Perspective
Evolution of Humans Outside the Genome
IZUMI NAKASHIMA
pg(s) 59- 64
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Complete sequencing of the whole genome of humans has revealed a surprisingly small difference between the genomes of humans and higher primates. I here propose that evolution has occurred in living organisms in two steps, fi rst within the genome and then outside the genome. The fi rst step of evolution is based on creation of new information in the genome (DNA), followed by selection after its vertical transmission to individuals of the next generation through reproduction. The second step includes accumulation of a huge amount of information translated into a “linguistic” code by memory and a natural process of computation that creates new patterns of information through thinking in the brain. The created patterns are selected positively or negatively by applying some criteria as to the usefulness for adaptation of humans to nature. When positively selected, the patterns are horizontally transmitted to other brains of a number of individuals, within and also beyond the generation recursively by the use of linguistic codes. This second step of evolution, in conjunction with the evolution of human language itself, has enabled the homo sapiens to attain an enormously high level of cognitive faculty for adaptation of the thought processes to needs in nature at an extraordinarily high speed.
Invited Review Articles
Modern Slice Culture for Direct Observation of Production and Migration of Brain Neurons
TAKAKI MIYATA, KANAKO SAITO, YUJI NISHIZAWA, AYAKO MURAYAMA, MAKOTO MASAOKA and MASAHARU OGAWA
pg(s) 65- 70
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For the understanding of histogenetic events in the three-dimensional brain primordia, direct observation of progenitor cells and young neurons is required. Although slice culture, which is one of the tissue or organ culture methods, effectively preserves the in vivo microenvironment where normal developmental processes occur, conventional phase-contrast microscopic observation of brain slices fails to provide good visibility of single cells. However, a combination of slice culture with the use of fl uorescent dyes and/or the introduction of fl uorescent protein genes provides live, three-dimensional information on cytogenetic and histogenetic events at the individual cell level. Dynamic cellular behaviors can then be vividly captured without destroying tissue structures.
The Midkine Family in Cancer, Inflammation and Neural Development
KENJI KADOMATSU
pg(s) 71- 82
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The midkine (MK) family consists of only two members, namely MK and pleiotrophin (PTN). MK and PTN share receptors and biophysical characteristics, such as a heparin-binding property. MK and PTN exert several biological activities, which include fi brinolytic, anti-apoptotic, mitogenic, transforming, angiogenic, and chemotactic ones. These activities suggest that these growth factors are involved in carcinogenesis. Indeed, strong expression of MK and PTN in human carcinomas, and the anti-tumor activity of antisense oligonucleotides for MK and ribozymes for PTN further support their importance in cancer. In addition, MK plays critical roles in the pathogeneses of various disorders involving infl ammation such as reperfusion- and cisplatin-induced renal dysfunction and vascular restenosis after angioplasty. MK antisense oligonucleotide ameliorates these disorders. Zebrafi sh and Xenopus MK can induce neural tissues. MK and PTN are localized in the radial glial processes of the embryonic brain, and are induced in reactive astrocytes by ischemic insults. I summarize here the biological signifi cance of the MK family in cancer, infl ammation and neural development.
Original Papers
Suicide Gene Therapy Using Adenovirus Vector for Human Oral Squamous Carcinoma Cell Line In Vitro
NORIYUKI YAMAMOTO, YASUSHI HAYASHI, HIDEAKI KAGAMI, TAKAFUMI FUKUI, HIROKAZU FUKUHARA, IWAI TOHNAI, MINORU UEDA, MASAAKI MIZUNO and JUN YOSHIDA
pg(s) 83- 91
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Recently, suicide gene therapy using the herpes simplex virus thymidine kinase (HSVtk) gene followed by ganciclovir (GCV) administration was evaluated for the treatment of cancer. The purpose of this study was to investigate the effectiveness of suicide gene therapy using the replication-defi cient recombinant adenovirus vector for human oral squamous carcinoma cell lines. To evaluate transduction effi ciency, each cell line was transduced in vitro with an adenovirus vector containing the β-galactosidase gene. By 24 hours after transduction, nearly 100% of the cells were transduced at a multiplicity of infection (MOI) of 10, and from 30 to 10% at an MOI of 1. Next, each cell line was transduced with an adenovirus vector containing the HSVtk gene, and a subsequent administration of GCV for the assessment of suicide gene therapy. A subsequent administration of GCV resulted in complete tumor cell death. In addition, we conducted a morphological analysis of that cell death using video-enhanced contrast differential interference contrast microscopy, and we observed that it included both apoptosis and necrosis after HSVtk gene and GCV treatment. These results suggest that adenovirus-mediated suicide gene therapy induced remarkable cytotoxicity with a bystander effect in human oral squamous cell carcinoma thus suggesting an effective treatment strategy for that tumor.
Correlation of MMSE, SKT and Clock Test Scores in Patients with Dementia
H.J. KOCH, K. GÜRTLER and A. SZECSEY
pg(s) 93- 99
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The objective of our study was to assess the correlation of routine neuropsychological test results in elderly patients referred to a gerontopsychiatric ward. MMSEs, Clocktests (CT) and SKTs were performed in 94 patients (Age: Median = 74 ys, Range = 54–89 ys; 64 f, 30 m; MMSE < 25:45 and MMSE > 25:37) with mild to moderate dementia and evaluated retrospectively. Linear and multiple regression was used. The scores of all 3 tests used were reciprocally correlated (p < 0.05). Multiple regression analysis showed a maximum correlation of 0.87 and marked standardized β values, if SKT was chosen as dependent variable. In conclusion, results of SKT, CT or MMSE in patients with dementia showed marked pairwise or multiple correlations and therefore it is not necessary to include more than two reliable tests in clinical psychogeriatric studies.
Requirement of Multiple Signaling Pathways for the Augmented Production of Hyaluronan by v-Src
YUKO NAITO, NORIKO SUZUKI, PENGYU HUANG, HITOKI HASEGAWA, YASUYOSHI SOHARA, TAKASHI IWAMOTO and MICHINARI HAMAGUCHI
pg(s)101-108
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Malignant transformation of cells is frequently associated with an augmented production of hyaluronan and the subsequent formation of a hyaluronan-matrix. In v-Src-transformed cells, hyaluronan directly activate cell motility in a tumor-specifi c manner. Despite its importance, the mechanism by which v-Src activates hyaluronan production remains unclear. Here we report that multiple signaling pathways are required for the augmented production of hyaluronan. Either the expression of a dominant negative Ras or the treatment of cells with manumycin A, a Ras farnesyltransferase inhibitor, was able to suppress hyaluronan production. In contrast, expression of MEK1EE, a constitutive form of MEK1, activated both hyaluronan synthase expression and hyaluronan production. AG-490, a Jak-2 inhibitor, or LY294002, a PI3K inhibitor, similarly suppressed the augmented production of hyarulonan. Taken together, our results suggest the involvement of multiple signaling pathways, including Ras-dependent and independent ones, in augmented hyaluronan production by v-Src.
Long-term Results of Osseointegrated Implant-Retained Facial Prostheses: A 5-Year Retrospective Study
MASAKI J. HONDA, TAKASHI HATANAKA, YASUHIRO OKAZAKI and MINORU UEDA
pg(s)109-116
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In this study a questionnaire survey was prepared and distributed to patients who had been fi tted with a facial prosthesis at least 5 years earlier, with the aim of: 1) reviewing the implants statistically, and 2) examining psychological changes before and after the use of an implant-supported prosthesis. Twelve patients had been fi tted with implant-supported prostheses that had a survival rate of 97.5% after 5 years. To examine psychological changes, the patients were given the Cornell Medical Index-Health Questionnaire (CMI) and a questionnaire we originally developed. Eight of the 12 responded to the questionnaire. The CMI results from those 8 patients confi rmed that none of them had sustained any emotional impairment. Our results revealed that, although the patients wore their prosthesis both indoors and out, eyeglasses were still necessary. However, wearing the prosthesis lessened the psychological impact of the facial defect, while also easing anxiety with regard to interpersonal relations.
Polymorphism of Dihydropyrimidine Dehydrogenase (DPYD) Cys29Arg and Risk of Six Malignancies in Japanese
DAISUKE TANAKA, ASAHI HISHIDA, KEITARO MATSUO, HIROJI IWATA, MASAYUKI SHINODA, YOSHITAKA YAMAMURA, TOMOYUKI KATO, SHUNZO HATOOKA, TETSUYA MITSUDOMI, YOSHITOYO KAGAMI, MICHINORI OGURA, KAZUO TAJIMA, MOTOKAZU SUYAMA, MARIKO NAITO, KAZUHITO YAMAMOTO, AKIKO TAMAKOSHI and NOBUYUKI HAMAJIMA
pg(s)117-124
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Dihydropyrimidine dehydrogenase (DPD) is the enzyme catalyzing the first step of pyrimidine metabolism. To date, genetic polymorphisms of pyrimidine-synthesizing enzymes have been reported to be associated with the risk of malignant lymphoma or colon cancer. Accordingly, there may be associations between dihydropyrimidine dehydrogenase (DPYD) polymorphism and the risk of malignancies. We conducted a prevalent case-control study to investigate the associations between a functional polymorphism of dihydropyrimidine dehydrogenase, DPYD T85C, and the risk of six malignancies. Controls were 445 Nagoya City inhabitants without a history of malignancy who had participated in a health check-up between August and September 2000. Case subjects were 901 patients with malignancies (99 esophageal, 131 gastric, 143 colon, 179 lung, 243 breast, and 106 malignant lymphomas) who had visited Aichi Cancer Center Hospital between March 1999 and December 2000. No DPYD CC individuals were found in either cases or controls. The frequency of DPYD TC genotype was 6.3% in control subjects and 5.9% in all case subjects (not signifi cant). In a subgroup analysis, the frequency of TC genotype was highest in patients with gastric cancer (9.1%), followed by those with lung cancer (8.3%), with the lowest frequency in those with malignant lymphoma (1.9%). The gender- and age- adjusted odds ratios and 95% confi dence intervals for the TC genotype of gastric cancer and malignant lymphoma were 1.52 (0.71–3.28) and 0.31 (0.71–1.34), respectively. Although prevalent cases were used, this study suggested that the infl uence of DPYD T85C posed only a limited risk for the six malignancies.