bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities of the adenomatous polyposis coli gene in human oral squamous‐cell carcinoma
Authors: Uzawa Katsuhiro , Yoshida Hidehiko , Suzuki Hiroyoshi , Tanzawa Hideki , Shimazaki Jun , Seino Susumu , Sato Kenichi
Published: February 2007

Recent studies have suggested that abnormalities in the adenomatous polyposis coir gene (APC gene) are associated with the development not only of familial adenomatous polyposis coli (FAP) but also of cancers in digestive organs. In order to elucidate whether abnormalities of the APC gene could contribute to the development of oral squamous‐cell carcinoma (SCC), genomic DNAs from tumors and normal tissues of 24 unrelated Japanese patients were examined by using PCR‐SSCP (polymerase chain reaction single‐strand conformation polymorphism) and sequence analyses. Five novel nudeotide substitutions of the APC gene in tumor tissues were identified in 3 patients with oral SCC (12.5%), resulting in 3 amino‐acid replacements or a truncation of the APC gene product. We also examined 24 tumor and 24 normal tissue samples for loss of heterozygosity (LOH) at exon 11 of the APC gene by PCR‐LOH assay. In this analysis, 45.8% of samples were informative and LOH was detected in 72.7% of informative cases. The frequency of LOH in oral SCC was similar to that previously reported in esopha‐geal SCC. These results suggest that abnormalities in the APC gene are associated with the development of human oral SCC.
PEG‐IL‐2 therapy of advanced cancer in the guinea pig. Impact of the primary tumor and beneficial effect of cyclopphosphamide
Authors: Balemans Lianne T. M. , Steerenberg Peter A. , Koppenhagen Frank J. , Kremer Bas H. A. , De Mulder Pieter H. M. , Claessen Anke M. E. , Scheper Rik J. , Otter Willem Den
Published: February 2007

The efficacy of tumor therapy using polyethylene‐glycolmodified interleukin‐2 (PEG‐IL‐2), alone or in combination with cyclophosphamide, was studied in advanced metastatic disease in the guinea pig. Line 10 (L10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor‐cell inoculation, and lymph‐node leukocytes were almost completely replaced by tumor cells on day 28. Local treatment of the intradermally growing L10 hepatocarcinoma in the guinea pig with a relatively low dose of PEG‐IL‐2 resulted in regression of the primary tumor and prevention of lymph‐node metastases. Therapy was completely curative (4 out of 5 animals) when started on day 7 or 14 after tumor‐cell inoculation. When started on day 21, therapy was effective in only some (2 out of 5 cured) of the treated animals. Anti‐tumor effects against the primary tumor and against lymph‐node metastases were observed only after intratumoral (i.t.) administration of PEG‐IL‐2. Injection of the agent into or near lymph‐node metastases in the absence of the primary tumor had no curative effect. In PBS/BSA‐treated control animals the primary tumor and metastases grew progressively. In the treatment of far advanced metastatic disease, the combination of i.t. administration of PEG‐IL‐2 and i.p. injection of cyclophosphamide (Cy) resulted in improved anti‐tumoral effects (5/5 guinea pigs were cured) when compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressive tumor‐growth. We conclude that large primary tumors and lymph‐node metastases can be treated effectively with PEG‐IL‐2. The i.t. route of administration is of major importance in the treatment of metastases, since administration of PEG‐IL‐2 near or into the lymph node had no therapeutic effect. Combination of PEG‐IL‐2 therapy with systemic injections of Cy significantly improved the curative effects of the treatment of advanced metastatic cancer.
Establishment of a human small‐cell lung‐cancer subline resistant to okadaic acid
Authors: Takeda Yuichiro , Nishio Kazuto , Kubota Naohiro , Miura Kaoru , Morikage Toshihiko , Ohmori Tohru , Kudoh Shoji , Niitani Hisanobu , Saijo Nagahiro
Published: February 2007

Okadaic acid (OA), a specific protein phosphatase inhibitor, has various biological functions. To elucidate the mechanism of OA resistance, we have established a small‐cell lung‐cancer subline (H69/OA100) resistant to the growth‐inhibitory effect of OA; this was done by using the parental cell line (H69) and increasing the concentration of OA. H69/OA100 was about 8 times more resistant to OA than H69. Intracellular retention of the fluorescent OA derivative in H69/OA100 was the same as that in H69. The catalytic activity of protein phosphatase from H69/OA100 was significantly reduced compared with that from H69. The protein phosphatase from H69/OA100 was 3.6 times more resistant to OA than that from H69. We examined the effect of OA on the activity of the immunoprecipitated protein phosphatase type 1 (PPI) and type 2A (PP2A) from the 2 cell lines. The PPI and PP2A from H69/OA100 showed more resistance to OA than those from H69. We next examined the effect of OA on the cell cycle of H69 and H69/OA100. In H69, G2/M block was observed at an OA concentration of 30 ng/ml whereas in H69/OA100, no G2/M block was observed at concentrations up to 100 ng/ml OA. We finally evaluated the amount of p34cdc2 kinase expression and the phosphorylation status of p34cdc2. There was no difference in p34cdc2 expression between H69 and H69/OA100 at several concentrations of OA. However, dephosphorylation of p34cdc2 was observed at 30 ng/ml OA in H69, but not in H69/OA100 up to 100 ng/ml OA. These data suggest that the resistance to OA and the resistance of the cell‐cycle block to OA in H69/OA100 might be due to alteration of protein phosphatase activity.
Down‐regulation of mitochondrial gene expression by the anti‐tumor arotinoid mofarotene (Ro 40‐8757)
Authors: Uchida Takafumi , Inagaki Naohito , Furuichi Yasuhiro , Eliason James F.
Published: February 2007

To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40‐8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast‐cancer cells was performed. Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI). This gene was down‐regulated in the breast‐cancer cell line MDA‐MB‐231 after treatment with the arotinoid for 3 to 6 hr. Down‐regulation of NDI was detected in 2 other breast‐carcinoma cell lines (ZR‐75‐1 and MCF‐7) and a pancreatic cancer cell line (BxPC3), but not in the normal fibroblast cell line Wi‐38 or several other tumor cell lines. This effect was blocked by addition of cycloheximide to the medium. The retinoids, all‐trans and 9‐cis retinoic acids, did not affect the expression of NDI in MDA‐MB‐231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic‐acid receptors. In the estrogen‐receptor‐expressing breast‐cancer line ZR‐75‐1, tamoxifen had no effect on NDI expression. The cytotoxic drugs doxorubicin, 5‐FU and vincristine also had no effect on regulation of this gene. Two mitochondrial proteins encoded in the nucleus, ATPase β subunit and mitochondrial transcription factor I, were not down‐regulated by mofarotene. Addition of mofarotene to cells incubated in glucose‐free medium led to their death. These results indicate that down‐regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti‐proliferative effects of this compound.
HIV‐associated lymphoma in Africa: An autopsy study in Ĉote D'ivoire
Authors: Lucas Sebastian B. , Diomande Mohenou , Hounnou Anatole , Beaumel Anne , Giordano Christian , Kadio Auguste , Peacock Christopher S. , Honde Michel , De Cock Kevin M.
Published: February 2007

HIV infection predisposes to the development of non‐Hodgkin lymphoma (NHL). The frequency of NHL among HIV‐positive adults and children in sub‐Saharan Africa is not known. In 1991–1992, a representative autopsy study of HIV infection was performed in Abidjan, Cǒte d'Ivoire. Of 247 HIV‐positive adult (> 14 years) medical patients dying in hospital, 2.8% had NHL, 1.6% with visceral NHL and 1.2% with primary cerebral lymphoma. The estimated crude incidence of NHL among HIV‐positive adults in Abidjan was 84/ 100,000 per year, 10‐fold greater than the expected pre‐AIDS incidence of NHL but less than the incidence observed among HIV‐positive adults in industrialised countries. None of 78 autopsied HIV‐positive children (median age = 17 months) had NHL. HIV infection augments the incidence of NHL among adults in Africa, but short survival with advanced HIV disease probably prevents the major increase in HIV‐associated NHL seen in industrialised countries. Survival of HIV‐positive children in Africa appears too short to permit the significant development of additional NHL; classic Burkitt lymphoma is not an AIDS‐associated tumour in Africa.
Testicular cancer in nine northern european countries
Authors: Adami Hans‐Olov , Bergström Reinhold , Möhner Matthias , Zatoôski Witold , Storm Hans , Ekbom Anders , Tretli Steinar , Teppo Lyly , Ziegler Hartwig , Rahu Mati , Gurevicius Romualdas , Stengrevics Aivars
Published: February 2007

The incidence of testicular cancer was examined in the Nordic and Baltic countries, Poland and Germany by collaboration among 10 cancer registries. Population‐based registers were used to analyze a total of 34,309 cases, diagnosed from the start of registration (varying from 1943 in Denmark to 1980 in Latvia and Lithuania) through 1989. An approximately 10‐fold geographical variation was found in 1980, with the highest age‐standardized incidence rate (7.8 per 105; world standard population) in Denmark and the lowest (0.9) in Lithuania. During the entire period of registration, incidence increased rapidly in all countries, by 2.3 to 3.4 per cent annually in the Nordic countries and by about 5 per cent in Poland and Germany; there was some evidence of a slower increase in Denmark and Poland after 1975. The rising trend was more pronounced for ages below 30. The age‐specific incidence peaked in all countries at ages 25 to 34, but the geographical variation was considerable. Our data indicate that environmental influences on testicular cancer are strong. Exposure to causal factors mostly takes place early in life, shows substantial geographical variation, and increases over time, so that the age‐standardized incidence doubles every 15 to 25 years. New aetiological hypotheses are needed to accommodate these salient features of the descriptive epidemiology, since risk factors considered so far cannot explain the observed pattern.
Mutations of the adenomatous polyposis coli gene in the mutation cluster region: Comparison of human pancreatic and colorectal cancers
Authors: Yashima Kazuo , Nakamori Shouji , Murakami Yoshinori , Yamaguchi Akio , Hayashi Kenshi , Ishikawa Osamu , Konishi Youichi , Sekiya Takao
Published: February 2007

We analyzed the adenomatous polyposis coli (APC) tumorsuppressor gene as one of the possible genes mutated in human pancreatic carcinomas. DNAs from 39 surgical specimens were subjected to single‐strand conformation polymorphism analysis of polymerase chain reaction products and the mutation cluster region (MCR) of the gene was examined. We also examined the same region of DNAs from 27 surgical specimens of sporadic colon carcinomas and detected mutations in 11 carcinomas (41%). This mutation frequency in colon carcinomas was similar to those reported previously. Using this system, we detected a mutated APC gene in one of 39 pancreatic carcinomas. The results indicated that mutation of the MCR in the APC gene is involved in genesis of some of human pancreatic carcinomas, but its frequency is much lower than in colorectal carcinomas.
Inhibitory effects of analogs of luteinizing hormone‐releasing hormone on the growth of the androgen‐independent dunning R‐3327‐AT‐1 rat prostate cancer
Authors: Pinski Jacek , Reile Herta , Halmos Gabor , Groot Kate , Schally Andrew V.
Published: February 2007

The effects of treatment with the luteinizing hormone‐releasing hormone (LH‐RH) antagonist SB‐75 and agonist [D‐Trp6] LH‐RH were investigated in Copenhagen rats bearing the anaplastic, androgen‐independent Dunning R‐3327‐AT‐1 pros‐tatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH‐RH antagonist SB‐75 and the LH‐RH agonist [D‐Trp6] LH‐RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB‐75 and [D‐Trp6] LH‐RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT‐1 cell line was strongly inhibited by the antagonist SB‐75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D‐Trp6] LH‐RH. Receptor assays on Dunning R‐3327‐AT‐1 tumor membranes showed high‐affinity binding sites for LH‐RH, epidermal growth factor (EGF) and insulin‐like growth factor‐1 (IGF‐1). Receptors for EGF were significantly down‐regulated by treatment with SB‐75. Therapy with SB‐75 also decreased EGF levels in tumor tissue to non‐detectable levels, as measured by specific RIA. Our results demonstrate that the LH‐RH antagonist SB‐75 and agonist [D‐Trp6] LH‐RH inhibit the growth of androgen‐independent Dunning R‐3327‐AT‐1 prostatic cancer in vivo and in vitro.
Circumvention of acquired tetraplatin resistance in a human ovarian carcinoma cell line by a novel Trans platinum complex, JM335 [Trans ammine (cyclohexylamine) dichloro dihydroxo platinum (IV)]
Authors: Mellish Kirste J. , Barnard Chris F. J. , Kelland Lloyd R. , Harrap Ken R.
Published: February 2007

Acquired resistance to tetraplatin [d, I ‐trans‐1,2‐diaminocyclohexane tetrachloroplatinum (IV)] has been generated in vitro in the human ovarian carcinoma cell line PXN94; the derived line, PXN94tetR, was 24‐fold resistant to tetraplatin. Intracellular tetraplatin accumulation was reduced in PXN94tetR compared with PXN94 by an average of 1.3‐fold across the concentration range 1–100 μM (2 hr exposure). There was no significant difference in glutathione levels between the 2 cell lines. PXN94tetR was 1.6‐fold more resistant to cadmium chloride than PXN94, suggesting that metallothionein levels may be elevated. However, no significant difference was observed between PXN94 and PXN94tetR in the levels of total platinum bound to DNA or DNA interstrand cross‐links immediately after tetraplatin exposure (10–100 μM x 2 hr). There was also no significant difference between the 2 cell lines in the rate of removal of total platinum or interstrand cross‐links from DNA following 2 hr exposure to 25 μM tetraplatin. Hence the major mechanism of acquired tetraplatin resistance in PXN94tetR appears to be increased tolerance of platinum‐DNA adducts. PXN94tetR was partially cross‐resistant to the bifunctional alkylating agents melphalan, chlorambucil and mitomycin C. Partial cross‐resistance was also observed to Adriamycin, bleomycin, etoposide, 5‐fluorouracil and vinblastine; however, no elevation in P‐glycoprotein levels was apparent in PXN94tetR. No cross‐resistance was observed to taxotere. PXN94tetR was partially cross‐resistant to cisplatin, carboplatin and several novel cis platinum complexes. In contrast, resistance was completely circumvented by the novel trans platinum complex JM335 [trans ammine (cyclohexylamine) dichloro dihydroxo platinum (IV)].
Inhibition of tumorigenic potential and prostate‐specific antigen expression in LNCaP human prostate cancer cell line by 13‐cis‐retinoic acid
Authors: Dahiya Rajvir , Park Hae Duck , Cusick John , Vessella Robert L. , Fournier George , Narayan Perinchery
Published: February 2007

Prostate‐specific antigen (PSA) is a member of the kallikrein family and has been an important biological marker for prostate cancer. The mechanisms regulating PSA expression in prostatic cancer cells are unclear. The present study was designed to elucidate the role of 13‐cis‐retinoic acid (RA) in regulation of PSA and the tumorigenic potential of the human prostate cancer cell line LNCaP. The growth regulation of LNCaP cells was examined by DNA synthesis and doubling time. The tumorigenic potential of prostate cancer cells was analyzed by soft agar colony‐forming assay, in vitro invasion assay, type IV collagenase assay and binding to extracellular matrix assay. The nuclear receptors for retinoic acid (RARα, ‐β, ‐γ and RXRα, ‐β,‐γ) as well as PSA mRNA were determined by Northern blot using specific oligonucleotide probes. Our results suggest that 13‐cis‐RA significantly inhibits PSA secretion and expression both at the mRNA and protein levels compared with untreated cells. Electron microscopic studies suggest that after 13‐cis‐RA treatment, cells become more differentiated as they contain lumina, lined by plasma membrane and microvilli. Prostate cancer cell growth and tumorigenic potential after 13‐cis‐RA treatment was significantly decreased compared with controls. Nude mice tumorigenicity studies showed that 13‐cis‐RA‐treated cells produced significantly smaller tumors compared with untreated cell tumors. There was also a significant increase in the expression of RXRa mRNA after 13‐cis‐RA treatment compared with untreated cells.
Volatile N‐nitrosamines and their precursors in chinese salted fish—a possible etological factor for NPC in China
Authors: Zou Xiao Nong , Lu Shih Hsin , Liu Bin
Published: February 2007

Epidemiological studies show that the consumption of Chinese salted fish is a causative factor for nasopharyngeal carcinoma (NPC) in southern China. In the present study, N‐nitrosamines and their precursors were analyzed in 145 samples of cooked, salted fish collected from various areas in China. The results show that N‐dimethylnitrosamine (NDMA), N‐diethylnitrosamine (NDEA), N‐nitrosopyrrolidine (NPYR) and N‐nitrosopiperidine (NPIP) were present in the salted fish. Total volatile N‐nitrosamines (TVN) in the salted fish were 0.028 to 4.54 mg/kg. The samples from areas with higher NPC risk showed a higher average level of TVN than those from areas of lower NPC risk. Positive correlations were found between the levels of NDMA, NDEA and TVN and mortality from NPC. Although neither the nitrates nor the nitrites in the salted fish were present at significantly high levels, in vitro data regarding nitrosation of salted fish showed that the N‐nitrosamine content had increased substantially. The results support the conclusion that the high NPC risk in southern Chinese may be attributed to consumption of salted fish containing high levels of N‐nitrosamines.
Lung cancer and cigarette smoking in women: A case‐control study in barcelona (Spain)
Authors: Agudo Antonio , Barnadas Agusti , Pallares Cinta , Martinez Ignacio , Fabregat Xavier , Rosello Josep , Estape Jordi , Planas Josep , Gonzalez Carlos A.
Published: February 2007

A case‐control study on lung cancer and the habit of cigarette smoking was carried out in Barcelona (Spain). Cases were 103 women newly diagnosed with primary lung cancer in 10 hospitals from the study area. Histologic confirmation was given in 101 cases, of which 53 were adenocarcinoma, 19 squamous‐cell carcinoma, 9 small‐cell carcinoma and 20 other types. Two controls per case were selected, matched by age, residence and hospital. Compared with the never‐smokers, the odds ratios (OR), with corresponding 95% confidence intervals (CI), were 1.61 (0.4 to 6.9) for ex‐smokers and 3.61 (1.6 to 8.3) for current smokers. The risk of lung cancer showed a good dose‐response relationship with duration of the habit, average number of cigarettes smoked daily and cumulative cigarette consumption. The risk of lung cancer increased by 62% for each 10 pack‐years. Depth of inhalation also showed a remarkable effect, independently of the intensity of the habit. Although mortality and incidence rates of lung cancer among women in Spain are lower than in other developed countries, the risk of lung cancer is that which would be expected according to the pattern of the smoking habit in Spanish women.
The tyrosine kinase activity of the C‐erbB‐2 gene product (p185) is required for growth inhibition by anti‐p185 antibodies but not for the cytotoxicity of an anti‐p185‐ricin‐a chain immunotoxin
Authors: Xu Feng Ji , Boyer Cinda M. , Bae Duk Soo , Wu Shu , Greenwald Marilee , O'Briant1 Kathy , Yu Yin Hua , Mills Gordon B. , Bast Robert C.
Published: February 2007

Our previous studies have demonstrated that 7 of 10 lgG antibodies against distinct epitopes on the extracellular domain of the c‐erbB‐2 gene product (p185) inhibit the anchorage‐independent growth of SKBr3 human breast‐cancer cells that overexpress this transmembrane tyrosine kinase growth‐factor receptor. Two of 7 growth‐inhibitory antibodies also block the binding and function of the gp30 and p75 c‐erbB‐2 ligands. In this report we have studied phosphorylation of p185 and different intracellular substrates after binding of antibodies that do or do not inhibit tumor‐cell growth. A correlation has been found between antibodies that inhibit growth and the intensity of tyrosine phosphorylation of p185. At late intervals, serine phosphorylation of at least 3 intracellular substrates is increased preferentially by growth‐inhibitory antibodies. To test the importance of p185 kinase activity more critically, NIH3T3 cells were transfected with an expression vector containing the full‐length human c‐erbB‐2 gene (cell line 17313), c‐erbB‐2 with deletion of the kinase region from codons 751–979 (cell line 9309) or c‐erbB‐2 with deletion of most of the intracellular domain from codons 684–1255 (cell line 9310). Unconjugated antibodies inhibited anchorage‐independent growth of 17313 cells as well as SKBr3 cells, but did not inhibit growth of either 9309 or 9310 cells. In contrast, the cytotoxic effect of anti‐p185‐ricin A chain (RTA) conjugates was comparable for 17313, 9309 and 9310. The tyrosine‐kinase activity of p185 is required for growth inhibition mediated by unconjugated anti‐p185 antibodies, but not for the cytotoxic activity of anti‐p185‐RTA immunotoxins.
Suppressed expression of insulin‐like growth factor binding protein‐1 mRNA in the endometrium: A molecular mechanism associating endometrial cancer with its risk factors
Authors: Rutanen Eeva‐Marja , Nyman Tuulikki , Lehtovirta Pentti , Ämmälä Martti , Pekonen Fredrika
Published: February 2007

The insulin‐like growth factor (IGF) system is thought to function as a mediator of steroid hormone actions in the endometrium. IGFs (IGF‐I and IGF‐II) are also potent mitogens in endometrial cancer. The biological actions of IGFs are modulated by specific binding proteins (IGFBP)—6 cloned and sequenced so far—which may either inhibit or enhance the effects of IGF at the cellular level. In the endometrium, IGFBP‐1 gene expression is stimulated by progesterone and inhibited by insulin, while IGFBP‐1 inhibits the mitogenic action of IGF‐I. In this study, we used a quantitative reverse transcriptase polymerase chain reaction (RT‐PCR) to investigate IGFBP‐I, IGFBP‐2, IGFBP‐4, IGFBP‐5 and IGFBP‐6 gene expression in endometrial cancer tissues. Endometrial cancer tissue samples were collected from 20 women (aged 54–79 yrs) with stage I to II well‐differentiated endometrial adenocarcinoma. Samples of normal endometrium (n = 14) obtained from women undergoing tubal ligation in various phases of the menstrual cycle, and normal early‐pregnancy endometrium (decidua) were studied for comparison. In endometrial cancer tissues, the IGFBP‐I mRNA was undetectable or minimally expressed when studied by RT‐PCR. The mean (+SD) levels of IGFBP‐2 and IGFBP‐4 and IGFBP‐5 mRNAs in endometrial cancer tissues did not differ from those in normal endometrium, in which no cyclic variation was observed, suggesting that the genes encoding IGFBP‐2, IGFBP‐4 and IGFBP‐5 are not hormonally regulated in the endometrium. The IGFBP‐6 mRNA expression showed a significant cyclic variation in normal endometrium, with low levels in late‐prolitferative and early‐ to mid‐secretory phases and high expression in late‐secretory and early‐prolitferative phases. In endometrial cancer tissues, the mean IGFBP‐6 mRNA level was similar to that in cycling endometrium during the peri‐ovulatory period. In summary, a continuous stimulation of the endometrial epithelial cells by IGFs with suppressed IGFBP‐1 expression may lead to an imbalance in the IGF system of the endometrium and trigger an uncontrolled cell proliferation, ultimately resulting in malignant transformation. © 1994 Wiley‐Liss, Inc.
Estrogen and progesterone receptor mrna levels in primary breast cancer: Association with patient survival and other clinical and tumor features
Authors: Nagai M. A. , Marques L. A. , Yamamoto L. , Fujiyama C. T. , Brentani M. M.
Published: February 2007

The relative expression of estrogen receptor (ER) and progesterone receptor (PR) mRNA transcripts was measured in 71 primary breast‐cancer biopsies. ER and PR binding activity were estimated in parallel by the dextran‐coated‐charcoal method. There was a close correlation between the amount of ER mRNA and estradiol binding activity. Tumors from post‐menopausal patients contained higher levels of ER mRNA than those from pre‐menopausal patients. Northern‐blot analysis indicated the presence of a major band of 6.3 kb in all ER mRNA‐positive tumors. Some tumors showed, in addition, 3,7‐ and 2.4‐kb transcripts. PR binding activity and overall PR mRNA levels correlated moderately. PR mRNA and ER mRNA were associated. Four PR mRNA species with estimated sizes of 11.4, 4.5, 3.7 and 2.5 kb were detected in 14% of the PR mRNA‐positive tumors. The 3.7‐kb transcript was detected to varying degrees in all PR mRNA‐positive biopsies, accompanied in some tumors by the 2.5‐kb species. ER and PR mRNA levels < 50 pg/5 μg total RNA correlated with prolonged survival of the patients. In addition, high ER mRNA levels were associated with absence of necrosis and vascular invasion together with absence or minimal level of tumor lymphocytic infiltration, but not with age, clinical stage, tumor size or overexpression of c‐myc or c‐erbB‐2 mRNA. PR mRNA was not statistically associated with any of the above clinicopathological features. A bivariate analysis showed that both ER and PR mRNA levels were able to predict overall survival independently of the lymph‐node status. © 1994 Wiley‐Liss, Inc.
Dietary factors and the risk of glioma in adults: Results of a case‐control study in melbourne, Australia
Authors: Giles Graham G. , McNeil John J. , Donnan Geoffrey , Webley Carole , Staples Margaret P. , Ireland Paul D. , Hurley Susan F. , Salzberg Michael
Published: February 2007

In a population‐based case‐control study of 416 incident gliomas in adults carried out in Melbourne, Australia, between 1987 and 1991, 409 age‐sex‐matched case‐control pairs (243 male and 166 female) had adequate data available to examine associations between the dietary intake of N‐nitroso compounds, N‐nitroso precursors, other nutrients including N‐nitroso inhibitors, and the risk of glioma. Dietary intakes were based on the reported frequency of consumption of 59 food items. Increased odds ratio (OR) were observed in males who consumed high levels of bacon, corned meats, apples, melons and oil. OR less than unity were observed in men consuming cabbage and cola drinks, and in women who consumed wholegrain bread, pasta, corned meat, bananas, cauliflower, broccoli, cola drinks and nuts. Generally, N‐nitroso associations were greater in men and micronutrient associations were greater in women. Elevated OR in men, but not women, were associated with the intake of N‐nitroso dimethylamine (NDMA), retinol and vitamin E. The intake of nitrate (largely of vegetable origin) was protective in women but not in men. When analyzed using multiple logistic regression, the association with NDMA intake in males was not modified by dietary micronutrient intakes. In females, beta carotene alone, though not directly associated with risk, modified the effect of NDMA. On balance, this study added only limited support to the N‐nitroso hypothesis of glial carcinogenesis. © 1994 Wiley‐Liss, Inc.
Oncostatin M, interleukin 2, interleukin 6 and interleukin 8 in breast cyst fluid
Authors: Lai Leslie C. , Kadory Sana , Siraj Abdul K. , Lennard Thomas W. J.
Published: February 2007

Women with breast cysts lined by apocrine epithelium (intracystic Na/K <3) may have a higher risk of developing breast cancer than those whose breast cysts are lined by “flattened” epithelium (intracystic Na/K <3). In this study, the concentrations of the cytokines, oncostatin M (OSM), interleukin 2 (IL‐2), interleukin 6 (IL‐6) and interleukin 8 (IL‐8) were measured in breast cyst fluid, OSM, IL‐2 and IL‐6 having been shown to have growth‐inhibitory actions on tumour cells. All cytokines were measured by “sandwich” enzyme immunoassays. IL‐2 was not detectable in breast cyst fluid. OSM, IL‐6 and IL‐8 concentrations were significantly higher in the high‐electrolyte‐ratio group. Although significant positive correlations were found between OSM and IL‐6, OSM and IL‐8, OSM and Na/K, IL‐6 and IL‐8, IL‐6 and Na/K and IL‐8 and Na/K when all samples were analysed together, analysis of the correlations between these analytes in each subgroup separately suggests that the control of production of these cytokines or the mechanism of entry into cyst fluid is likely to be different for the 2 cyst types. The significantly higher intracystic concentrations of OSM and IL‐6 in the high‐electrolyte‐ratio group may partly explain the lower risk of breast cancer in this group of women. © 1994 Wiley‐Liss, Inc.
TP53 gene mutations and CCND1 gene amplification in head and neck squamous cell carcinoma cell lines
Authors: Xu Li , Davidson Bruce J. , Murty V. V. V. S. , Li Rong‐Guo , Sacks Peter G. , Garin‐Chesa Pilar , Schantz Stimson P. , Chaganti R. S. K.
Published: February 2007

Mutations of the tumor‐suppressor gene TP53 and amplification of CCNDI gene have been reported to occur frequently in head and neck squamous cell carcinomas (HNSQCC). In experimental systems, TP53 mutations have been shown to lead to genomic instability, including an increased propensity for gene amplification. We have examined I6 HNSQCC cell lines for the association between TP53 over‐expression/mutation and CCNDI amplification. p53 over‐expression was detected in 50% of the cell lines by immunohistochemistry using the monoclonal antibody (MAb) PAbI80l. TP53 mutations were also detected in 50% of the cell lines by analysis of single‐strand conformation polymorphism (SSCP) and DNA sequencing of exons 4 through 9. Six cell lines showed TP53 mutations and over‐expression of the protein, 2 cell lines showed TP53 mutations but no p53 expression, and 2 cell lines showed over‐expression of p53 protein but no TP53 gene mutations. CCNDI amplification was found in 38% of the cell lines by Southern blot analysis. Only I cell line showed both TP53 mutation and CCNDI amplification, whereas 7 of 8 cell lines with TP53 mutations had no CCNDI amplification. pRb expression was detected by Western blot analysis, and the level of pRb did not correlate with either CCNDI amplification or TP53 mutation. Our findings suggest that TP53 mutation and CCNDI amplification are common genetic alterations in HNSQCC and that the occurrence of either genetic event may be sufficient to abrogate normal cell cycle control. © 1994 Wiley‐Liss, Inc.
Low‐dose chemotherapy delays relapse of a dominated and resistant sub‐population in a heterogeneous human sclc xenograft in nude mice
Authors: Aabo Kristian , Vindeløv Lars L. , Christensen Ib J. , Spang‐Thomsen Mogens
Published: February 2007

We investigated the influence of cellular heterogeneity on the response to low‐dose BCNU chemotherapy of an artificially mixed human small‐cell lung cancer (SCLC) xenograft in nude mice containing a BCNU‐sensitive and dominating sub‐population and a BCNU‐resistant and undetectable (dominated) sub‐population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry (FCM). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low‐dose treatments with BCNU or no treatment. After a further 3 to 4 weeks, a high‐dose treatment (LD10) was given to both groups of treated tumors. Changes in the relative proportions of and cell lines in the tumors were measured by FCM on fine‐needle tumor aspirates. At the time of low‐dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response was seen after low‐dose treatment. After the highdose treatment, a similar short response was seen. In the non‐treated group, the sensitive cells continued to dominate. At the time of tumor regrowth after the low‐dose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression after the response to the high‐dose treatment, the resistant cell line was the predominant population. If compared with a single high‐dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing sub‐population influenced the outcome of the treatment. © 1994 Wiley‐Liss, Inc.
EGF modulation of the ras‐related rhoB gene expression in human breast‐cancer cell lines
Authors: De Cremoux Patricia , Gauville Christiane , Closson Violaine , Linares Gustavo , Calvo Fabian , Tavitian Armand , Olofsson Birgitta
Published: February 2007

The mRNA levels of the ras‐related human rhoA, rhoB and rhoC genes were studied in human breast‐cancer cell lines (HBCal), and in normal and immortalized mammary epithelial cells (HMEC) by Northern blot analysis and in situ hybridization. In contrast to the ubiquitous rhoA and rhoC gene expression, dramatic variations in the mRNA level of the rhoB gene were evidenced. The rhoB mRNA level appeared to be inversely correlated to the amounts of the epidermal‐growth‐factor(EGF) receptors in these cells. The rhoB transcripts were detected at high levels in ZR75‐1, MCF7, HSL 53, HSL 59, HSL 90, T47D and SKBR3 HBCal, at hardly detectable levels in BT 20, MDA‐MB 231 and H466B HBCal and at intermediate levels in normal and immortalized breast epithelial cells. Rapid and transient induction of the rhoB transcription was observed after EGF treatment in serum‐deprived MDA‐MB231, T47D and immortalized epithelial cells. In contrast, no modulation of rhoB expression by EGF could be objectified in the MCF7 and ZR75‐1 cell lines. Yet a normal function of EGF receptors was evidenced, since the immediate early gene c‐fos was rapidly induced, suggesting a constitutive expression of rhoB in these cell lines bypassing the regulation by EGF. In human mammary epithelial cells, rhoB mRNA is rapidly and transiently induced with EGF concentrations known to stimulate cell proliferation. This suggests that the rhoB product might be involved in a cascade that initiates or promotes cell proliferation, and plays an important role in EGF‐stimulated growth of breast normal and cancer cells. © 1994 Wiley‐Liss, Inc.
Family history and the risk of endometrial cancer
Authors: Parazzini Fabio , La Vecchia Carlo , Moroni Simona , Chatenoud Liliane , Ricci Elena
Published: February 2007

The association between a family history of endometrial, breast and ovarian cancer and the risk of endometrial cancer was analyzed on the basis of data from a case‐control study conducted in northern Italy between 1983 and 1993. A total of 726 histologically confirmed endometrial‐cancer patients (median age 61) admitted to a network of general and teaching hospitals in the Greater Milan area were interviewed. The controls were 2, 123 women (median age 59), admitted for acute, non‐neoplastic, non‐hormone‐related diseases to the same network of hospitals were the cases had been identified, with admission diaagnoses unrelated to any of the known or suspected risk factors for endometrial cancer. Among cases, 37 (5.1%) reported a history of endometrial cancer in first‐degree relatives. The corresponding figure among controls was 77 (3.6%). In comparison with women with no family history of endometrial cancer, the odds ration (OR) of endometrial cancer was 1.5 (95%CI[confidence interval], 1.0‐2.3) in women with a history of endometrial cancer in first‐degree relatives. NO relation emerged between endometrial cancer and a family history of breast or wvarian cace. These results suggest that a family history of endomertial cancer increases the risk of contracting the same disease. However, the proportion of cases attributable to this factor was small: less than 1%of endometrial cancers in this population were attributable to familial (and hence potentially genetic) factors. © 1994 Wiley‐Liss, Inc.
Human‐papillomavirus DNA in cholesteatomas
Authors: Bergmann Krister , Hoppe Florian , He Yukai , Helms Jan , Müller‐Hermelink Hans‐Konrad , Stremlau Armin , De Villiers Ethel‐Michele
Published: February 2007

Cholesteatoma of the middle ear is a relatively common disorder, often with severe consequences. Histologically, the aggressively growing, bone‐destructing form shows papillary growth and koilocytosis, which are characteristic of papillomavirus‐induced lesions. A PCR (polymerase chain reaction) method using degenerate primers for the detection of any known or as yet unknown HPV (human papillomavirus) type was applied in screening 51 biopsies from 42 patients. A resulting 36% (16/45) of the cholesteatomas were found to contain papillomavirus DNA, which hybridized under stringent conditions with an HPV‐II DNA probe. In 3 cases the presence of HPV‐II DNA could be confirmed by sequencing the PCR products. The mere presence of this HPV DNA does not prove an etiological role of this group of viruses in the induction of cholesteatomas. It does, however, identify another group of human proliferative lesions putatively linked to papillomavirus infections. © 1994 Wiley‐Liss, Inc.
Haemopoietic progenitor and myeloid cell kinetics in humans treated with interleukin‐3 and granulocyte/macrophage colony‐stimulating factor in combination
Authors: Lord Brian I. , Testa Nydia G. , Bretti Sergio , Chang James , Demuynck Hilda , Coutinho Lucia , De Campos Edson , Fitzsimmons Lesley , Howard Scarffe J.
Published: February 2007

Patients with advanced adenocarcinoma of the colon, rectum or pancreas were entered into trials for evaluation of treatment with sequential doses of IL‐3 and GM‐CSF. They received 0.25 to 5μgIL‐3/kg/d for up to 7days, followed by I μgGM‐CSF/kg/day for a maximum of 10 further days. We assessed the kinetics of bone‐marrow cell proliferation and of blood production using tritiated thymidine labelling in vitro and in vivo. Megakaryocytic‐CFC were unaffected but proliferation rates of GM‐CFC and BFU‐E were increased. Progenitor cells were mobilized (12‐fold over baseline) into the peripheral blood. The proliferative activity of maturing cells in the marrow was increased (cell‐cycle times were reduced by at least 30%). This translated into amplified blood cell production (WCC ∼30 × 109/1), a 2.2‐fold increase in platelet counts and significant eosinophilia. Newly generated neutrophils appeared in the circulation at the normal time and their peripheral half‐life was also normal. The calculated 3.2‐fold amplification in neutrophil production required nearly 2 extra divisions in the marrow, shared between the progenitors and the proliferating granulocytic cells. The results were compared with those of a previous trial using GM‐CSF only, although at a 10‐fold higher dose level. Comparable levels of peripheral neutrophils were obtained in both trials but significant ineffective granulopoiesis developed in the earlier study. This was overcome in the present study, the priming dose of IL‐3 apparently giving the latitude to utilize lower doses of GM‐CSF with less risk of complications. © 1994 Wiley‐Liss, Inc.
At least one in seven cases of cancer is caused by smoking. Global estimates for 1985
Authors: Parkin D. M. , Pisani P. , Lopez A. D. , Masuyer E.
Published: February 2007

Tobacco smoking is accepted as a major cause of cancers of the lung, larynx, oral cavity and pharynx, oesophagus, pancreas, kidney and bladder. The proportions of these cancers that are due to smoking were estimated for the year 1985 for 24 areas of the world. Fifteen percent—1. 1 million new cases per year—of all cancer cases are attributed to cigarette smoking, 25% in men and 4% in women. In developed countries, the tobacco burden is estimated at 16% of all annual incident cases. In developing countries, the corresponding figure is 10%. In total, 85% of the 676 000 cases of lung cancer in men are attributable to tobacco smoking. The highest attributable fractions (AF: 90–93%) are estimated in areas where the habit of cigarette smoking in men has been longest established: North America, Europe, Australia/New Zealand and the former USSR. Among the other 6 cancer sites considered in this analysis, those with the largest fractions of tobacco‐related cases are the larynx, mouth and pharynx (excluding nasopharynx) and oesophagus. In regions where males have smoked for several decades, 30 to 40% of all cancers in this sex are attributable to tobacco. Unless tobacco‐control efforts in developing countries are strengthened, the massive rise in cigarette consumption over the last few decades will produce a comparable rise in cancer in these countries within the next 20 to 30 years. © 1994 Wiley‐Liss, Inc.
Expression of stromelysin‐1 and timp‐1 in the involuting mammary gland and in early invasive tumors of the mouse
Authors: Li Feng , Friis Robert R. , Djonov Valentin , Altermatt Hans‐Jörg , Saurer Susanne , Niemann Heiner , Andres Anne‐Catherine
Published: February 2007

The mammary gland, during post‐lactational involution, is subjected to extensive tissue reconstruction. This process is governed by the concerted expression of extracellular‐matrixdegrading enzymes and their inhibitors. During carcinogenesis, the invasive growth of tumor cells is characterized by the penetration of the basement membrane and stromal invasion. We compared the expression of the tissue‐remodeling enzymes stromelysin‐l, a matrix metalloproteinase, and its inhibitor, tissue inhibitor of metalloproteinase‐l (TIMP‐l), during mammary gland involution and carcinogenesis in mouse. In involuting mammary glands, stromelysin‐l was expressed in myoepithelial cells, whereas TIMP‐l was confined to the stromal tissue. To analyze the involvement of these tissue‐remodeling genes in tumor development, we examined mammary tumors of transgenic mice expressing either the activated Ha‐ras or c‐myc oncogene under the control of a milk‐protein gene promoter. In the undifferentiated and metastasizing Ha‐ras‐induced tumors, stromelysin‐l expression was comparable to that seen in involution, whereas TIMP‐l expression was greatly elevated. During Ha‐ras‐induced carcinogenesis, stromelysin‐l expression was first detected in the myo‐epithelial cells surrounding preneoplastic lesions. In contrast, in the well‐differentiated and non‐metastatic mammary tumors induced by c‐myc, no expression of either gene was observed. Thus, expression of stromelysin‐l and TIMP‐l is confined to the aggressively growing tumors and is induced in the earliest stages of carcinogenesis. © 1994 Wiley‐Liss, Inc.
Immunocytochemical localization of BCL‐2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy
Authors: Gee Julia M. W. , Robertson John F. R. , Ellis Ian O. , Willsher Peter , McClelland Richard A. , Hoyle Helen B. , Kyme Susan R. , Finlay Pauline , Blamey Roger W. , Nicholson Robert I.
Published: February 2007

The protein product of the bcl‐2 gene is thought to be involved in inhibition of apoptosis; it may therefore be important in the modulation of hormonal/anti‐hormonal responsiveness exhibited by tumours. This study immunocytochemically investigates (i) relationships between bcl‐2 protein expression in primary breast cancers and other markers of prognostic and therapeutic value and (ii) associations of the bcl‐2 protein with breast cancer responsiveness to endocrine therapy. The bcl‐2 protein was found within the tumour epithelial cell cytoplasm of 32/46 breast cancer specimens; inter‐patient staining was heterogeneous. Immunostaining for steroid hormone receptors was strongly associated with that for the bcl‐2 protein, and it is thus possible that this protein, like progesterone receptor, is under oestrogen regulation via oestrogen receptor. The protein was inversely related to 2 markers of endocrine insensitivity, epidermal growth factor receptor (EGFR) and c‐erbB‐2 oncoprotein, while no associations were observed with either transforming growth factor (TGF)‐alpha or Ki‐67 proliferative status. A highly significant relationship was observed between response to endocrine therapy and the presence of bcl‐2 protein. Indeed, bcl‐2 immunostaining proved to be a more accurate predictor of response than oestrogen receptor status. Patients with elevated bcl‐2 immunostaining (particularly those who co‐expressed high oestrogen receptor levels) appeared to derive the greatest benefit from endocrine therapy. Our results are paradoxical since it was expected that the bcl‐2 protein would counteract the tumour inhibitory effects of endocrine therapies as it is thought to prevent programmed cell death.
Microvascular expression of mala‐2 correlates with In vivo lymphocyte trafficking and is preferentially enhanced in tumors by tumor necrosis factor‐α and interleukin‐1α
Authors: Dean Phillip A. , Ramsey Patrick S. , Donohue John H. , Nelson Heidi
Published: February 2007

The role of endothelial cell adhesion molecule expression in the immune response to tumors is unknown. We have investigated the expression of murine lymphocyte activation antigen (MALA‐2), the murine equivalent of intercellular adhesion molecule‐1 (ICAM‐1), in blood vessels of normal murine tissues and in melanoma tumors and evaluated the relationship between MALA‐2 expression and lymphocyte trafficking in vivo. C3H/HeN mice were injected both i.p. and s.c. with a clone of K‐1735 syngeneic melanoma cells. Day 11 tumor‐bearing mice were killed and vascular expression of MALA‐2 was quantified using immunohistochemistry. MALA‐2 expression was high in lung, liver and spleen and low in lymph node, small bowel, muscle and tumor. Systemic administration of either recombinant tumor necrosis factor α (rTNFα) or recombinant interleukin‐1α(rIL‐Iα) over 2 days prior to organ harvest resulted in an increase in the number of tumor vessels expressing MALA‐2, with no change in MALA‐2 expression in other tissues. In vivo lymphocyte trafficking was evaluated using cultured, activated splenocytes radiolabeled with 111In. 111In‐labeled splenocyte distribution correlated closely with MALA‐2 expression, with high localization to spleen, liver and lung and poor localization to lymph node, small bowel, muscle and tumor. Systemic administration of rTNFα, but not rIL‐Iα, resulted in a significant increase in 111In‐labeled splenocyte distribution to tumor, but neither rTNFα nor rIL‐Iα altered 111In‐labeled splenocyte distribution to normal organs. Our data demonstrate the in vivo pattern of vascular MALA‐2 expression in normal murine tissues and tumors and suggest that the expression of MALA‐2 can be preferentially enhanced in tumors by systemic administration of cytokines. Lymphocyte distribution in vivo correlates closely with the pattern of MALA‐2 expression, and these data support the conclusion that MALA‐2 plays an important role in the regulation of lymphocyte trafficking.