carriers (LL, LM, and LS), were significantly higher in patients with lung adenocarcinoma than those of control subjects. The adjusted odds ratio (OR) for lung adenocarcinoma with class L allele vs non-L allele (M+S) was 1.6 [95% confidence interval (CI) 1.0-2.5, P=0.03] and that with L allele carriers vs. non-L allele carriers was 1.8 (95% CI 1.1-3.0, P=0.02). Furthermore, the risk of lung adenocaricinoma for L allele carriers versus non-L allele carriers was much increased in the group of male smokers (OR=3.3, 95% CI 1.5-7.4, P=0.004). However, in the female non-smokers, the proportion of L allele carriers did not differ between patients and control subjects (OR=0.93, 95% CI 0.4-2.0, P=0.85). These findings suggest that the large size of a (GT)(n) repeat in the HO-1 gene promoter may be associated with the development of lung adenocarcinoma in Japanese male smokers.

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The present study aimed to explore the status of deliberate self-harm (DSH) among junior high-school students, and investigate the relationship between DSH and substance use and childhood hyperactivity. Subjects were 239 boys (mean age = 14.16 years, SD = 0.67) and 238 girls (14.22, 0.68) from a junior high-school in Kanagawa, Japan. A self-reporting questionnaire consisting of original questions on self-cutting, self-hitting, and tobacco and alcohol use was employed with the Wender Utah Rating Scale (WURS) for assessing childhood hyperactivity. Overall, 8.00% and 27.70% of males and 9.30% and 12.20% of females reported self-cutting and self-hitting, respectively. Regarding substance use, 33.10% and 74.10% of males and 14.30% and 63.40% of females reported tobacco and alcohol use, respectively. Comparisons of WURS scores between those with and without experience of problematic behaviors revealed that with all problematic behaviors in both genders, scores of those with experience were significantly higher than those without (P < 0.01 except for self-cutting in females, P < 0.05). The present study indicated that DSH is an important problem, even among children as young as junior high-school age. An association between DSH and childhood hyperactivity was also suggested.

Aim: Insight in schizophrenia is considered to have a multidimensional construct, and cognitive insight is thought to be an important dimension of insight: an ability to evaluate and correct one's own distorted beliefs and misinterpretations. The Beck Cognitive Insight Scale (BCIS) was developed to measure cognitive insight, and studies have shown that cognitive insight is associated with several clinical features in schizophrenia. The aim of the present study was to develop a Japanese version of the BCIS (BCIS-J) and assess the psychometric properties of this instrument. Methods:The BCIS-J was completed by university students (n = 183) and patients with schizophrenia (n = 30). The Japanese version of the Schedule for the Assessment of Insight was used to measure clinical insight in patients with schizophrenia, and its association with the BCIS-J was investigated.Results: Factor analysis in the university students indicated that the BCIS-J was composed of two factors, self-reflectiveness and self-certainty, as was seen in the original BCIS. The relation between the specific dimensions of clinical insight and each component of the BCIS-J in patients with schizophrenia indicated that overconfidence in their belief or judgment may be involved in their attitude to treatment and openness to feedback, and objectivity might be essential to attribute one's symptoms as part of mental illness. Conclusions:The BCIS-J is a reliable and valid instrument to measure cognitive aspects of insight and appears to complement clinical insight scales.