bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmentation of Anti‐tumor Immunity in Low‐responder Mice by Various Biological Response Modifiers: Analysis of Effector Mechanism
Authors: Toko Toshiyuki , Fujimoto Shigeyoshi
Published: August 2005

In order to elucidate the role of biological response modifiers (BRMs) in anti‐tumor immunotherapy, we examined their effect on the induction of anti‐tumor immunity in low‐responder mice which hardly exhibit anti‐tumor resistance against syngeneic Rous sarcoma virus (RSV)‐induced tumors, such as BIO or B10.BR mice. The anti‐tumor immunity induction in the low‐responder mice was 0% on immunization with mitomycin C‐treated syngeneic tumor cells alone. However, if BRMs were used as an adjuvant, BCG cell wall skeleton, OK‐432 or lentinan augmented the induction of anti‐tumor immunity to 50%, 33% and 33%, respectively. In the low‐responder mice treated with BRMs, the anti‐tumor immune cells had antigen‐specificity at the induction phase of in vitro restimulation but not at the effector phase of target cell lysis by the stimulated cells. When T cells were depleted from immune spleen cells just before in vitro stimulation, cytotoxicity was not induced. Furthermore, cytotoxicity was not induced if accessory cells were removed from immune spleen cells at the induction phase. However, cytotoxicity at the effector phase was not mediated by T‐lymphocytes, but by non‐T cells. These results suggested that the induced cytotoxicity in low‐responder mice was associated with the delayed‐type hypersensitivity‐like effector mechanism.
The × Gene of Hepatitis B Virus Induced Growth Stimulation and Tumorigenic Transformation of Mouse NIH3T3 Cells
Authors: Shirakata Yumiko , Kawada Minako , Fujiki Yukio , Sano Haruhiko , Oda Munehiro , Yaginuma Katsuyuki , Kobayashi Midori , Koike Katsuro
Published: August 2005

To examine the transforming potential of the × gene product of hepatitis B virus (HBV), the X‐gene‐containing region (referred to as the HBx region) was introduced into mouse NIH3T3 cells. Each transformed cell line expressed X‐coding mRNA at a different level. A positive correlation was found between the level of X‐coding mRNA and the saturation density of the cells. The HBx‐transformed cell lines exhibited × protein production and tumor formation in nude mice. The function of HBV in oncogenesis may involve the continuous expression of the X‐gene‐coded product in the HBV DNA‐integrated cells.
Random Segregation of DNA Strands in Epidermal Basal Cells
Authors: Kuroki Toshio , Murakami Yoshinori
Published: August 2005

According to the hypothesis proposed by Cairns, stem cells retain the older of the two parental DNA strands, whereas differentiating daughter cells receive the newly synthesized strand, so that a set of “immortal strands” persists in stem cells through successive cell divisions. To test this hypothesis, five successive divisions were induced in basal epidermal cells in vivo by two injections of cholera toxin into mouse skin and cells labeled with [3H]thymidine at the first cell cycle were chased for 50 days. If selective segregation occurs, the labeled strand should be transferred into a non‐stem daughter cell after the second division and labeled cells would eventually be eliminated from the epidermis. However, the results suggest random segregation of DNA strands in epidermal basal cells. Labeled basal cells were persistently present throughout the whole epidermis for 50 days. Furthermore, labeled mitotic cells were found after the third division and their numbers of grains decreased exponentially through 5 cycles of divisions.
Epidermal Growth Factor Receptor‐mediated Selective Cytotoxicity of Antitumor Agents toward Human Xenografts and Murine Syngeneic Solid Tumors
Authors: Amagase Harunobu , Kakimoto Masanori , Hashimoto Ken , Fuwa Tohru , Tsukagoshi Shigeru
Published: August 2005

Severe toxic side effects of antiproliferative agents limit their clinical usefulness as anti tumor drugs. Recently we observed that the anti tumor efficacy of various anti tumor agents (5‐fluorouracil, tegafur, adriamycin, mitomycin C, cyclophosphamide, and cisplatin) against experimental solid tumors was enhanced by prior or simultaneous administration of human epidermal growth factor (EGF). However, coadministration of EGF did not enhance the toxicity of anti tumor agents as measured by LD50 and body weight loss. The above selective potentiation of efficacy of the anti tumor agents by human EGF can be characterized as follows. In a dose‐dependent manner, human EGF enhanced the efficacy of an antitumor agent (5‐FU) treatment against human epidermoid carcinoma A431 transplanted sc in atliymic nude mice [ED50=2.9 (0.2–49.7, 95% confidence interval) μg/kg, sc]. Various degrees of enhancement were also observed against other experimental tumors transplanted sc. The degrees of enhancement were directly proportional to the numbers of human EGF binding sites present on tumor cell plasma membrane (threshold of binding site density=1.5×103 sites/cell) using 5‐FU or cisplatin as an anti tumor agent, thus suggesting that the binding of EGF to the receptors on tumor cells is an essential process in enhancing the susceptibility of tumor cells to anti tumor agents. Normal cells including intestinal epithelial and bone marrow cells are endowed with fewer EGF binding sites (less than 103 sites/cell). This may explain partially the absence of EGF‐enhanced cytotoxicity by antitumor agents toward normal cells.
Differential Diagnosis of AH109A Tumor and Inflammation by Radioscintigrap with l‐[Methyl‐11C]methionine
Authors: Kubota Kazuo , Matsuzawa Taiju , Fujiwara Takehiko , Sato Tachio , Tada Masao , Ido Tatsuo , Ishiwata Kiichi
Published: August 2005

For the evaluation of tumor imaging with l‐[methyl‐11C]methionine (11C‐Met), a basic study on the differentiation of tumor from inflammation with 11C‐Met and a comparison of the diagnostic value of the image with that obtained using 67Ga citrate, a conventional scintigraphic agent, are important. 11C‐Met accumulations into inflammatory lesions, AH109A tumor and normal tissues of rats were examined by means of a tissue distribution study. Aseptic inflammatory lesions on the back of Donryu rats induced by croton oil and 1.5% carrageenan showed significantly lower accumulations of 11C‐Met than the AH109A tumor. Histologically, croton oil induced granulomatous inflammation and carrageenan, acute exudative inflammation. Whole‐body antoradiography with l4C‐Met, a substitute for 11C‐Met, was negative in the carrageenan lesion and showed a slightly increased activity at the periphery of the croton oil lesion, in contrast with the high tumor activity. Whole‐body autoradiogra‐phy with 67Ga citrate was performed to compare the imaging ability with that of 14C‐Met; it showed high activities in the tumor, bone, and intestine, and a broad increased activity at the periphery of the croton oil lesion, but was negative in the carrageenan lesion. 11C‐Met accumulations in the inflammations were very low and clinical application with positron emission tomography, should be useful for the differential diagnosis of tumor from inflammation.
Caffeine Enhancement of the Effect of Anticancer Agents on Human Sarcoma Cells
Authors: Tomita Katsuro , Tsuchiya Hiroyuki
Published: August 2005

It is necessary to find modifiers which enhance the effects of known anticancer agents in order to improve both survival rate and local curability of patients with high‐grade sarcomas. In this study, the effect of anticancer agents combined with caffeine was examined on cultured sarcoma cells and fresh human sarcoma specimens, utilizing the human tumor clonogenic assay technique. The combination of cisplatin and caffeine showed a synergistic inhibition of the growth of two strains of cultured sarcoma cells tested, and 14 of 18 fresh human sarcoma specimens (77.8%). This synergistic effect of caffeine was also observed with cyclophosphamide (44.8%), mitomycin C (44.8%) and adriamycin (27.8%). The combination of vincristine or methotrexate with caffeine, however, did not exhibit a synergistic effect. Caffeine, therefore, enhanced the effect of four cytotoxic DNA damaging agents. No antag‐ onistic effects were seen in our series. This study suggests that caffeine may be useful in enhancing the tumoricidal effect of anticancer drugs, especially DNA‐damaging agents, and possibly may aid in overcoming natural drug resistance.
Antitumor Effect of PSK: Role of Regional Lymph Nodes and Enhancement of Concomitant and Sinecomitant Immunity in the Mouse
Authors: Ebina Takusaburo , Kohya Hidehiko , Ishikawa Keiko
Published: August 2005

PSK, a Coriolus preparation, inhibited the growth of not only the right but also the left, non‐treated tumor in a double grafted tumor system. In order to examine the role of lymph nodes and the spleen in the antitumor activity of PSK, regional (axillary and inguinal) lymph nodes and spleen were resected. Since in resected mice the antitumor activity of PSK against the right and left tumors was weakened, the regional lymph nodes and the spleen probably have a very important role in the antimetastatic effect of intratumoral administration of PSK. TIL (tumor‐infiltrating lymphocytes) obtained from left and right side tumors treated with PSK were examined by Winn assay for their antitumor activity against Meth‐A sarcoma in BALB/c mice. TIL from both sides clearly inhibited the growth of admixed Meth‐A cells, but control TIL did not. A primary growth of Meth‐A sarcoma inoculated into the right flank resulted in the generation of concomitant immunity to the growth of a second graft of the same tumor cells in the left flank. A significant inhibitory effect on the proliferation of the tumor cells inoculated secondarily was shown in mice bearing a primary right tumor that had previously been inoculated with PSK 3 times. After surgical excision of the primary tumor on day 6, daily oral administration of PSK significantly inhibited the growth of the secondary tumor inoculated on day 21, that is, PSK treatment also enhanced sinecomitant immunity. These observations suggest that presurgical intratumoral injection and postoperative oral administration of PSK are highly effective in eradicating metastatic tumors.
Low Incidence of Point Mutation of c‐Ki‐ras and N‐ras Oncogenes in Human Hepatocellular Carcinoma
Authors: Tsuda Hitoshi , Hirohashi Setsuo , Shimosato Yukio , Ino Yoshinori , Yoshida Teruhiko , Terada Masaaki
Published: August 2005

We examined the incidence of point mutation in codons 12, 13 and 61 of c‐Ki‐ras and N‐ras genes in human hepatocellnlar carcinoma (HCC) using the polymerase chain reaction and oligonucleotide hybridization techniques. Among 34 tissue specimens surgically resected from 30 patients and 5 cell lines of human HCC, only two had ras point mutations; in one case, codon 12 of c‐Ki‐ras was altered from GGT, coding glycine, to GTT, coding valine; in the other case, codon 61 of N‐ras was altered from CAA, coding glutamine, to AAA, coding lysine. Thus, point‐mutational activation of ras oncogenes is an uncommon event in human HCC.
Amplification and Specific Detection of Transforming Gene Region of Human Papillomavirus 16, 18 and 33 in Cervical Carcinoma by Means of the Polymerase Chain Reaction
Authors: Shimada Masamitsu , Fukushima Michio , Mukai Hiroyuki , Kato Ikunoshin , Nishikawa Akira , Fujinaga Kei
Published: August 2005

We have established a highly sensitive method for specific detection of human papillomavirus (HPV) 16, 18 and 33, by using the polymerase chain reaction (PCR). A HPV‐related sequence (140 bp) in the E6 transforming region was specifically amplified and detected by gel electrophoresis and by the use of a specific oligonucleotide probe. The PCR could detect 10‐5–10‐6 copies per cell (maximum sensitivity). Furthermore, HPV 16, 18 and 33 DNAs were synthesized in a common reaction solution and specifically detected by HPV type‐specific probes. The PCR detected the HPV sequence from tissues which were negative to Southern hybridization. This detection technique may contribute significantly to the precise analysis of HPV in small proliferative lesions in the cervix.
Mutational Activation of H‐ras and K‐ras Genes Is Absent in N‐Nitroso‐N‐methylurea‐induced Liver Tumors in Rats
Authors: Sakai Hirotsuka , Ogawa Katsuhiro
Published: August 2005

We examined mutational activation of H‐ and K‐ras genes in hyperplastic nodules and hepatocellular carcinomas induced by N‐nitroso‐N‐methylurea or diethylnitrosamine using the polymerase chain reaction, followed by dot‐blot hybridization. No mutational activation was detected in these hepatic lesions. The results indicate that low incidence of the activation of H‐ and K‐ras genes in rat liver tumors is due to the organ specificity rather than the nature of the carcinogens used.
Implications of the Carcinogenic Hazard of Low Doses of Three Hepatocarcinogenic N‐Nitrosamines1
Authors: Berger Martin R. , Schmähl Dietrich , Edler Lutz
Published: August 2005

The data of a large‐scale experiment on single and combination effects of very low doses of the hepatocarcinogenic N‐nitrosamines N‐nitrosodiethylamine (NDEA), N‐nitrosopyrrolidine (NPYR), and N‐nitrosodiethanolamine (NDE1A) were modeled by new statistical methods to derive implications of the carcinogenic hazard of dose ranges so low as to result in long‐term toxic effects only slightly different from the background. According to this model a linear relationship was found to exist between daily exposure to low N‐nitrosamine levels and time to death with liver tumor. Extrapolation of these data to zero exposure suggested the occurrence of one to ten percent of spontaneous liver tumors in animals surviving more than 1000 days. At this advanced age a further reduction of carcinogen‐induced liver tumor incidence does not contribute to a longer overall survival due to competitive, probably independent, causes of death. A quasi‐threshold in terms of a “no‐observed‐effect level” can thus be derived from the data. The observed combination effect indicates a mere additivity in liver tumor occurrence, even at very low doses which alone cause no significant carcinogenic effect during the animal's lifetime. Within the combination of NDEA, NPYR and NDE1A, N‐nitrosodiethylamine was found to be the most carcinogenic agent: it contributes by at least 17 orders of magnitude more to the relative risk of dying with liver tumor than the other two compounds, if the daily dose is increased by one unit (0.1 mg/kg). Likewise, NDEA shows the steepest slope when assessing the relationship between daily carcinogen doses and time to liver tumor occurrence; relative to NDE1A—the least potent carcinogen on a weight basis—and NPYR a 40‐fold and 9‐fold quicker appearance of liver tumors has to be expected, if the daily doses are increased by an equivalent amount.
Structure‐Activity Relations in Promotion of Rat Urinary Bladder Carcinogenesis by Phenolic Antioxidants
Authors: Kurata Yasushi , Fukushima Shoji , Hasegawa Ryohei , Hirose Masao , Shibata Masa‐Aki , Shirai Tomoyuki , Ito Nobuyuki
Published: August 2005

The urinary bladder tumor‐promoting potentials of the phenolic antioxidants, 2‐tert‐butyl‐4‐methyl‐phenol (TBMP), propylparaben, catechol, resorcinol and hydroquinone, which are structurally related to butylated hydroxyanisole (BHA), were investigated in 170 male F344 rats. The animals were initially given 0.05% N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) as an initiator in their drinking water for 4 weeks. Three days later, groups of 20 rats received diet containing 1.0% TBMP, 3% propylparaben, 0.8% catechol, 0.8% resorcinol, 0.8% hydroquinone or basal diet alone until the end of week 36. Significant increases in the incidences and average numbers of the putative preneoplastic lesions, papillary or nodular (PN) hyperplasia, and papillomas of the urinary bladder were only observed in the group given TBMP after BBN. Development of these lesions was not enhanced by diet containing the other test compounds and no induction was associated with any of the test chemicals alone. The results thus clearly showed that TBMP, which most closely resembles BHA, promoted urinary bladder carcinogenesis. The similar effects of TBMP and BHA on urinary bladder carcinogenesis suggest a direct link between chemical structure and biological potency.
Inhibitory Effects of Antioxidants on N‐Bis(2‐hydroxypropyl)nitrosamine‐induced Lung Carcinogenesis in Rats
Authors: Hasegawa Ryohei , Furukawa Fumio , Toyoda Kazuhiro , Takahashi Michihito , Hayashi Yuzo , Hirose Masao , Ito Nobuyuki
Published: August 2005

Potential second‐stage modifying effects of 8 antioxidants on lung tumorigenesis initiated by N‐bis(2‐hydroxypropyl)nitrosamine (DHPN) were examined in male F344 rats. After an initial 2‐week treatment with DHPN (0.1% in drinking water), rats were administered one of the antioxidants supplemented in the diet for 30 weeks. Although the incidences of lung adenomas were not affected, those of carcinomas were lowered by 2% butylated hydroxyanisole (BHA, 2 rats/20 rats), 1% butylated hydroxytoluene (BHT, 1/20), 0.8% ethoxyquin (EQ, 3/20) and 1%α‐tocopherol (α‐TP, 2/20) treatments as compared to the control level (9/20), while 5% sodium l‐ascorbate (SA), 0.8% catechol (CC), 0.8% resorcinol (RN), and 0.8% hydroquinone (HQ) did not exert any significant effect on incidence. Quantitative analysis of adenomas and carcinomas (numbers and areas of lesions per unit area of lung section) revealed obvious inhibitory effects of SA, CC, and RN as well as BHA, BHT, EQ, and α‐TP. Among the antioxidants, BHT exerted the strongest inhibitory activity. In contrast, DHPN‐induced thyroid tumorigenesis was significantly enhanced by BHT (14/20) and EQ (20/20) treatments (control=5/20). Thus the antioxidants showed opposite effects on lung and thyroid carcinogenesis in the rat.
Suppression by Interleukin 4 of Activation of Human Blood Monocytes to the Tumoricidal State
Authors: Nishioka Yasuhiko , Sone Saburo , Okubo Akio , Ogura Takeshi
Published: August 2005

The effect of interleukin 4 (IL‐4) on expression of antitumor activity of blood monocytes purified by counter‐flow centrifugal elutriation from healthy donors was examined. The blood monocytes were incubated for 24 h in medium with lipopolysaccharide, interferon γ (IFN‐γ) or desmethyl muramyl dipeptide (norMDP) or with IFN‐γ and norMDP in the presence of IL‐4, and then their tumoricidal activity was assayed by measuring 125IUdR release from human melanoma (A375) cells. Irrespective of activation stimulus, addition of IL‐4 to cultures of monocytes and activators resulted in dose‐dependent suppression of the tumoricidal activity of monocytes against parent A375 melanoma cells and the variant cells, A375‐R resistant to IL‐1 and tumor necrosis factor α. IL‐4 suppressed the early induction phase of monocyte activation. Rabbit anti‐IL‐4 antisera completely blocked the IL‐4‐mediated suppression of monocyte activation to the tumoricidal state. These findings suggest that IL‐4 is important in vivo in down‐regulation of anti‐tumor expression of monocytes.
High‐level Expression of Human c‐jun Gene Causes Cellular Transformation of Chicken Embryo Fibroblasts
Authors: Suzuki Takeshi , Hashimoto Yoshiko , Okuno Hiroyuki , Sato Hironori , Nishina Hiroshi , Hideo Hideo
Published: August 2005

To analyze the transforming activity of c‐jun, a Rous sarcoma virus (RSV) variant that carries human c‐jun Instead of v‐src (JH1) was constructed. After infection onto chicken embryo fibroblasts (CEF), JH1 formed foci with a titer comparable to that of wild‐type RSV, and the infected cells grew in soft agar, indicating that the human c‐jun gene has transforming potential, like the v‐jun gene. The expression of Fra‐2, one of the recently isolated Fos‐related antigens, hut not Fos was detected in both JHl‐infected CEF and CEF infected with the control retrovirus vector (DS3). Gel shift analysis using nuclear extracts from DS3‐infected CEF revealed that the Fra‐2/Jun complex contributes to the basal level of AP‐1 DNA binding activity. A similar activity was detected in JHl‐infected CEF, but these cells have an additional AP‐1 binding activity derived from Jun homodimers that seems to play important roles in the cellular transformation.
Appearance of Malignant Phenotype with Partial Loss of Hormone Dependency in Androgen‐dependent Shionogi Carcinoma 115 Transfected with hst‐1 Gene
Authors: Furuya Yuzo , Sato Naohide , Watabe Yoshio , Shimazaki Jun
Published: August 2005

Shionogi Carcinoma 115 (SC 115) and Chiba Subline 2 (CS 2) are an androgen‐dependent mouse tumor and an androgen‐independent subline derived from SC 115, respectively. Since new expression of the transforming oncogene hst‐1 might be related with autonomous progression in CS 2, the present study was designed to examine the influence of expression of hst‐1 gene on SC 115. The transfectants of SC 115 with hst‐1 still retained androgen sensitivity of growth, although the cells could grow without androgen. The transfectants, however, developed fibroblast‐like appearance in the absence of androgen, in contrast to SC 115, which showed epithelial‐like appearance after deprivation of androgen. The transfectants acquired an ability to form colonies in soft agar in the absence of androgen. SC 115 could not form tumors in intact mice, but the transfectants formed tumors at a high rate in male mice but not in female ones. From these results, it was concluded that expression of hst‐1 was able to alter the phenotype of the androgen‐dependent tumor with partial loss of androgen‐dependency, and these changes might be advantageous for malignant progression.
Inhibition of Azoxymethane‐induced Colon Carcinogenesis in Rat by Green Tea Polyphenol Fraction
Authors: Yamane Testsuro , Hagiwara Nobuyuki , Tateishi Masaya , Akachi Shigemitsu , Kim Mujo , Okuzumi Jyunichi , Kitao Yoshitaka , Inagake Masao , Kuwata Katsuya , Takahashi Toshio
Published: August 2005

The effect of green tea polyphenol fraction (GTP) on azoxymethane(AOM)‐induced colon carcino‐genesis was investigated in male Fischer rate. The rats were given AOM (7.4 mg/kg body weight) s.c. once a week for 10 weeks. A week after the treatment, they were divided into three groups: AOM‐control (26 rats), AOM‐GTP1 (26 rats) and AOM‐GTP2 (25 rats). AOM‐GTPl and AOM‐GTP2 groups respectively received 0.01 and 0.1% GTP in drinking water from week 11 to 26. AOM‐control group received tap water throughout this experiment. Autopsy on week 26 showed that tumor incidence and average numbers of tumors per rat in the AOM‐GTPl and AOM‐GTP2 groups were significantly lower than those of the AOM‐control group: 38.1% and 47.6% versus 77.3%; 0.6 and 0.7 versus 1.5. Thus, it was concluded that GTP inhibited the development of AOM‐indnced colon carcinogenesis. The inhibition by GTP did not show significant dose dependence.
Establishment of an α‐Fetoprotein‐producing Gastric Cancer Cell Line in Serum‐free Media
Authors: Terashima Masanori , Ikeda Kenichiro , Maesawa Chihaya , Kawamura Hidenobu , Niitsu Yorikazu , Satoh Masao , Saito Kazuyoshi
Published: August 2005

A new cell line, designated Ist‐1, was established in serum‐free medium from a 63‐year‐old gastric cancer patient with an extremely high serum level of α‐fetoprotein (AFP). ISt‐1 exhibited a typical morphology of epithelial cells in culture. The population doubling time was 31 hours. Production of AFP was demonstrated by immmunohistochemical study and high levels of AFP were detected in the conditioned medium of ISt‐1 cells. Ist‐1 is considered to be an AFP‐producing gastric cancer cell line and will provide a useful tool for the study of production and secretion of AFP from cells.
Accumulation of p60lck in HTLV‐I‐transformed T Cell Lines Detected by an Anti‐Lck Monoclonal Antibody, MOL 171
Authors: Moroi Yoichi , Koga Yasuhiro , Nakamura Kazuhiko , Ohtsu Masumi , Kimura Genki , Nomoto Kikuo
Published: August 2005

The lck gene encodes a protein tyrosine kinase of nonreceptor type, p56lck, whose expression occurs almost exclusively in T lymphocytes. MOL 171, an anti‐p56lck monoclonal antibody, was produced by using a 25‐amino‐acid synthetic polypeptide as the antigen, its structure corresponding to the N‐terminal region deduced from the lck cDNA sequence. Immunoblot analysis with MOL 171 showed the accumulation of 60 kD form of Lck protein, p60lck, and the decrease of p56lck in human T cell leukemia virus type I (HTLV‐I)‐transformed T cell lines. Another anti‐Lck monoclonal antibody, MOL 294, raised by using a synthetic peptide corresponding to the C‐terminal region deduced from the lck cDNA sequence, also detected the accumulation of p60lck in those HTLV‐1‐transformed T cell lines. The appearance of p60lck with the decrease of p56lck in normal T lymphocytes after stimulation suggested the origin of p60lck in HTLV‐I‐transformed T cells.
A 50‐Year Projection of Lung Cancer Deaths among Japanese Males and Potential Impact Evaluation of Anti‐smoking Measures and Screening Using a Computerized Simulation Model
Authors: Yamaguchi Naohito , Mizuno Shoichi , Akiba Suminori , Sobue Tomotaka , Watanabe Shaw
Published: August 2005

The lung cancer death rate among Japanese males was projected for 50 years to the year 2041 by a computerized simulation model. Long‐term effects of anti‐smoking measures and mass screening on lung cancer deaths were also evaluated. The simulation showed that the age‐adjusted lung cancer death rate would increase and reach a peak of 166 per 100,000 in 1989 and then decrease to 148 per 100,000 in 2003. It then shows an increasing tendency again, up to 255 per 100,000 in 2028. The smoking initiation rates estimated from the observed lung cancer death rates showed that the changes in death rates may be attributed to a lower smoking initiation rate among those born in the 1930's. Promotion of mass screening programs is effective more quickly than anti‐smoking measures but the reduction in annual cancer deaths is expected to be only 11%, even if 100% participation is achieved by the year 2000. A reduction in smoking initiation rate, on the other hand, affects lung cancer deaths very slowly. It was predicted that a 1% annual reduction in smoking initiation rate would result in a 20% decrease in the number of lung cancer deaths in 2041. A smoking cessation program is intermediate with regard to promptness. The predicted reductions in lung cancer deaths in 2041 were 13%, 47%, and 66%, respectively, when the annual smoking cessation rate was increased from 0.46% (present status) to 1%, 3%, and 5%. In conclusion, the combined application of all three preventive measures seems essential to realize the most effective reduction in lung cancer deaths.
Serodiagnostic Assay of Hepatitis C Virus Infection Using Viral Proteins Expressed in Escherichia coli
Authors: Mori Shigehisa , Ohkoshi Showgo , Hijikata Makoto , Kato Nobuyuki , Shimotohno Kunitada
Published: August 2005

Infection with hepatitis C virus (HCV) was analyzed by an enzyme‐linked immunosorbent assay based on recombinant viral proteins encoded by regions of the putative viral core, NS3, NS4 and NS5, which were expressed in E.coli Results showed that 106 of 124 cases (85.5%) of non‐A, non‐B chronic hepatitis and 43 of 45 cases (95.5%) of hepatocellular carcinoma, negative for HBV marker, were positive for antibodies against at least one of these viral proteins. One of 87 healthy individuals with normal alanine aminotransferase activity was positive for antibody against only the viral core, but was negative for HCV RNA. The serum of one patient with chronic hepatitis was positive for one of these proteins, but negative for HCV RNA. These findings in combination with results on detection of HCV RNA in the sera of patients with non‐A, non‐B chronic hepatitis indicated that 105 of 124 cases (84.6%) were positive for HCV infection. Sera that were negative for HCV antibodies against all these proteins were also negative for HCV RNA assayed by reverse transcription followed by the polymerase chain reaction. Screening of HCV infection by detecting viral antibodies in circulating blood using all these viral proteins is useful for reducing the number of ambiguous results in screening for viral infection. Thus, this assay system may be useful diagnostic purposes.
Precise Localization of the Excision Repair Gene, ERCC5, to Human Chromosome 13q32.3‐q33.1 by Direct R‐Banding Fluorescence in situ Hybridization
Authors: Takahashi Ei‐ichi , Shiomi Naoko , Shiomi Tadahiro
Published: August 2005

The genomic DNA fragment encoding the excision repair gene, ERCC5, was mapped by direct R‐banding fluorescence in situ hybridization. The signals were localized to human chromosome 13q32.3‐q33.1. This result was in agreement with previous reports, and the gene was assigned to a narrower region.
Human Lung Cancer Cell Line Producing Hepatocyte Growth Factor/Scatter Factor
Authors: Yoshinaga Yasuteru , Fujita Shin , Gotoh Masahiro , Nakamura Toshikazu , Kikuchi Masahiro , Hirohashi Setsuo
Published: August 2005

Hepatocyte growth factor (HGF)/scatter factor (SF) is a cytokine which is produced by mesenchymal cells and stimulates the motility of some epithelial cells, including cancer cells and vascular endothelial cells. Two human lung cancer cell lines, PC‐1 and PC‐13, were found to produce a protein which was indistinguishable from HGF/SF with regard to biological activities and immunological characteristics, although they were derived from epithelial cells. In general, highly aggressive cancer cells often show some mesenchymal characteristics, and production of HGF/SF by cancer cells is also considered as a phenomenon of acquisition of mesenchymal phenotype, which may be involved in cancer invasion and progression. These cell lines showed no apparent response to exogenous HGF/SF. In addition, no c‐met proto‐oncogene product was detectable in these cells by Western blot analysis. Although the function of HGF/SF produced by cancer cells, either autocrine or paracrine stimulation, remains to be studied, this is the first report to describe cancer cells producing HGF/SF.
3,2′‐Dimethyl‐4‐aminobiphenyl‐induced Gallbladder Carcinogenesis and Effects of Ethinyl Estradiol in Hamsters
Authors: Hasegawa Ryohei , Ogawa Kumiko , Takaba Katsumi , Shirai Tomoyuki , Ito Nobuyuki
Published: August 2005

The effects of ethinyl estradiol (EE) on 3,2′‐dimethyl‐4‐aminohiphenyl (DMAB)‐induced carcinogenesis were examined in Syrian golden hamsters. DMAB was subcutaneously injected in corn oil at a concentration of 100 mg/kg once a week for 20 weeks and EE was administered in the diet at a dose of 0.75 ppm throughout the experiment. Some animals were killed at week 20 and ail surviving ones were killed at week 50. Gallbladder tumors (adenomas and carcinomas) were induced in 6 of 15 hamsters (40%) in the DMAB + EE group and 5 of 14 (36%) in the DMAB alone group in males, and in 6 of 13 (46%) in the DMAB + EE group and 1 of 8 (13%) in the DMAB alone group in females at week 50. A clearer enhancing effect of EE on DMAB gallbladder carcinogenesis was observed for tumor multiplicity (No./animal) for both sexes; from 0.36 to 0.67 in males and from 0.14 to 0.62 in females. Thus, DMAB was demonstrated to be carcinogenic in the gallbladder of hamsters and EE enhanced this DMAB‐induced gallbladder tumorigenesis.
Antimetastatic Activity of Polymeric RGDT Peptides Conjugated with Poly(ethylene glycol)
Authors: Saiki Ikuo , Yoneda Junya , Igarashi Yu , Aoki Miho , Kusunose Naoto , Ono Kei‐ichi , Azuma Ichiro
Published: August 2005

Polymeric peptides containing defined repetitive or cyclic structures of RGDT sequence, (RGDT)n (n = 1 to 11) and cyclo(RGDT)n (n=2 to 4), at a dose of 500 μg exhibited an inhibitory effect on experimental lung metastasis upon co‐injection with tumor cells and the magnitude of the effect increased in parallel with the increase of degree of repetition of the RGDT sequence. The conjugation of (RGDT)n (n = 1, 5, 11) with poly(ethylene glycol), PEG as a polymeric carrier led to enhanced inhibition of lung metastasis in proportion to the degree of RGDT sequence repetition and in a dose‐dependent manner. Multiple i.v. administrations of PEG‐(RGDT)11, at 2‐day and 3‐day intervals before the excision of primary tumors, effectively inhibited spontaneous lung metastasis by s.c. inoculation of tumors, whereas (RGDT)11 exhibited inhibition of lung metastasis only when given at 2‐day intervals. This indicates that the conjugation of PEG with (RGDT)n allowed the prolongation of administration interval, implying a sustained inhibitory effect on tumor metastasis. In support of this supposition, a decrease in the arrest of radiolabeled tumor cells in the lungs was observed when PEG‐(RGDT)11 was co‐injected i.v. with tumor cells, or injected i.v. one day before tumor inoculation. In contrast, (RGDT)11 significantly inhibited the tumor cell arrest in the lungs only upon co‐injection with tumor cells. We also noted that (RGDT)n, cyclo(RGDT)n and PEG‐(RGDT)11 inhibited tumor cell invasion into Matrigel in a concentration‐dependent manner and in proportion to the degree of RGDT sequence repetition, indicating that the peptide‐mediated antimetastatic effect is partly associated with the anti‐invasive potential. Thus, the conjugation of anti‐cell adhesive and antimetastatic RGDT peptide with PEG might provide a therapeutically promising basis for the prevention of cancer metastasis (“anti adhesion therapy”).
DNA Damage and Cell Killing by Camptothecin and Its Derivative in Human Leukemia HL‐60 Cells
Authors: Yoshida Akira , Ueda Takanori , Wano Yuji , Nakamura Toru
Published: August 2005

Camptothecin (CPT) has heen recognized as a topoisomerase I (Topo I) inhibitor. However, the mechanism of cytotoxicity of this agent remains unknown. In the present study, we analyzed the kinetics of Topo I‐mediated DNA single‐strand breaks and internucleosomal DNA cleavage produced by CPT and its derivative, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), in HL‐60 cells. DNA single‐ strand breaks were detected using alkaline sucrose gradient centrifugation when HL‐60 cells were incubated with 10 μM CPT or 10 μM SN‐38 for 30 min. These DNA single‐strand breaks were rapidly repaired after drug removal, while the cytotoxic action of these drugs was sustained. Treatment of HL‐60 cells with CPT or SN‐38 for 3 h produced extensive degradation of DNA. Agarose gel electrophoresis showed a ladder of DNA fragments consisted of multimers of approximately 200 base pairs, characteristic of apoptosis. Interestingly, this type of DNA fragmentation was also induced within 4 h after repair of DNA single‐strand breaks, and subsequently loss of cell viability was observed. When zinc ion, a potent inhibitor of endonuclease, was added to drug‐free medium after treatment with CPT or SN‐38, internucleosomal DNA cleavage was abolished. Furthermore, addition of zinc ion reduced the loss of cell viability. These data suggest that Topo I‐mediated DNA single‐strand breaks may be necessary but are not sufficient for cell death, and the endonuclease involved in induction of internucleosomal DNA cleavage may play an important role in HL‐60 cell death induced by Topo I inhibitor.
Quantitative Comparison of Initiation and Mutation Phenotypes in Hepatocytes of the Analbuminemic Rat
Authors: Dragan Yvonne P. , Laufer Christopher , Koleske Anthony J. , Drinkwater Norman , Pilot Henry C.
Published: August 2005

The potential relationship between mutagenesis and carcinogenesis has been examined in the Nagase analbuminemic rat treated with a single dose of benzo[a]pyrene, an incomplete liver carcinogen. The apparent mutation rate at the albumin locus was calculated by determining the number of hepatocytes expressing a cross‐reactive product of albumin in analbuminemic rats treated with benzo[a]pyrene. The rate of initiation, the first stage in carcinogenesis, was determined by assessing the number of hepatocytes expressing the placental isozyme of glutathione S‐transferase (PGST) after administration of benzo[a]pyrene. Since the expression of PGST may represent hepatocellular changes independent of initiation, promotion with phenobarbital was employed to clonally expand those putatively initiated hepatocytes expressing PGST. With immunohistochemical measures to assess changes in albumin expression, a threefold increase in the number of hepatocytes expressing albumin was detected after administration of benzo[a]pyrene in Nagase analbuminemic rats. A more than five‐fold increase in altered hepatic foci (AHF) exhibiting increased PGST expression was observed in animals given benzo[a]pyrene treatment followed by phenobarbital, compared with those given benzo[a]pyrene alone. The number of albumin‐expressing single hepatocytes detected was of the same order of magnitude as the number of individual hepatocytes and AHF expressing PGST, suggesting that similar events may be involved in their formation. Since 3 × 106 single hepatocytes expressing albumin were found in the analbuminemic rat liver after a single administration of benzo[a]pyrene, while less than 2 × 104 AHF expressing PGST were observed, formation of individual hepatocytes expressing albumin was a far more frequent event than clonal expansion of initiated hepatocytes in the Nagase analbuminemic rat. However, the number of loci of PGST expression including AHF and single hepatocytes is comparable to that of single hepatocytes expressing albumin.
The effect of involuntary job loss on smoking intensity and relapse
Authors: Falba Tracy , Teng Hsun‐Mei , Sindelar Jody L. , Gallo William T.
Published: August 2005

Aims To assess the impact of involuntary job loss due to plant closure or layoff on relapse to smoking and smoking intensity among older workers.

Design, participants, sample Data come from the Health and Retirement Study, a nationally representative survey of older Americans aged 51–61 in 1991 followed every 2 years beginning in 1992. The 3052 participants who were working at the initial wave and had any history of smoking comprise the main sample.

Methods Primary outcomes are smoking relapse at wave 2 (1994) among baseline former smokers, and smoking quantity at wave 2 among baseline current smokers. As reported at the wave 2 follow‐up, 6.8% of the sample experienced an involuntary job loss between waves 1 and 2.

Findings Older workers have over two times greater odds of relapse subsequent to involuntary job loss than those who did not. Further, those who were current smokers prior to displacement that did not obtain new employment were found to be smoking more cigarettes, on average, post‐job loss.

Conclusions The stress of job loss, along with other significant changes associated with leaving one's job, which would tend to increase cigarette consumption, must outweigh the financial hardship which would tend to reduce consumption. This highlights job loss as an important health risk factor for older smokers.
Ethno‐specific patterns of adolescent tobacco use and the mediating role of acculturation, peer smoking, and sibling smoking
Authors: Asbridge Mark , Tanner Julian , Wortley Scot
Published: August 2005

Aims The objectives of this study are to identify the relationship between ethnic identity and tobacco use, and to examine the mediating effects of peer and sibling smoking and acculturation.

Design and measurements Data were drawn from a cross‐sectional survey of 3400 Toronto students, sampled from 30 schools between 1998 and 2000. Primary ethnic identity was based on adolescents’ self‐identification of their ethnic heritage condensed to 12 groups for analysis. Tobacco use was measured as a dichotomy, predicting non‐smoking in the past year. Multivariate logistic regression models were employed to test for baseline differences in non‐smoking by ethnic identity. Subsequent models adjusted for controls (age, gender, social class, religious attendance, educational achievement) and introduced mediators.

Findings Results indicated that smoking varied among adolescents of differing ethnic identities. Adolescents of western European, eastern European and southern European ethnicity were considerably less likely to be non‐smokers, while Chinese, South Asian and East Indian and West Indian youth were more inclined to be non‐smokers. The discrepancies in rates of non‐smoking among western European and South Asian and East Indian adolescents were explained by a combination of peer and sibling smoking and acculturation; among southern European and eastern European youth via peer and sibling smoking; and by neither peer and sibling smoking nor acculturation for Chinese and West Indian youth.

Conclusions This paper demonstrates that disparities in tobacco use among certain ethnic groups can be explained by peer and sibling smoking and acculturation; however, for other ethnic groups, knowledge of the processes that account for differences in tobacco use remains less clear.
Supporting frail older people and their family carers at home using information and communication technology: cost analysis
Authors: Magnusson Lennart , Hanson Elizabeth
Published: August 2005

Aim.  This paper describes a cost analysis of a home‐based support service for frail older people and their family carers in two municipalities in West Sweden and using information and communication technology.

Background.  A key challenge facing nurse managers across Europe is an increasingly aged population, combined with reduced numbers of young adults of working age. New solutions are needed to provide quality, cost‐effective community care services to frail older people and their family carers.

Methods.  A case study methodology involving five families was used, and included a detailed cost description of the technology‐based service compared with usual services. Cost data were collected in June 2002. This work formed part of a larger project exploring the impact of a technology‐based service known as, Assisting Carers using Telematics Interventions to meet Older Persons’ Needs (ACTION). In addition to cost data, information was gathered on the quality of life of frail older people and their family carers, and the job satisfaction and work methods of nurses and other practitioners based in the community. The cost analysis comprised a description of the family and their caring situation, the perceived benefits of the telematic based support service and an assessment of its impact on the use of other care services. These analyses were carried out with the help of needs assessors who were known to the families, and nurses working in the ACTION call centre. All results were validated by the five participating families.

Results.  Cost savings were achieved in all cases, and the benefits to older people and their carers were also considerable. As a result of the cost analysis and overall evaluation data, ACTION has been implemented as a mainstream service in the municipalities involved.

Conclusion.  Researchers, nurses, other practitioners and community care managers can work together with frail older people and their family carers to develop quality, cost‐effective support services that reduce demands on staff whilst providing benefits to users.
Can the study of ethics enhance nursing practice?
Authors: Allmark Peter
Published: August 2005

Aim.  The aim of this paper is to suggest that the study of ethics and ethical theories can enhance nursing practice.

Discussion.  Knowledge of ethical theories can be of practical use to nurses in at least three ways. First, it can help nurses uncover to what extent a problem is an ethical one. The questions faced in practice can be empirical, formal or philosophical. Very often, a practical decision requires us to tackle all three types. In the example of a ‘Do not attempt resuscitation’ order, deciding on whether such an order is appropriate requires us to answer empirical questions such as how likely any attempt is to achieve success. It also requires us to answer formal questions such as whether the law permits such an order in the present circumstance. Finally, it requires us to answer ethical/philosophical questions, such as how we should weigh up quality of life against quantity. Second, it can enable practitioners to develop skills and tools to tackle ethical/philosophical questions. In this paper I describe two such tools: Socratic questioning and Aristotelian dialectic. Third, it can help practitioners to develop the soundness of their ethical values and beliefs. All ethical reasoning requires us to use our values and beliefs, and attending to them enhances the quality of our reasoning.

Conclusion.  The study of ethics can enhance nursing practice.
Patient satisfaction with diabetes care
Authors: Hornsten Asa , Lundman Berit , Selstam Eva Kihl , Sandstrom Herbert
Published: August 2005

Aim.  The aim of this paper is to report the findings of a study that elucidated the experiences and reflections of people with type 2 diabetes about clinical encounters.

Background.  Several patient satisfaction surveys have focused on privacy, cheerfulness and amenities rather than on how the care was delivered. A great deal of research has also focused on communication and various consultation styles, particularly within health promotion and diabetes care, but how these factors tie up with patient satisfaction has rarely been discussed. This study was performed in order to elucidate patients’ perspectives about clinical encounters in diabetes care.

Method.  Interviews were carried out during 2001 with 44 patients with diabetes. The transcribed interviews were analysed using qualitative content analysis.

Results.  Five themes were connected to patient satisfaction and dissatisfaction, namely ‘being in agreement vs. in disagreement about the goals’; ‘autonomy and equality vs. feeling forced into adaptation and submission’; ‘feeling worthy as a person vs. feeling worthless’; ‘being attended to and feeling welcome vs. ignored’; and, lastly, ‘feeling safe and confident vs. feeling unsafe and lacking confidence’.

Conclusion.  Despite efforts to individualize diabetes care and find ways to communicate with patients, many people have experiences of clinical encounters that they find dissatisfying. Experiences of dissatisfying encounters have elements that may threaten their perception of self and identity, while elements included in satisfying encounters are those characterizing patient‐centred care.
Sleep tendency during extended wakefulness: insights into adolescent sleep regulation and behavior
Authors: TAYLOR DANIEL J. , JENNI OSKAR G. , ACEBO CHRISTINE , CARSKADON MARY A.
Published: August 2005

Sleep tendency (latency to sleep onset) was examined during extended waking in prepubertal and mature adolescents to determine whether sleep pressure is lower near bedtime in the latter group. Participants were nine prepubertal (pubertal stage Tanner 1, mean age 11.1 years, SD ± 1.3 years, five males) and 11 pubertally mature adolescents (Tanner 5, 13.9 ± 1.2 years, three males). They spent 10 nights at home on an identical fixed 10‐h sleep schedule followed by a 36‐h constant routine with sleep latency tests at 2‐h intervals using standard polysomnography. Saliva was collected to assess dim‐light melatonin onset (DLMO) phase. DLMO was earlier in the Tanner 1 (mean clock time = 20:33 hours, SD = 49 min) than Tanner 5 group (21:29 hours ± 42 min). Sleep latency compared at a ‘critical period’ spanning 12.5 (20:30 hours clock time) to 18.5 h (02:30 hours) after waking did not differ at 20:30 hours, but was shorter for the Tanner 1 group at 22:30 hours (Tanner 1 = 9.2 ± 6.3 min; Tanner 5 = 15.7 ± 5.8 min), 00:30 hours (Tanner 1 = 3.6 ± 1.7 min; Tanner 5 = 9.0 ± 6.4 min), and 02:30 hours (Tanner 1 = 2.0 ± 1.7 min; Tanner 5 = 4.3 ± 3.2 min; trend). These differences were apparent controlling for circadian phase by partial correlation. Sleep tendency after 14.5, 16.5, and 18.5 h awake was lower in mature versus prepubertal adolescents, supporting our hypothesis that a developmental change of intrinsic sleep–wake regulation may provide physiologically mediated ‘permission’ for later bedtimes in older adolescents.