bluuebunny/crossref_metadata_2025 huggingface dataset:
The causal link between human papillomavirus and invasive cervical cancer: A population‐based case‐control study in colombia and spain
Authors: Munoz N. , Bosch F. X. , de Sanjose S. , Tafur L. , Izarzugaza I. , Gili M. , Viladiu P. , Navarro C. , Martos C. , Ascunce N. , Gonzalez L. C. , Kaldor J. M. , Guerrero E. , Lorincz A. , Santamaria M. , De Ruiz P. Alonso , Aristizabal N. , Shah K.
Published: February 2007

To evaluate the association between human papillomavirus (HPV) and cervical cancer, we performed a population‐based case‐control study in Colombia and Spain, the former country having an incidence rate of cervical cancer about 8 times higher than the latter. It included 436 cases of histologically confirmed invasive cervical cancer and 387 randomly selected population controls. Information on demographic variables, sexual behaviour and other risk factors was obtained by interview. HPV‐DNA was measured in cervical‐swab specimens with 3 hybridization assays: ViraPap™, Southern hybridization (SH) and polymerase chain reaction (PCR). The presence of HPV‐DNA and detection of types 16, 18, 31, 33 and 35 were strongly associated with cervical cancer in each country regardless of the assay used. For both countries combined the adjusted odds ratios and 95% confidence intervals were: ViraPap OR = 25.9 (10.0–66.7); SH OR = 6.8 (3.4–13.4); and PCR OR = 28.8 (15.7–52.6). HPV‐16 was the most common type detected in both cases and controls. Our results indicate that there is a very strong association between HPV 16, 18, 31, 33 and 35 and invasive cervical cancer and that this association is probably causal. © 1992 Wiley‐Liss, Inc.
Risk factors for cervical cancer in Colombia and Spain
Authors: Bosch F. X. , Muñoz N. , de Sanjosé S. , Izarzugaza I. , Gili M. , Viladiu P. , Tormo M. J. , Moreo P. , Ascunce N. , Gonzalez L. C. , Tafur L. , Kaldor J. M. , Guerrero E. , Aristizabal N. , Santamaria M. , De Ruiz P. Alonso , Shah K.
Published: February 2007

A population‐based case‐control study of cervical cancer was conducted in Spain and Colombia to assess the relationship between cervical cancer and exposure to human papillomavirus (HPV), selected aspects of sexual and reproductive behaviour, use of oral contraceptives, screening practices and smoking. The study included 436 cases of histologically confirmed squamous‐cell carcinoma and 387 age‐stratified controls randomly selected front) the general population that generated the cases. The presence of HPV DMA in cervical scrapes was assessed by PCR‐based methods and was the strongest risk factor (OR = 23.8; 13.4–42.0). Risk estimates for any other factor were only slightly modified after adjusting for HPV status. Among women found positive for HPV DNA, only the use of oral contraceptives was a risk factor for cervical cancer (OR = 6.5; 1.3–31.4 for ever vs. never use). Patients with cervical cancer who were HPV DMA‐negative retained most of the established epidemiological features of this disease. This suggests that some instances of HPV infection went undetected or that other sexually transmitted factor(s) contribute to the causation of cervical cancer. Early age at first intercourse (OR = 4.3; 2.1–9.0 for age < 16 vs. 24+) and early age at first birth (OR = 5.0; 1.8–14.2 for 9ge < 16 vs. 24+) were associated with increased risk of cervical cancer; these effects were independent of one another. Low educational level was a risk factor (OR = 2.5; l.6–3.9). Number of sexual partners was in our study a surrogate for HPV infection. Smoking and parity after age 24 were weakly and inconsistently associated with the risk of cervical cancer. Previous screening (OR = 0.7; 0.5–1.0) and ever having undergone a Caesarean section (OR = 0.4; 0.2–0.8) were protective factors. © 1992 Wiley‐Liss, Inc.
Transforming growth factor β1 (TGF‐β1) inhibits growth of a human ovarian carcinoma cell line (OVCCR1) and is expressed in human ovarian tumors
Authors: Jozan S. , Guerrin M. , Mazars P. , Dutaur M. , Monsarrat B. , Cheutin F. , Bugat R. , Martel P. , Valette A.
Published: February 2007

The effects of EGF and TGF‐β1 on the proliferation of 2 ovarian carcinoma cell lines (IGROV1 and OVCCR1) were evaluated. The cell lines were adapted to grow in a restricted serum (0.5%) medium. EGF was required for proliferation of both ovarian cell lines. Low doses of TGF‐β1 inhibited clonogenic capacity and attenuated the EGF‐mediated stimulation of DNA synthesis in OVCCR1 cells. TGF‐β1 inhibited OVCCR1 cell proliferation by blocking the cell cycle at the G1/S transition. TGF‐β1 did not affect either clonal or monolayer growth of IGROV1 cells. Both cell lines express type‐I and type‐III TGF‐β1 receptors, suggesting that the unresponsiveness of IGROV1 cells to TGF‐β1 occurs at a post‐receptor level. TGF‐β1 mRNA was detected in OVCCR1 cells and in 8 out of 11 of the ovarian tumor specimens examined. © 1992 Wiley‐Liss, Inc.
H‐2Db gene transfer into highly metastatic D122 cells results in tumor rejection in allogeneic recipients, but does not affect metastasis in syngeneic recipients. Implications for mechanisms of allorejection
Authors: Plaksin Daniel , Gelber Cochava , Eisenbach Lea
Published: February 2007

Highly metastatic, weakly immunogenic Lewis lung carcinoma clones express very low levels of H‐2Kb and moderate levels of H‐2Db class‐1 major histocompatibility complex antigens. These cells metastasize spontaneously in mice with C57BL/6 genetic background possessing the H‐2Db locus, and grow as local tumors across allogeneic barriers. Transfection of the H‐2Db genes into the highly metastatic clone D122 did not alter the growth or metastatic capacity of these cells in syngeneic mice. However, these cells were rejected in allogeneic mice. Transfection of the H‐2Kd or H‐2Kk genes into D122 elicited a CTL population that cross‐reacted with cells bearing native H‐2Db antigens. These data suggest that overlapping allo‐CTL populations are induced by a native alloantigen and by alloantigen peptides presented through self class‐l molecules. © 1992 Wiley‐Liss, Inc.
Treatment of liver metastases of human colon cancers in nude mice with somatostatin analogue RC‐160
Authors: Qin Yunfeng , Schally Andrew V. , Willems Gerard
Published: February 2007

Hepatic metastases of colon 320 DM and WidR human colon cancers in nude mice were treated by s.c. injections of somatostatin analogue RC‐160 for 4 weeks. Chronic administration of RC‐160 significantly inhibited the incidence and growth of liver metastases of these 2 colon‐cancer cell lines. After RC‐160 treatment, the incidence of liver metastases decreased by 25% for colon 320 DM cells and by 37.5% for WidR cells. The mean number of metastatic tumors in each liver decreased by 47.9% for colon 320 DM and 42.6% for WidR. Survival times of mice with liver tumors of colon 320 DM and WidR cells were prolonged by 20 days and 7 days, respectively. The inhibitory effect of RC‐160 on the growth of these 2 colon cancers implanted s.c. was also observed. After administration of RC‐ 160 for 4 weeks, the mean tumor volume in the treated groups was only 39.8% of that of controls for the colon 320 DM line and 58% for the WidR line. Tumor‐growth rate and final tumor weight were also significantly decreased, while tumor‐volume doubling time and tumor‐growth delay time were prolonged. The effect of RC‐160 on cellular proliferation in the tumors was studied by in vivo labelling with bromodeoxyuridine and immunoperoxidase staining. The mean labelling index in the treatment group was reduced by 14.9% and 19.5%, respectively, for colon 320 DM and WidR tumors. The cytostatic effect of RC‐160 was also evident from the apparent reduction in DNA and protein content in the tumor tissues of these cancer lines. Our findings suggest that somatostatin analogue RC‐160 may be useful for the treatment of patients with hepatic metastases of colon cancer. © 1992 Wiley‐Liss, Inc.
Early superoxide dismutase alterations during SV40‐transformation of human fibroblasts
Authors: Bravard A. , Hoffschir F. , Sabatier L. , Ricoul M. , Pinton A. , Cassingena R. , Estrade S. , Luccioni C. , Dutrillaux B.
Published: February 2007

The expression of superoxide dismutases (SOD) 1 and 2 was studied in 4 clones of human fibroblasts after their infection by simian virus 40 (SV40), in parallel with the alterations of chromosomes 21 and chromosome 6q arms, carrying the genes that encode for SOD1 and SOD2 respectively. For all clones, a similar scheme with 2 main phases was observed for both chromosome and SOD variations. The first phase, defined as the pre‐crisis phase, was characterized by chromosomal instability, but maintenance of normal numbers of chromosome 6q arms and chromosomes 21. The level of SOD2 mRNA was high, while SOD2 activity and immunoreactive protein were low. SOD1 protein and activity were decreased. In the second phase, defined as the post‐crisis phase, the accumulation of clonal chromosomal rearrangements led to the loss of 6q arms, while the number of chromosomes 21 remained normal. SOD2 mRNA level was decreased and SOD2 immunoreactive protein and activity remained low. SOD1 protein and activity increased with passages, reaching values similar to those of control cells at late passages. As in established SV40‐transformed human fibroblast cell lines, good correlation was found between SOD2 activity and the relative number of 6q arms. These results allow us to reconstruct the sequence of events leading to the decrease of SOD2, a possible tumor‐suppressor gene, during the process of SV40‐transformation of human fibroblasts. © 1992 Wiley‐Liss, Inc.
Effect of IL‐1 on experimental bone/bone‐marrow metastases
Authors: Arguello Francisco , Baggs Raymond B. , Graves Brian T. , Harwell Shari E. , Cohen Harvey J. , Frantz Christopher N.
Published: February 2007

Bone metastasis is a common event and a major cause of morbidity in cancer patients. The hematopoietic marrow of the bones, rather than the bone tissue per se, is the target organ in bone metastasis. In the bone marrow, IL‐1 induces the release of hematopoietic growth factors that may affect tumor‐cell growth. We treated groups of mice with rhulL‐1α to examine its role in the establishment of experimental bone/bone‐marrow metastasis. We found that injection of 2 μg of rhulL‐1α 24 hr prior to, simultaneously with or 24 hr after the injection of 104B16 melanoma cells into the left cardiac ventricle of mice resulted in a 2‐fold increase in the average number of colonized bones per mouse. GM‐CSF is produced by bone‐marrow stromal cells in response to IL‐1, and its receptor has been found on tumor cells, including melanoma cells. However, the administration of rmuGM‐CSF to mice by either multiple injections or continuous infusion did not affect the number of colonized bones. Many of the biologic effects of IL‐1 are mediated by prostaglandins. Treatment of mice with 100 μg of indomethacin, a potent inhibitor of prostaglandin synthesis, prior to the injection of rhulL‐ 1α, prevented the increase in number of bone metastases. To determine whether constitutive productions of IL‐1 and/or prostaglandins are involved in the pathogenesis of bone/bone marrow metastasis, we treated mice with antimouse IL‐1α neutralizing antibodies, rhulRAP (an inhibitor of IL‐1 activity) or indomethacin. We found no difference in the average number of colonized bones per mouse between treated and control mice. We conclude that exogenous administration of IL‐1 enhances experimental bone/bone‐marrow metastases, and that this phenomenon is mediated through prostaglandins. However, neither the constitutive production of IL‐1 nor that of prostaglandins appear to play a role in the pathogenesis of bone/bone‐marrow metastasis in our murine model system. © 1992 Wiley‐Liss, Inc.
The p53 tumor‐suppressor gene and ras oncogene mutations in oral squamous‐cell carcinoma
Authors: Sakai Eiki , Rikimaru Koichi , Ueda Masayoshi , Matsumoto Yukie , Ishii Naoko , Enomoto Shoji , Yamamoto Hajime , Tsuchida Nobuo
Published: February 2007

The frequencies of mutations in the p53 tumor‐suppressor gene and ras proto‐oncogenes were investigated systematically in surgically resected oral squamous‐cell carcinomas (SCCs) using single‐strand conformation polymorphism (SSCP) and/or dot‐blot hybridization analysis of DNA fragments which had been amplified by the polymerase chain reaction (PCR). p53 gene mutations, within the region of exons 5 to 8, were detected in 17 out of 27 (63%) tumor specimens. The role of p53 mutations in cell‐line establishment was investigated. p53 gene mutations were detected in 5 out of 6 tissue samples from which cell lines were established and in 4 out of 5 specimens from which cell lines could not be established, suggesting that the presence of p53 gene mutations is not by itself sufficient for cell‐line establishment. Tumor samples were also analyzed for point mutational activation of the ras proto‐oncogenes. One out of 30 (3%) tumors showed an activating point mutation in codon 12 of H‐ras, this being consistent with reports from Europe and USA but not with any from India. Compared to frequencies of the other genetic changes so far reported for oral SCC, the p53 mutations have been observed most often to undergo genetic change. p53 gene mutation is thus intimately involved in the genesis of oral SCC and consequently should be useful as a marker for the diagnosis of this neoplasm. © 1992 Wiley‐Liss, Inc.
Neutralizing activity of human antibodies against the structural protein of human T‐cell lymphotropic virus type I
Authors: Inoue Yukiko , Kuroda Naotaka , Shiraki Hiroshi , Sato Hiroyuki , Maeda Yoshiaki
Published: February 2007

We have identified and mapped the regions responsible for neutralization in the human T‐cell leukemia virus type I (HTLV‐I) structural proteins by using region‐specific human antibodies derived from seropositive blood donors. We have obtained 18 kinds of region‐specific antibody (2 in the p 19 gag, 10 in the gp46 env and 6 in the gp21 env proteins) from seropositive human plasma by means of an affinity column coupled with the synthetic peptides corresponding to the antigenic regions of the HTLV‐I structural proteins. These antibodies were highly specific in ELISA using synthetic peptides as an antigen. Subsequently, we examined the neutralizing activity expressed by the inhibition of virion‐induced syncytium formation by region specific antibodies. Twelve of 16 antibodies derived from the env protein were able to inhibit syncytium formation induced by co‐cultivation of 8C cells with HTLV‐I antigen‐positive T cells. The antibodies derived from the p19 gag protein and the seronegative plasma used as the control showed no significant activity. The sequences recognized by the 10 neutralizing antibodies were sites corresponding to amino acids 20 to 49, 89 to 115, 136 to 160, 175 to 199, 213 to 236, 235 to 254, 277 to 292, 332 to 352, 350 to 386, 382 to 403, 426 to 448 and 458 to 488 from the amino terminal of the env protein. These observations suggest that the neutralizing epitopes were widely distributed in the env proteins of HTLV‐I. © 1992 Wiley‐Liss, Inc.
Establishment of a murine model of malignant mesothelioma
Authors: Davis M. R. , Manning L. S. , Whitaker D. , Garlepp M. J. , Robinson B. W. S.
Published: February 2007

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with previous asbestos exposure and is generally found to be resistant to conventional forms of therapy. Adequate scientific and clinical assessment of this disease has been severely limited by the relatively low incidence of mesothelioma and the lack of representative cell lines and animal models. The purpose of this study was to develop an asbestos‐induced murine model of MM both as an in vivo‐passaged malignancy and as in vitro‐established cell lines. Such a model system would be invaluable for use in the study of various cellular, molecular and genetic aspects of the disease, and for the pre‐clinical evaluation of potential therapeutic agents. BALB/c and CBA mice were injected intraperitoneally with crocidolite asbestos. Seven to 25 months after exposure, 35% of the mice developed mesothelioma (5 BALB/c, 9 CBA), as determined by standard cytological and histological parameters. From these primary tumours, 12 continuously growing cell lines (5 BALB/c, 7 CBA) were established in culture. All have been confirmed as mesothelioma by cytological and ultrastructural (electron microscopy) analyses. These lines have been in culture for 7 to 24 months and have achieved passages above 32 (range 32 to 106). As in the human disease, the murine mesothelioma lines vary in their morphology and growth rates (doubling times ranging from 14 to 30 hr). All cell lines produced tumours when injected into syngeneic mice. © 1992 Wiley‐Liss, Inc.
Novobiocin‐induced accumulation of etoposide (VP‐16) in wehi‐3B D+ leukemia cells
Authors: Lorico Aureiio , Rappa Germana , Sartorelli Alan C.
Published: February 2007

A previous report from this laboratory demonstrated that novobiocin produced supra‐additive cytotoxicity when combined with etoposide (VP‐16) or teniposide (VM‐26) in WEHI‐3B D+ and A549 cells. The increase in cytotoxicity was accompanied by an increase in the formation of drug‐stabilized protein‐DNA covalent complexes. We now report that novobiocin increased the amount of VP‐16‐induced covalent complexes between the 170 kDa form of topoisomerase II and DNA in WEHI‐3B D+ cells, as measured by the band‐depletion immuno‐blotting assay, while it did not affect the extractable topoisomerase II activity, measured by the unknotting of P4 phage DNA and by a DNA cleavage assay. Novobiocin progressively increased the steady‐state concentration of intracellular VP‐16. Removal of novobiocin resulted in a rapid return of VP‐16 to levels comparable to those seen with VP‐16 alone. The increased accumulation of VP‐16 was accounted for by an increase in the exchangeable fraction only. The novobiocin‐mediated increase in the steady‐state concentration of VP‐16 occurred whether novobiocin was added simultaneously with VP‐16 or was added after a steady‐state level of VP‐16 had been achieved. Novobiocin did not affect the initial rate of uptake of VP‐16; however, it inhibited the efflux of the epipodophyllotoxin. In fact, when cells were loaded with the same level of VP‐16 in the presence or absence of novobiocin, the efflux curves in the presence or absence of novobiocin were significantly different. We conclude that the inhibition of VP‐16 efflux by novobiocin is responsible for the increase in VP‐16 accumulation, leading to increased formation of VP‐16‐stabilized topoisomerase‐II‐DNA covalent complexes and increased cytotoxicity. © 1992 Wiley‐Liss, Inc.
Analysis of factors associated with the tumorigenic potential of 12 tumor clones derived from a single rat colon adenocarcinoma
Authors: Zennadi R. , Garrigue L. , Ringeard S. , Ménoret A. , Blanchardie P. , le Pendu J.
Published: February 2007

We analyzed several factors which could influence the immunogenicity of colon tumor cells, using a series of clones derived from a single chemically induced rat adenocarcinoma cell line. These clones display variable tumorigenic potential in syngeneic immunocompetent animals, and it has been established that in this model the tumorigenicity of the cells depends on their ability to escape immune surveillance. The results show an absence of relationship between tumorigenicity and expression of MHC‐class‐I antigens, cell adhesion to rat fibroblasts or fibroblast extracellular matrix. The secretion of latent and active TGFβ I appeared to be quite variable from one clone to the other, but was unrelated to tumorigenicity. Unexpectedly, some regressive clones produced elevated levels of this cytokine, suggesting that in this model, spontaneous secretion of TGFβ I is not sufficient to impair the immune system of the host. In contrast, the more tumorigenic clones were more resistant than less tumorigenic ones to cytotoxicity mediated by NK or LAK cells. They also showed arrest of cell proliferation after reaching confluence, something not observed in the less tumorigenic clones. Finally, the strongest relationship with tumorigenicity was found for expression of blood‐group carbohydrate antigens. Increased expression of blood‐group‐H antigen and, conversely, decreased expression of β‐galactoside precursors of this antigen correlated with increased tumorigenicity. © 1992 Wiley‐Liss, Inc.
Inhibition by squalene of the tumor‐promoting activity of 12‐O‐Tetradecanoylphorbol‐13‐acetate in mouse‐skin carcinogenesis
Authors: Murakoshi Michiaki , Nishino Hoyoku , Tokuda Harukuni , Iwashima Akio , Okuzumi Junichi , Kitano Hirokazu , Iwasaki Ryozo
Published: February 2007

Squalene inhibited the effect of tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), such as increased 32Pi incorporation into phospholipids of HeLa cell membrane, induction of Epstein‐Barr‐virus early antigen in Raji cell and induction of ornithine decarboxylase in mouse skin. Squalene also markedly suppressed the promoting activity of TPA on skin carcinogenesis in 7, 12‐dimethylbenz[a]anthracene‐initiated mice. © 1992 Wiley‐Liss, Inc.
The development of human tumor‐cell resistance to TNF‐α does not confer resistance to cytokine‐induced cellular cytotoxic mechanisms
Authors: Zyad Abdelmajid , Branellec Didier , Mahé Yann , Tursz Thomas , Chouaib Salem
Published: February 2007

We have derived a TNF‐α‐resistant clone (RA‐I) from the parental TNF‐sensitive human breast‐adenocarcinoma cell line (MCF‐7). The acquisition of TNF‐resistance was not associated with endogenous TNF production or with differential levels of TNF receptors since both MCF‐7 and RA‐1 display comparable TNF‐receptor expression. We have investigated the relationship between acquisition of resistance to TNF and susceptibility to lysis by cytokine‐activated effectors. Experiments were performed using human peripheral‐blood monocytes stimulated with IL‐2, IFN or GM‐CSF, and lymphokine‐activated killer cells as effector cytotoxic cells. Our data indicate that both TNF‐resistant (RA‐I) and TNF‐sensitive (MCF‐7) cells were killed by IL‐2‐activated monocytes. Incubation of monocytes with IFN also resulted in the activation of their tumoricidal activity against MCF‐7 and RA‐I. When stimulated monocytes were pre‐incubated in the presence of a TNF‐specific neutralizing monoclonal antibody, prior to co‐culture with target cells, no effect on their lytic capacity was observed. Thus, the monocyte killing does not appear to involve the membrane form of TNF. These observations suggest that, in our experimental system, IL‐2 and IFN are able to induce non‐TNF‐mediated mechanisms of cytotoxicity by monocytes. Experiments performed using GM‐CSF and LPS for monocyte stimulation indicate that, although both reagents were efficient in inducing the membrane form of TNF on monocytes, they did not enhance the cell‐killing capacity towards MCF‐7 and RA‐1 targets. Furthermore, using IL‐2‐stimulated LGL as effector cells, we show in this study that the TNF‐resistant clone RA‐1 was as sensitive as MCF‐7 to human LAK cells. © 1992 Wiley‐Liss, Inc.
Cancer‐cell traffic in the liver. I. Growth kinetics of cancer cells after portal‐vein delivery
Authors: Barbera‐Guillem Emilio , Smith Isabel , Weiss Leonard
Published: February 2007

Following the intrasplenic injection of B16F10 melanoma cells into mice, at first single cells, and later multicellular tumor foci were observed at different times in the liver. Cell numbers and tumor volumes were determined over the next 12 days, by confocal microscopy of thick liver sections. Fifteen minutes after injection, approximately 20% of the melanoma cells were identified in the liver microvasculature; after 48 hr, only 0.68% of these retained morphologic integrity; by 5 days only 0.13% of the originally detected cells incorporated BUdR; and, by 12 days, these subsequently grew into tumor nodules. Tumor volume changes with time were not exponential and, following a non‐replicative period during the first 2½ days, the volume doubling times increased from approximately 8 to 39 hr at 12 days. BUdR incorporation indicated that this was probably due to a diminishing proliferative fraction in the cancer‐cell population. When animals were killed at 12 days, tumor foci were centered on the liver sinusoids and appeared to represent expansive growth of arrested cells, with no evidence of parenchymal invasion by migrating cancer cells, in spite of the absence of a subendothelial basement membrane. Our direct observations indicate that, in this model system, the post‐delivery phase of hepatic colonization is characterized by high levels of inefficiency with respect to cancer‐cell survival, growth and extravasation. © 1992 Wiley‐Liss, Inc.
Analysis of anti‐tax antibody of HTLV‐I carriers in an endemic area in Japan
Authors: Shioiri Shigemasa , Tachibana Nobuyoshi , Okayama Akihiko , Ishihara Shiro , Tsuda Kazunori , Essex Max , Stuver Sherri O. , Mueller Nancy
Published: February 2007

Sera from 1197 adult residents in Miyazaki district, an area in Japan endemic for human T‐cell leukemia virus type I (HTLV‐I), were tested for anti‐Tax antibody by the recombinant Tax (r‐Tax) Western blot assay. Among HTLV‐I‐seropositive individuals, including 21.5% of 484 males and 28.6% of 713 females, the prevalence of anti‐Tax antibody were 59.6% and 58.3% respectively, with no apparent difference in age. There was a significant 6‐fold difference in the prevalence of anti‐Tax among seropositive subjects with titer > 1:8192 (84.6%) compared with those with the lowest titer of 1:16 (14.3%), suggesting the increased production of antibodies to viral structural proteins in anti‐Tax‐positive individuals. Furthermore, among those anti‐Tax‐positive subjects, the intensity of serum reactivity to r‐Tax protein in the high antibody titer (1:1024 or higher) group was significantly stronger than that in the lower antibody titer (1:512 or lower) group. We also found that 1.6% (14/889) of individuals without detectable levels of HTLV‐I antibody had anti‐Tax antibody. HTLV‐I pro‐viral DNA signals could not be detected in DNA sample from the lymphocytes of these individuals by the nested polymerase chain reaction method. Further evaluation is needed to clarify the significance of an anti‐Tax‐only status population in which HTLV‐I is endemic.
Basic fibroblast growth factor in human pheochromocytoma: A biochemical and immunohistochemical study
Authors: Statuto M. , Ennas M. G. , Zamboni G. , Bonetti F. , Pea M. , Bernardello F. , Pozzi A. , Rusnati M. , Gualandris A. , Presta M.
Published: February 2007

Biopsies of human normal adrenal medulla, adrenal pheochromocytoma, and chemodectoma were studied for the presence of basic fibroblast growth factor (bFGF). An immunoreactive Mr 18,000 bFGF‐like molecule was detected both in normal and neoplastic tissues. This molecule was identified as bFGF on the basis of its molecular weight, its affinity for heparin, and its capacity to induce plasminogen activator production in cultured endothelial GM 7373 cells. The levels of immunoreactive and biologically active bFGF appeared to be significantly higher in the extracts of adrenal pheochromocytoma and chemodectoma than in the extracts of normal adrenal medulla. bFGF immunostaining was detectable in the nuclei of chief (Type‐I) cells and of endothelial cells both in normal adrenal medulla and in pheochromocytoma. Cytoplasmic bFGF positivity of endothelial cells was also observed in pheochromocytoma but not in normal tissue. The data are in keeping with the hypothesis that bFGF may exert autocrine and paracrine functions in the growth and neovascularization of human pheochromocytoma.
ras Gene mutations and hpv infection are common in human laryngeal carcinoma
Authors: Anwar Khurshid , Nakakuki Kazuya , Naiki Hironobu , Inuzuka Manabu
Published: February 2007

To evaluate the role of ras activation and human papillomavirus (HPV) infection in laryngeal carcinoma, we analyzed tumor DNA from 43 cases, including 25 primary laryngeal tumors, 12 lymph‐node and one skin metastases, and 5 recurrent laryngeal carcinomas. Thirteen normal laryngeal tissues and 7 benign laryngeal nodule biopsy specimens along with normal tissue surrounding laryngeal carcinoma in 2 cases were also included. The polymerase‐chain‐reaction technique was used to amplify DNA fragments containing codon 12 and 61 of H‐, K‐ and N‐ras, also HPV 16, 18 and 33 DNA, subsequently hybridized with sequence‐specific oligonucleotides. DNA samples from 22 patients with laryngeal carcinoma revealed ras mutations (18 in N‐ras codon 12, 6 in H‐ras codon 61, and 3 in K‐ras codon 61). Likewise, HPV DNA was found in 16 cases (HPV 16, 18 and 33 in 3 cases, 14 cases and 1 case respectively). ras mutations were significantly higher in metastatic tumors (10 of 13 cases) than in primary (11 of 25 cases) and recurrent laryngeal carcinomas (1 of 5 cases). HPV DNA was detected in 60% of recurrent, 44% of primary and 15% of metastatic tumors. Only 2 of the 13 normal laryngeal tissues and 1 out of 7 laryngeal nodule specimens were found to contain HPV DNA. These results suggest that ras activation, especially in N‐ras codon 12.1 (GGT → AGT) and HPV infection are 2 important factors in (multistage) laryngeal carcinogenesis. The ras mutation may be associated with metastatic ability of the tumor.
Bcl‐2 proto‐oncogene expression in epstein‐barr‐virus‐associated nasopharyngeal carcinoma
Authors: Lu Qi‐Long , Elia G. , Lucas S. , Alero Thomas J.
Published: February 2007

The bcl‐2 proto‐oncogene product inhibits apoptosis. Increased levels of bcl‐2 protein are associated with prolonged B‐cell survival and have been demonstrated in a high proportion of follicular B‐cell lymphoma. Recent studies have shown that bcl‐2 protein expression in B cells immortalized by Epstein‐Barr virus (EBV) in vitro is up‐regulated by the EBV‐latency‐associated antigen, latent membrane protein (LMP) I. The epithelial malignancy, undifferentiated nasopharyngeal carcinoma (UNPC), has a well‐established association with EBV and the tumour cells characteristically display a restricted latent viral phenotype including LMP I. This study has investigated the relationship between the presence of EBV DNA, EBV phenotypic profiles and bcl‐2 protein expression in conventionally processed and cryopreserved samples of NPC using in situ hybridization, immunocytochemical and immunoblotting techniques. bcl‐2 was detected in most (80%) samples of UNPC as well as in 1/3 samples of keratinizing NPC and 2/2 samples of nasopharyngeal adenocarcinoma. However, no close correlation was found between the presence of EBV DNA, and profiles for LMP I and bcl‐2 protein expression in 45 UNPC. In addition, bcl‐2 protein was shown to be selectively expressed in the basal compartment of normal nasopharyngeal epithelia. bcl‐2 protein expression has not been reported previously in malignant tumours of epithelial origin. The findings in this study implicate a role for bcl‐2 both in normal keratinocyte differentiation and in the pathogenesis of epithelial malignancy.
Flow cytometry in comparison with mitotic index in predicting disease outcome in transitional‐cell bladder cancer
Authors: Lipponen P. K. , Nordling S. , Eskelinen M. J. , Jauhiainen K. , Terho R. , Harju E.
Published: February 2007

The DNA content and S‐phase fraction were measured by flow cytometry in 448 tumour biopsy specimens from transitional‐cell bladder cancer (TCC). The samples were also analyzed for mitotic index, WHO grade and papillary status, and histological and flow cytometric data were then correlated to clinical behaviour of turnours during a mean follow‐up period of 9.9 years. TNM classification, WHO grade, papillary status, mitotic index, DNA ploidy and S phase fraction were significantly interrelated. Twenty‐four percent of tumours showed heterogeneous DNA indices when measured from multiple samples (measured in 94 cases). Of the histological parameters, independent predictors of progression in superficial tumours were the S‐phase fraction and mitotic index. In superficial tumours, S‐phase fraction and the mitotic index included all the available independent prognostic information in survival analysis, whereas in muscle‐invasive tumours T category was the most important prognostic factor. The results suggest that DNA ploidy has no independent prognostic value in transitional‐cell bladder cancer, whereas proliferation indices (SPF, mitotic index) are important prognostic factors. Accordingly, malignancy classification of papillary bladder tumours can be based on proliferation indices alone. Nodular tumours run an unfavourable course and their malignancy grading by flow cytometry or by mitotic index is not relevant.
Fundal atrophic gastritis as a risk factor for gastric cancer
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Nakaizumi Akihiko , Okuda Shigeru , Taniguchi Haruo , Hiyama Tomohiko , Tsukuma Andhideaki , Oshima Akira
Published: February 2007

The role of atrophic gastritis of the gastric corpus (fundal atrophic gastritis) as a high‐risk factor was investigated by studying operative findings and follow‐up data on 690 patients with benign gastric diseases recorded at the Osaka Cancer Registry. The extent of fundal atrophic gastritis was determined by the endoscopic Congo red test. The patients were followed‐up from the time of endoscopic examination (1968 to 1976) to December 31, 1987. The vital status of 654 patients (94.8%) at the end of the observation period was determined. During the follow‐up period, 22 patients were found to have gastric cancer. The extent of fundal atrophic gastritis was shown to be closely related with the risk of developing gastric cancer. Patients who had been diagnosed as having severe fundal atrophic gastritis showed significantly higher risk of gastric cancer than patients who had been diagnosed as having little or no fundal atrophic gastritis (5.76‐fold, calculated with adjustments for age, sex and the follow‐up period). A positive linear relationship was found between the risk of developing gastric cancer and the extent of fundal atrophic gastritis. The observed number of gastric cancers was compared with the expected number calculated from the incidence in Osaka Prefecture. Analysis of the results showed that the observed and expected numbers of gastric cancers in patients with severe fundal atrophic gastritis were 11 and 4.8, respectively, the ratio of observed to expected numbers being 2.3 (p < 0.05). These findings indicate that severe fundal atrophic gastritis is a major risk factor for gastric cancer.
Phosphoinositide metabolism in a polyoma‐bk‐virus‐transformed pancreatic islet cell line: Evidence for constitutively activated phospholipase C
Authors: Giæver A. K. , Husom Haukland H. , Bertinussen A. , Vonen B. , Malm D. , Huseby N. E. , Florholmen J.
Published: February 2007

We have characterized the phosphoinositide metabolism in a polyoma‐BK‐virus‐transformed rat pancreatic islet cell line which has highly malignant characteristics, expresses viral T‐antigen and has lost insulin‐secreting capacity. After incorporation with [3H]linositol to isotopic equilibrium, all inositol metabolites were analyzed. When comared with normal pancreatic islets, increased levels of inositol 1,4,5‐trisphosphate (Ins‐ 1,4,5‐P3), inositol 1,3,4‐trisphosphates and inositol tetrakisphosphate (Ins‐P4), and decreased levels of phosphatidylinositol monophosphate (PIP) and phosphatidylinositol bisphosphate (PIP2) were found. The Ins‐1,4,5‐P3/PIP2 ratio increased, whereas the PIP2/PIP ratio was not altered after the transformation. In the pancreatic islet cell line there was a stable accumulation of inositol phosphates at 3.3 mM glucose. Glucose, KCL, cholecystokinin (CCK) and carbachol with and without LiCL were all without effect on the accumulation of inositol phosphates. Somatostatin inhibited the accumulation of inositol phosphates but a Ca2+‐free/EDTA solution did not. Preincubation with cholera toxin or pertussis toxin inhibited the accumulation of inositol phosphates at 3.3 mM glucose except for Ins‐P4, whereas no effect was obsewed on the phosphoinositides. NaF stimulated the accumulation of inositol phosphates, with a concomitant decrease in the phosphoinositides, whereas neomycin was without effect on the inositol phosphates. In normal pancreatic islets, pertussis toxin inhibited the CCK‐ induced increase in Ins‐ 1,4,5‐P3, whereas no effect was seen at 3.3 mM glucose. Finally, pertussis toxin inhibited the CCK‐ induced increase in the Ins‐ 1,4,5‐P3/PIP2 ratio in normal pancreatic islets. The same inhibition was also found in the pancreatic islet cell line at 3.3 mM glucose. We conclude that in the transformed pancreatic islet cell line the phosphoinositide hydrolysis is constitutively activated at the level of phospholipase C, with a substantial loss of regulatory control.
Gangliosides and organ‐specific metastatic colonization
Authors: Coulombe Josée , Pelletier Guy
Published: February 2007

To investigate whether metastatic specificity is associated with a variation in the ganglioside profile of the parent cell lines, we have analyzed and compared the ganglioside content of subcutaneous (s.c.) tumors to that of the corresponding metastases. C57BL/6 mice were injected with either the Lewis lung carcinoma (3LLc) or its cloned variants, M27, exclusively metastatic to the lung, and H59, metastasizing preferentially to the liver. Gangliosides were extracted, purified and separated on HPTLC. H59 liver metastases contained significantly more GM2 (27.80%) than the H59 s.c. tumor (7.6%). The ganglioside profiles of 3LLc or M27 s.c. tumors were no different from those of their corresponding metastases. GM2 predominated in the liver (90.8%) while GM3 (48.8%) and GM2 (33.8%) were prevalent in the lung. Unidentified gangliosides designated G1, G2, G4 and G5 were present in tumor cells but absent from normal lung and liver. This study indicates that the ganglioside compositions of the 3LLc cell line and of its M27 variant were not modified under the influence of different sites of growth. Furthermore, the ganglioside profiles of the metastases were distinct from those of their respective target organs. The results of these studies suggest a possible relationship between GM2 and the establishment of H59 metastases in the liver.
Effect of novobiocin on cisplatin cytotoxicity and dna interstrand cross‐link formation in a cisplatin‐resistant, small‐cell lung carcinoma cell line
Authors: De Jong Steven , Timmer‐Bosscha Hetty , De Vries Elisabeth G. E. , Mulder Nanno H.
Published: February 2007

Studies were performed to determine whether novobiocin can be used to enhance cisplatin (CDDP) cytotoxicity in a human small‐cell lung carcinoma cell line, GLC4/CDDP, resistant to CDDP. Continuous incubation with novobiocin enhanced the cytotoxicity of CDDP treatment 1.9‐fold in the parental cell line GLC4, but had no effect on its cytotoxicity in the resistant cell line GLC4/CDDP. Short incubation with novobiocin enhanced the cytotoxicity of CDDP treatment in GLC4 and GLC4/CDDP by a factor of 4.1 and 2.8, respectively. Using the latter schedule, the amount of CDDP‐induced DNA interstrand cross‐links (DNA ISC) at 4 hr as well as at 24 hr after novobiocin and CDDP treatment was higher in GLC4 than in GLC4/CDDP. In this case, the amount of DNA ISC had increased 1.6‐fold in GLC4and 1.3‐fold in GLC4/CDDP at 4hr, and 2.7‐fold and 1.4‐fold, respectively, in these cell lines at 24 hr after treatment compared to CDDP treatment alone. Our results suggest an effect of novobiocin on the formation of DNA ISC. The decreased efficacy of novobiocin, an inhibitor of DNA topoisomerase (Topo) II catalytic activity, in GLC4/CDDP may be due to the increased Topo II activity previously found in the resistant cells. In the present study, we showed that increased Topo II activity was not due to changes in amounts of Topo II in nuclei or nuclear extracts of GLC4/CDDP. Further analysis of the chromatin, that includes Topo II, showed that the chromatin in nuclei of GLC4/CDDP was more sensitive to micrococcal nuclease digestion than GLC4. In addition, the amount of a 56‐kDa protein was increased 2‐fold in nuclei and nuclear matrices from GLC4/CDDP. The reduced efficacy of novobiocin to increase the CDDP cytotoxicity as well as the formation of DNA ISC in GLC4/CDDP compared to GLC4 may be due to changes in the chromatin structure of the resistant cells.
Induction of the fundic mucosa‐specific glycolipid with dimethylformamide in gastric‐cancer cell lines
Authors: Dohi Taeko , Nakasuji Miyuki , Oshima Mieko
Published: February 2007

We have previously reported that a glycolipid GalNAcβ I‐4[NeuAcα2‐3]Galβ I‐4GlcNAcβ I ‐3Galβ I‐4Glc‐Cer named NGM‐I is present specifically in the human gastric fundic mucosa, but not in other organs. In gastric‐cancer tissue and cancer cell lines, this glycolipid completely disappears. These findings imply that NGM‐I is expressed only in well‐differentiated fundic mucosa. The purpose of this study is to examine the expression of NGM‐I as a differentiation‐related molecule. A gastric cell line AZ52I was cultured in the medium with various reagents which had been reported to induce differentiation in cancer cells. The growth of AZ52I was suppressed by the addition of 0.8% dimethylformamide (DMF) to the medium, but not by addition of dimethylsulfoxide (DMSO), retinoic acid or butyric acid. In the ganglioside fraction of the cells cultured with DMF. a glycolipid regarded as NGM‐I which had not been present before treatment was detected using a monoclonal antibody. Suppression of the proliferation of AZ52I by eliminating the serum from the medium could not induce the expression of NGM‐I. A colonic cell line treated with DMF also failed to express the glycolipid. The synthase activity of NGM‐I was elevated in the AZ52I cells treated with DMF, but not with DMSO. These results demonstrate that the expression of NGM‐I is induced by DMF specifically in gastric‐cancer cells, and suggest the possibility that NGM‐I is a differentiation‐related molecule.
Incidence pattern of thyroid cancer in norway: Influence of birth cohort and time period
Authors: Akslen Lars A. , Haldorsen Tor , Thoresen Steinar Ø. , Glattre Eystein
Published: February 2007

The incidence of thyroid cancer in Norway increased about 2‐fold for both sexes during the period 1955 to 1989 (4691 cases). In the last 5‐year period, however, a decline was observed, especially among females. The ratio between age‐ adjusted incidence rates in Northern Norway compared with Southern Norway was 1.6 for females and 1.5 for males, and the incidence pattern during the period was similar in the 2 regions. The analysis of age‐cohort‐period models showed a strong cohort effect in both sexes. The reason for this is not clear, although radiation treatment during childhood and dietary habits may possibly be involved. A weaker but statistically significant and transient period effect was also present, giving relatively higher incidence rates, especially in the 1970s. Although this result may be consistent with an influence of radioactive fallout in the northern area, more detailed studies are needed.
Linkage mapping in familial breast cancer: Improved localisation of a susceptibility locus on chromosome 17q12‐21
Authors: Porter D. E. , Cohen B. B. , Wallace M. R. , Carothers A. , Steel C. M.
Published: February 2007

Fifteen pedigrees with a total of 75 cases of breast cancer, 10 of ovarian cancer and 53 of other cancers have been collected. Polymorphic markers on chromosome 17q have been screened to locate a putative breast‐cancer gene using DNA from relevant individuals within these families. Pairwise LOD scores have been calculated for markers CMM86, NM23, 42D6 and MFD188. The maximal summated LOD for the 15 families 4.45 at 8 = 0.025 using 42D6. All cases of bilateral breast cancer and ovarian cancer appear to be linked to this region. Recalculating LOD scores on the assumption of linkage in these cases increases the maximal rummated LOD to 5.62 at 8 = 0.025 using 4206. A genetic exclusion map of critical recombinants linked families suggests that the gene is flanked by markers 42D6 and MFD188, a region 5 to 10 cm in length.
Evaluation of the new (1987) TNM classification for thoracic esophageal tumors
Authors: Kato Hoichi , Tachimori Yuji , Watanabe Hiroshi , Iizuka Toshifumi
Published: February 2007

A total of 351 patients with thoracic esophageal carcinoma were prospectively classified according to the new (1987) TNM classification. Sixty‐two patients received chemotherapy and/or radiotherapy without surgery. Esophagectomy was performed on 291 patients, among whom 139 underwent cervical, mediastinal and abdominal lymph adenectomy (3‐field dissection). The number of stage IIB patients was unnaturally small, and the 3‐year survival rates of stages IIA and IIB were similar. The survival curves for patients of T, N and M categories distributed well except for those of stages IIA and IIB. Numbers of patients in N and pN categories and those in M and pM categories showed poor coincidence. The 5‐year survival rate for MI patients (IO.Wo) was too good, which suggested the mingling of patients with rather better prognosis. When MI (LYM) patients were excluded from M I, the 3‐year survival rate fell to 0.3%. The 5‐year survival rate for pM I (LYM) patients who underwent 3‐field dissection was 38.2%. Survival rates and numbers of positive nodes showed negative correlation in patients who underwent 3‐field dissection. According to these results, we propose the following revision in the next TNM classification: (I) to group stage IIA and stage IIB together to form Stage II; (2) to include cervical and coeliac lymph nodes among the regional lymph nodes, or to designate metastasis in non‐regional lymph nodes separately from metastasis in viscera; and (3) to divide N I into N1 and N2 according to the number of positive lymph nodes.
Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis
Authors: McCredie Margaret , Stewart J. H. , Day N. E.
Published: February 2007

A population‐based case‐control study of kidney cancer was carried out in New South Wales using data from structured interviews with 489 cases of renal‐cell cancer and 147 cases of renal pelvic cancer diagnosed in 1989 and 1990, together with 523 controls from the electoral rolls. This study showed that the risk of renal pelvic cancer was increased by phenacetin/aspirin compound analgesics (RR = 12.2; 95% CI 6.8‐22.2) to a far greater extent than by paracetamol (RR = 1.3; 95% CI 0.7‐2.4; not significant). There was a doubling of risk (RR = 2.0; 95% CI 0.94.4) in the highest tertile of paracetamol taken in any form compared with values for non‐users of any type of analgesic. By contrast, the risk of renal‐cell cancer appeared to be increased to a similar degree by phenacetin/aspirin compound analgesics (RR = 1.4; 95% CI 0.9‐2.3) and paracetamol taken in any form (RR = 1.5; 95% CI 1.0‐2.3). When both drugs were treated as alternative forms of the same risk factor, the risk was increased by 1.7 (95% CI 1.2‐2.4). On this evidence, we postulate that phenacetin/aspirin compounds are weakly carcinogenic in the renal parenchyma through the metabolic conversion of phenacetin to paracetamol, and potently carcinogenic in the renal pelvis by different or additional pathways involving renal papillary necrosis. In addition, there is an indication of a weak link between paracetamol and renal pelvic cancer.