Antitumor activities of OK-432-stimulated peripheral blood mononuclear cells (PBMC) were examined. Killer activity against natural killer (NK) cell-sensitive K562 as well as lymphokine activated killer (LAK) cell-sensitive Daudi and PC3 target cells were detected among PBMC cultured with a low dose (0.0125-0.05 KE/ml) of OK-432. Kinetic analysis of killer activity showed that it reached a plateau level by 48 h of culture. Various freshly isolated tumor cells from oral cancer patients were also lysed by both the autologous and allogeneic OK-432-stimulated PBMC (OK-MC), suggesting that the specificity of the killer was not restricted by HLA and was thus non-specific. Fluorescence activated cell sortor (FACS) analyses showed that CD57⁺/CD25⁺ and CD16⁺/CD25⁺ cells were increased in PBMC after 48-h stimulation with OK-432. The killer activity was further augmented by the addition of rIL-2 at the time of killer assay.
Tumor growth inhibitory factor () activity, which we previously reported, was found in the culture supernatant (CSN) of OK-MC from various cancer patients. The titer of from these patients was high enough, 16-64 × of the reciprocal dilution of the CSN, which was almost equivalent to the activity from normal healthy controls.
These results suggest that two kinds of antitumor activities were induced in the OK-432-stimulated PBMC in vitro, the one being cell-mediated and the other lymphokine-mediated (). OK-MC is thus supposed to be effective for adoptive immunotherapy (AIT) in oral cancer patients.

抄録全体を表示

This paper presents a developmental learning model for joint attention between a robot and a human caregiver. The basic idea of the proposed model comes from the insight of the cognitive developmental science that the development can help the task learning. The model consists of a learning mechanism based on evaluation and two kinds of developmental mechanisms: a robot's development and a caregiver's one. The former means that the sensing and the actuating capabilities of the robot change from immaturity to maturity. On the other hand, the latter is defined as a process that the caregiver changes the task from easy situation to difficult one. These two developments are triggered by the learning progress. The experimental results show that the proposed model can accelerate the learning of joint attention owing to the caregiver's development. Furthermore, it is observed that the robot's development can improve the final task performance by reducing the internal representation in the learned neural network. The mechanisms that bring these effects to the learning are analyzed in line with the cognitive developmental science.

抄録全体を表示

This study argues how human infants acquire the ability of joint attention through interactions with their caregivers from a viewpoint of cognitive developmental robotics. In this paper, a mechanism by which a robot acquires sensorimotor coordination for joint attention through bootstrap learning is described. Bootstrap learning is a process by which a learner acquires higher capabilities through interactions with its environment based on embedded lower capabilities even if the learner does not receive any external evaluation nor the environment is controlled. The proposed mechanism for bootstrap learning of joint attention consists of the robot's embedded mechanisms: visual attention and learning with self-evaluation. The former is to find and attend to a salient object in the field of the robot's view, and the latter is to evaluate the success of visual attention, not joint attention, and then to learn the sensorimotor coordination. Since the object which the robot looks at based on visual attention does not always correspond to the object which the caregiver is looking at in an environment including multiple objects, the robot may have incorrect learning situations for joint attention as well as correct ones. However, the robot is expected to statistically lose the learning data of the incorrect ones as outliers because of its weaker correlation between the sensor input and the motor output than that of the correct ones, and consequently to acquire appropriate sensorimotor coordination for joint attention even if the caregiver does not provide any task evaluation to the robot. The experimental results show the validity of the proposed mechanism. It is suggested that the proposed mechanism could explain the developmental mechanism of infants' joint attention because the learning process of the robot's joint attention can be regarded as equivalent to the developmental process of infants' one.

抄録全体を表示

がん細胞も正常細胞の派生であると大きくは捉えられるが，その代謝は大きく異なっていることが指摘されている。その1つがWarbarg効果である。このような嫌気性解糖と固形がんの悪性度の根源とも言えるがん転移現象との関わりは十分には解明されてない。本研究では，生化学的なアプローチによりWarbarg効果の鍵酵素とがん転移との関連性につき，若干の知見を得たので最近の報告を踏まえて概説する。

抄録全体を表示

Adoptive immunotherapy using OK-432-activated mononuclear cells (OK-MCs) offers cell-mediated and cytokine-mediated pathways for antitumor activity. The effectiveness of direct intratumoral administration of OK-MCs via a catheter/reservoir system was studied in patients with malignant brain tumors. Seventeen patients, 12 with malignant glioma, four with metastatic adenocarcinoma, and one with primary sarcoma of the brain, were treated by OK-MC therapy (1.0 to 11.2 × 10⁷ cells/person) between June 1989 and April 1999. The OK-MC therapy was given to patients with tumors progressing despite previous cytoreductive surgery, radiation, or chemotherapy. Adverse effects seen after the therapy were fever in 10 patients, seizure in two patients, and hypotension in one patient. Evaluation by computed tomography or magnetic resonance imaging revealed that seven patients showed no change including three with minor response, and 10 showed progressive disease. Adoptive immunotherapy using OK-MC was safe and well tolerated, but the therapeutic potential is limited.

抄録全体を表示

We are beginning to understand the molecular biology of hydrocephalus and its related diseases. X-linked hydrocephalus (XLH), holoprosencephaly (HPE), Dandy–Walker malformation (DWM), and neural tube defect (NTD) can all be discussed with respect to their available molecular genetics knowledge base and its clinical applications. XLH is single gene disorder caused by mutations in the neural cell adhesion molecule-encoding L1CAM (L1) gene. Our knowledge of the molecular basis of XLH is already being applied clinically in disease diagnosis, disease classification, and prenatal diagnosis. However, the molecular mechanism underlying XLH-related hydrocephalus still needs to be clarified. Sixteen causative genes for HPE have been identified, of which mutations are most often found in SHH, ZIC2, SIX3, and . Genetic interactions, gene complexity, and the wide variety of HPE phenotypes and genotypes are topics for future study. For DWM, two important loci, 3q24, which includes the FOXC1 gene, and 6q25.3, which includes the ZIC1 and ZIC4 genes, were recently identified as causative areas. The planar cell polarity (PCP) genes CELSR1, CELSR2, VANGL1, and VANGL2 have been implicated in NTD; these genes have roles in neural tube closure and ependymal ciliary movement.

抄録全体を表示

KNOX homeodomain (HD) proteins encoded by KNOTTED1-like homeobox genes (KNOX genes) are considered to work as important regulators for plant developmental and morphogenetic events. We found that OSH3, one of the KNOX genes isolated from a cultivar of Oryza sativa (Nipponbare), encodes a novel HD, which has two amino acid substitutions at invariant positions. Sequence analysis of OSH3 from various domesticated and wild species of rice has revealed that these substitutions are distributed only in Japonica and Javanica type of O. sativa, two groups of domesticated rice in Asia. Surprisingly, nucleotide sequences in the first intron are almost conserved in the rice strains that have the substitutions at the invariant amino acids. Overexpression studies revealed that these invariant amino acids are critical for the function of OSH3 in vivo. The facts that these substitutions occurred specifically at the functionally important amino acids and the sequences are conserved in intron where neutral mutations accumulate suggest the substitutions at the invariant positions of OSH3 have been fixed by artificial selections during domestication. Based on these observations, we hypothesize that OSH3 is responsible for one of the traits that are selectively introduced during the domestication of most of Japonica and a part of Javanica type of rice.

抄録全体を表示

Monosomy 18p syndrome is caused by partial deletion of the short arm of chromosome 18. Monosomy 18p is an autosomal deletion syndrome. Since the first report of monosomy 18p in 1963, more than 150 cases have been reported. We describe a 2-month-old boy who had monosomy 18p with bilateral cleft lip and palate. Chromosome analysis showed that the karyotype was 45,XY,der （18;21） （q10;q10）. At 5 months 1 year of age, cheiloplasty was performed. At 3 years of age, palatoplasty was performed. Further follow-up will be continued to check his development, including maxillofacial growth.

抄録全体を表示

Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas (ESC) and is associated with resistance of ESC to drug-induced apoptosis. In cervical squamous cell carcinoma (CSCC) cell lines, amplification and overexpression of cIAP1 was also observed. CSCC cell lines with cIAP1 amplification showed significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of CSCC and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.

抄録全体を表示

Transcultured human skin derived precursors (tSKPs) from adherent monolayer culture system have similar characteristics as traditional skin derived precursors (SKPs), making tSKPs a suitable candidate for regenerative medicine. tSKPs can differentiate into fibroblasts. However, little is known about the molecular mechanism of the transition from tSKPs to fibroblasts. Here, we compared the transcriptional profiles of human tSKPs and tSKPs-derived fibroblasts (tFBs) by RNA-Sequence aiming to determine the candidate genes and pathways involving in the differentiation process. A total of 1042 differentially expressed genes (DEGs) were identified between tSKPs and tFBs, with 490 genes up-regulated and 552 genes down-regulated. Our study showed that these DEGs were significantly enriched in tumor necrosis factor signaling pathway, focal adhesion, extracellular matrix-receptor interaction and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. A further transcription factors (TFs) analysis of DEGs revealed the significantly down-expressed TFs (p21, Foxo1and Foxc1) in tFBs were mostly the downstream nodes of PI3K-Akt signaling pathway, which suggested PI3K-Akt signaling pathway might play an important role in tSKPs differentiation. The results of our study are useful for investigating the molecular mechanisms in tSKPs differentiation into tFBs, making it possible to take advantage of their potential application in regenerative medicine.

抄録全体を表示

GnRH plays an essential role in neuroendocrine control of reproductive function. In mammals, the pattern of gonadotropin secretion includes both pulse and surge phases, which are regulated independently. The pulsatile release of GnRH and LH plays an important role in the development of sexual function and in the normal regulation of the menstrual cycle. The importance of GnRH pulsatility was established in a series of classic studies. Fertility is impaired when GnRH pulsatility is inhibited by chronic malnutrition, excessive caloric expenditure, or aging. A number of reproductive disorders in women with including hypogonadotropic hypogonadism, hypothlamic amenorrhea, hyperprolactinemia and polycystic ovary syndrome (PCOS) are also associated with disruption of the normal pulsatile GnRH secretion. Despite these findings, the molecular mechanisms of this pulsatile GnRH regulation are not well understood. Here, we review recent studies about GnRH pulsatility, signaling and transcriptional response, and its implications for disease.

抄録全体を表示

KNOX homeodomain proteins are encoded by knotted1-like homeobox (knox) genes that constitute a gene family in plants. Similar to the animal homeodomain proteins, KNOX proteins are considered to be key transcriptional regulators that control the expression of genes involved in plant organogenesis at the shoot apical meristem. Therefore, in order to understand the developmental processes in plants, it is important to elucidate the molecular mechanisms underlying KNOX protein regulation of gene expression. In this review, we discuss the structural features of KNOX proteins and the mechanisms by which they interact with and regulate target gene expression.

抄録全体を表示

Low concentrations of exogenously added recombinant interleukin 2 (rIL-2) were able to augment OK-432-induced natural killer (NK) cell activity. This kind of augmenting effect depended on the dose of rIL-2 and manifested itself only in PBMC stimulated with OK-432 (OK-MC) followed by rIL-2; augmentation did not happen in the reverse order. The existence of CD16⁺/CD25⁺ (IL-2 receptor positive; IL-2R⁺) and CD57⁺/CD25⁺ double positive cells which possess NK cell surface markers in OK-MC markedly increased in a long-term culture (12 days). A strong positive correlation was observed between the IL-2-dependent augmentation of NK activity and the quantitative changes in cell populations that possessed NK cell phenotypes. Treatment of the day-12-OK-MC with monoclonal anti-CD56 antibody plus complement could almost completely abrogate the augmented NK cytotoxicity. Furthermore, this augmenting effect was detectable within 4hr after addition of rIL-2 at single cell level, suggesting that the effect did not require NK cell's DNA synthesis. Thus it was suggested that OK-432 could promote and upregulate the expression of IL-2 receptor (CD25) on CD56⁺ NK cell populations. Moreover, it was considered that the interaction of low concentration rIL-2 with IL-2 receptors on OK-432-activated NK cells could augment their lytic function.

抄録全体を表示

We have developed a sophisticated method called “The Gene Network” for elucidating the relationships existing among all genes. This was accomplished by employing 24222 gene symbols contained in the MEDLINE database of Entrez rel. 12.0, then determining their inter-relationships by examining the frequency of appearance among one another. This new method enables construction of gene maps which graphically show their relationships, there by enhancing the understanding of them. We expect The Gene Network will have the future capability to allow navigation through the “world of genes.”

抄録全体を表示

音声合成をより使いやすくかつ表現力豊かにするために，我々は階層型音声合成記述言語 MSCL を開発した．MSCL は記述という方法によりニュアンスや心情，感情などを合成音声に付加することが可能である．MSCL は S 層，I 層，P 層の 3 つの階層を有し，初学者から音声学的知識を有する者まで対応可能にする．一方，MSCL の S 層が提供する新たなコマンドの作成手法そして I 層に備わる韻律制御コマンドによって生じる聴感上の効果（印象）の検討は MSCL における課題となっていた．そこで，本研究は MSCL の課題である韻律制御と印象の関係について実験を通じて見出した，8 つの制御規則を提案し，それぞれの主な印象について連想法を通じて分析した．また，制御規則を組み合わせて得られる印象の変化についても分析を行った．さらに，韻律制御コマンドを利用する上での留意点について言及する．音声合成での韻律制御を行うための 1 つのアプローチを提案する．

抄録全体を表示