bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of second antibody clearance on the distribution and dosimetry of radiolabelled anti‐cea antibody in a human colonic tumor xenograft model
Authors: Pedley R. Barbara , Dale Roger , Boden Joan A. , Begent Richard H. J. , Keep Pat A. , Green Alan J.
Published: February 2007

Radioimmunotherapy in humans is limited by toxicity to normal tissues, caused by circulating radio‐antibody. Second antibody directed against the first (anti‐tumor) antibody accelerates clearance of first antibody from normal tissues, and may thus improve the therapeutic ratio. The effect of second antibody both on anti‐tumor antibody distribution and on tumor and normal tissue radiation doses, has been investigated in nude mice bearing colonic tumor xenografts. Second antibody, given either 6 or 24 hr after the first, rapidly cleared circulating activity and reduced the calculated radiation dose to all tissues except the spleen, where it rose by 11 and 43% respectively. The dose received by the blood fell by 87% and 71%, while that to the tumor was reduced by 81% and 58%, after 6 or 24 hr second antibody. Administration of second antibody therefore improved the tumor to blood ratios. Tumor identification by gamma camera was greatly facilitated by the use of second antibody, and required no background subtraction. Results obtained from this system demonstrate the utility of second antibody in protecting normal tissues from prolonged circulating radioactivity during radioimmunotherapy.
Immunocytochemical detection of the onco‐developmental protein oncomodulin in pre‐neoplastic and neoplastic hepatocellular lesions during hepatocarcinogenesis in rats
Authors: Bernaert D. , Brewer L. M. , Macmanus J.‐P. , Galand P.
Published: February 2007

Oncomodulin is a calcium‐binding protein, detectable in extra‐embryonic human and rat placental cells and in a wide variety of tumors, but not in any normal embryonic or adult rodent or human tissues. It is also absent from proliferatively active fetal or regenerating adult rat liver. The presence of this oncodevelopmental marker was investigated in preneoplastic and neoplastic liver lesions during hepatocarcinogenesis induced in rats by DENA treatment, using an antibody raised against purified oncomodulin. Positive immunostaining was observed in foci of altered hepatocytes, in neoplastic nodules and in HC, but not in the histologically normal surrounding liver parenchyma. The proportion of oncomodulin‐positive foci gradually rose from 20–25% at 2–3 months after DENA treatment, to about 88% at 6 months and later. The proportion of positive neoplastic nodules increased from 50% at 5 months to about 73% (range 36–100) at 9 months and later; 88% of the HC found 10 to 20 months after DENA treatment were also positive. That early neoplastic nodules are oncomodulin‐positive in a proportion (50%) similar to that of foci after the same duration of treatment is consistent with a lineage relationship between them but makes it unlikely that oncomodulin expression conditions the focusnodule transition. The role, if any, of oncomodulin in malignant progression remains to be elucidated. It seems out of the question that it is a simple correlate of proliferative activity.
A case‐control study of cancer of the esophagus and gastric cardia in linxian
Authors: Li Jun‐Yao , Ershow Abby G. , Chen Zhi‐Jian , Wacholder Sholom , Li Guang‐Yi , Guo Wande , Li Bing , Blot William J.
Published: February 2007

A case‐control study involving interviews with 1,244 patients (758 males and 486 females) with cancer of the esophagus or gastric cardia and 1,314 population‐based controls (789 males, 525 females) was carried out in Linxian, a rural county in North Central China with one of the world's highest mortality rates for these tumors. Cancer risks tended to rise with increasing intake of wheat and corn, but no association was found with adult intake of pickled vegetables, the leading a priori suspect, and risks were not elevated among those consuming low quantities of fresh vegetables or fruits. Few differences in preparation or storage of food or water were detected, although cancer patients reported less fluid intake than controls. Few persons reported drinking alcoholic beverages. Smoking was reported by 61% of the male cases and was a mild risk factor, related more to cancer of the cardia than of the esophagus. The risk was increased by 70% among those whose parents had esophageal or stomach cancer, but only slightly among those whose spouses had such cancers, suggesting that exposure early in life and/or genetic effects may be involved.
Risk factors for cancer of the cervix in a rural chinese population
Authors: Zhang Zuo‐Feng , Parkin D. M. , Yu Shun‐Zhang , Estève J. , Yang Xue‐Zhi
Published: February 2007

A population‐based case‐control study of 109 women with invasive squamous‐cell cervical cancer and 545 controls matched for age and area of residence was carried out in Jingan, China, to evaluate the importance of different risk factors and the effect of cervical cancer screening. After controlling for the protective effect of cervical cancer screening, several factors were found to make an independent contribution to risk. These included the number of sexual partners of the subjects and their husbands (OR: 3.9 for 2 or more sexual partners other than the current spouse, relative to none), 5.9 for 2 or more other partners of the husband relative to none, and poor genital hygiene (OR: 4.8 for absence of daily genital washing relative to washing every day; 0.3 for use of sanitary napkin), these are consistent with an infectious etiology. In addition, menstrual characteristics also had a strong relationship to the risk of cervical cancer (OR: 2.2 for 4 or more days' menstruation relative to shorter duration; 5.4 for irregular menstruation).
Blood group abh‐related antigens in normal and malignant bladder urothelium: Possible structural basis for the deletion of type‐2 chain abh antigens in invasive carcinomas
Authors: Ørntoft Torben F. , Wolf Hans , Clausen Henrik , Dabelsteen Erik , Hakomori Sen‐Itiroh
Published: February 2007

A complete panel of mouse monoclonal antibodies (MAbs) against Type‐2 chain (Galβ1‐4GlcNAc‐R) blood‐group antigens (N‐acetyl‐lactosamine, Lex, H, Ley, A monofucosylated, ALey, repetitive A) was used in a detailed immunohistological study of the modulation of these carbohydrate antigens in transitional‐cell carcinomas. The histological and cellular locations of these antigens were studied in 19 normal bladder biopsies and 53 transitional‐cell carcinomas with as well as without neuraminidase treatment of tissue sections in order to uncover potential sialylated antigens. The antigen expression was correlated to individual A1A2BO, Lewis, and secretor status. Several alterations of blood group expression were found: (1) loss of A and H antigens with accumulation of Ley antigens; (2) loss of correlation between antigen expression and secretor status; (3) disruption of the orderly stratification of blood‐group antigen expression in relation to cell layers; and (4) changes in subcellular location of antigen expression. The present data indicate that deletion of Type‐2 chain ABH antigens in transitional‐cell carcinomas is associated with α1‐3 fucosylation of the H antigen leading to accumulation of Ley antigens.
Tumor‐associated glycoprotein (TAG‐72) expression in ulcerative colitis
Authors: Thor A. , Itzkowitz S. H. , Schlom J. , Kim Y. S. , Hanauer S.
Published: February 2007

Monoclonal antibody (MAb) B72.3 reactive with the high‐molecular‐weight (Mr > 106) tumor‐associated glycoprotein (TAG)‐72 is being increasingly utilized in vivo and in vitro for a variety of purposes in colon cancer patients. Recent evidence has suggested that the TAG‐72 antigen expression may be enhanced in inflammatory bowel disease, particularly ulcerative colitis (Thor et al., 1986a: Cancer Res., 46, 3118–3124). We have utilized 117 paraffin‐embedded formalin‐fixed colonic specimens from 56 ulcerative colitis patients which demonstrate a spectrum of epithelial abnormalities (reactive atypia, dysplasia, and carcinoma) as well as 11 inflammatory controls to evaluate TAG‐72 expression. Our selected patient population all had pan‐colitis and demonstrated a generally increasing incidence of dysplasia or carcinoma with duration of disease (20% at 0 to 10 years, 50% at 11 to 20 years, 59% at 21 to 30 years, and 100% at more than 31 years). TAG‐72 expression was similar in the control and non‐dysplastic colonic epithelia, and increased with low‐ or high‐grade dysplasia as well as carcinomatous lesions (mean cellular reactivities 23.7%, 26.5%, 36.7%, 70% and 84.3%, respectively). Epithelium with low‐grade dysplasia exhibited a focal perinuclear, superficial crypt staining (when present). High‐grade dysplastic epithelium showed pancytoplasmic, pan‐cryptic reactivity. Invasive disease showed cytoplasmic as well as extracellular mucin staining. Biopsies from patients with active disease showed significantly more immunoreactive cells for TAG‐72 than patients with quiescent disease. For any given biopsy specimen the percentage of cells reactive did not always correlate with the degree of dysplasia. TAG‐72 expression in quiescent disease generally increased with duration of disease, in contrast to active disease which showed no correlation between MAb B72.3 staining and duration of disease. The frequent expression of TAG‐72 in actively inflamed colonic mucosa (ulcerative colitis and other colitides) may limit the clinical utility of this antigen for detecting colon cancer in ulcerative colitis patients by serological assay or in vivo radiolocalization techniques. The tendency for TAG‐72 expression to correlate with disease duration in patients with quiescent disease and to increase with more severe degrees of dysplasia suggests that the expression of this gene product correlates with the dysplasia‐to‐carcinoma sequence.
Urokinase‐type plasminogen activator biosynthesis is induced by the EJ‐Ha‐ras oncogene in CL26 mouse colon carcinoma cells
Authors: Testa J. E. , Medcalf R. L. , Cajot J.‐F. , Schleuning W.‐D. , Sordat B.
Published: February 2007

CL26 murine colon carcinoma cells express urokinase‐type plasminogen activator (u‐PA) mRNA and activity after transfection with the activated c‐Ha‐ras‐1 (EJ‐ras) oncogene cloned from the EJ bladder carcinoma. PA activity and mRNA in control cells transfected with the non‐mutated c‐Ha‐ras‐1 (CO‐ras) gene remained negative. Ras mRNA was detected in EJ‐ras‐ and CO‐ras‐transfected cells, but not in untransfected or pSV2‐neo‐transfected cells. These results indicate that u‐PA biosynthesis can be modulated by EJ‐Ha‐ras‐dependent pathways of signal transduction.
Differential response of adherent and unanchored melanoma cells to bromodeoxyuridine evidenced by specific lectin‐binding protein changes
Authors: Rieber Manuel , Rieber Mary S. , Urbina Cecilia , Lira Renée
Published: February 2007

The possible differential response of adherent and nonadherent cells of the same tumor type to pyrimidine analogues has been investigated. We show that bromodeoxyuridine (BUdR) increases interactions of attached cells with their substrate without markedly affecting the cell adhesion properties of the same cells when these are not anchored. However, evidence for an adhesion‐independent response of both cell types to BUdR has been obtained with lectin binding assays using 125I‐labelled Lens culinaris agglutinin (LCA). This revealed a greatly increased binding of LCA to a large glycoconjugate in all cultures exposed to the halogenated pyrimidine. Attachment‐dependent effects of BUdR were manifested in flattened cells by a greater LCA‐binding to a 240‐kDa protein and by increased interaction of 125labelled wheat‐germ agglutinin (WGA) with a 200‐kDa protein and a large glycoconjugate sharply defined in electrophoresis. Although both tumor cell aggregates and anchored cells exhibit detectable responses to pyrimidine analogues such as BUdR, the corresponding effects are thus manifested unequally in cells with different adhesion properties.
A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activity
Authors: Meyer Thomas , Regenass Urs , Fabbro Doriano , Alteri Enrica , Röusel Johannes , Möller Marcel , Caravatti Giorgio , Matter Alex
Published: February 2007

Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non‐selective inhibitor of in vitro protein kinase C (PKC) activity (IC50 6.0 nm). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nm but showed a high degree of selectivity when assayed for inhibition of cyclic AMP‐dependent protein kinase (IC50, 2.4 μm). 56 kinase (IC50 5.0 μm). and tyrosine‐kinase‐specific activity of epidermal growth factor receptor (IC50 3.0 μm). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T‐24, human promyelocytic leukemia line HL‐60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre‐treated with 12‐O‐tetradecanoyl‐phorbol‐13‐acetate at non‐toxic concentrations. In vivo anti‐tumor activity was examined in T‐24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti‐tumor activity (2p < 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 μm in all in vitro enzyme and anti‐proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti‐proliferative and anti‐tumor activity.
Ganglioside GM2 expression on human melanoma cells correlates with sensitivity to lymphokine‐activated killer cells
Authors: Hoon Dave S. B. , Ando Iwao , Sviland Greg , Tsuchida Tetsuya , Okun Edward , Morton Donald L. , Irie Reiko F.
Published: February 2007

Ganglioside GM2 is expressed on cell surface membranes of a variety of human malignant cells and has been demonstrated to be immunogenic in humans. We have assessed the role of the antigen GM2 on melanoma cells as a recognition structure for lymphokine‐activated killer (LAK) cells. LAK cells were generated by stimulation of non‐adherent peripheral blood lymphocytes (PBL) from human donors with recombinant interleukin‐2 (IL‐2). The selection of target cells was based on GM2 content and included II human melanoma cell lines and 2 human leukemia lines. Using a single‐cell binding assay, LAK cell binding to target lines expressing high levels of GM2 was significantly greater than to those expressing minimum GM2. This cell‐binding was specifically inhibited by addition of purified GM2 but not by other gangliosides. LAK‐melanoma cell‐binding was also specifically inhibited by anti‐GM2 monoclonal antibody (MAb). For further analysis LAK cell lysis of melanoma target cells expressing various amounts of GM2 was assessed. A significant correlation occurred with GM2 expression and LAK cell lysis (p < 0.025; r = 0.623). Three other gangliosides commonly expressed on human melanoma, GM3, GD3 and GD2, had no correlation with LAK cell lysis. These studies suggest that GM2 on melanoma cells is a marker for LAK cell sensitivity, as well as indicate that GM2 is a potential target recognition structure for human LAK cells.
Effect of retinyl acetate on cAMP‐dependent protein kinase in transformed mouse 10t1/2 cells
Authors: Hohmann Philip
Published: February 2007

The effect of retinyl acetate (RAC) on the activity of cAMP‐dependent protein kinase (PKA) was studied in mouse 10T1/2 cells. The studies revealed that normal 10T1/2 cells had about 13‐fold more PKA activity than did methylcholanthrene‐transformed cells (MCA cells). The addition of RAC to MCA cells increased the activity of PKA about 3‐fold as measured by the in vitro phosphorylation of a specific site in H1 histone (site A) or Kemptide. The increased PKA activity coincided with a reduction in the rate of cell replication of MCA cells, about 24 hr after exposure to the retinoid. Addition of forskolin to RAC‐treated MCA cells resulted in a further reduction in the rate of cell replication, and this suggested that the enhanced PKA activity was also capable of action in vivo. To test this notion, MCA cells were grown with and without RAC, and the phosphorylation of the H1 histone at site A, a site known to be phosphorylated by PKA in cells treated with hormones or other agonists which activate PKA, was studied in vivo. RAC, by itself, was capable of causing an increase in the phosphorylation of the H1 histone at site A, demonstrating that the retinoid‐mediated increase in PKA activity was sufficient to cause the enhanced phosphorylation of a known substrate.
Growth stimulation of human breast epithelial cells by basic fibroblast growth factor in serum‐free medium
Authors: Takahashi K. , Suzuki K. , Kawahara S. , Ono T.
Published: February 2007

Growth‐stimulating activities of basic and acidic fibroblast growth factors (FGFs) toward human breast epithelial cells were examined and compared with the mitogenic activity of bovine pituitary extract (BPE) by the use of a serum‐free medium which contained epidermal growth factor, insulin, transferrin, hydrocortisone, ethanolamine, phosphoethanolamine, prolactin and prostaglandin. Addition of 1 ng/ml of basic FGF (bFGF) to the serum‐free medium significantly enhanced the growth potential of epithelial cells derived from human breast carcinoma, and the number of cells grown for 7 days with bFGF was more than 1 1/2 times higher than that in the serum‐free medium containing BPE instead of prolactin and prostaglandin. Growth responsiveness toward bFGF of epithelial cells derived from histologically non‐malignant breast tissues was lower than that of carcinoma‐derived cells, and the growth‐stimulating activity of bFGF was lower than that of BPE, which could significantly enhance the growth potential of the cells. Contrary to bFGF, acidic FGF at 1 ng/ml had no significant effect on the growth potential of breast epithelial cells which had grown out from either carcinoma or non‐malignant tissues. The present results suggest that bFGF is a putative growth‐stimulating factor for human breast epithelial cells, especially for carcinoma‐derived cells, and can substitute at least in part for BPE in serum‐free monolayer culture of the cells.
Effects of low‐ and high‐density lipoproteins on the proliferation of human breast cancer cells In vitro: Differences between hormone‐dependent and hormone‐independent cell lines
Authors: Rotheneder Martina , Kostner Gerhard M.
Published: February 2007

The influence of low‐ and high‐density lipoproteins on the proliferation of human breast cancer cells in culture was studied. We compared total cell number after incubation for 48 hr in culture medium containing or lacking plasma lipoproteins. Marked differences were found between hormone‐dependent (MCF‐7, T‐47‐D, ZR‐75) and hormone‐independent (MDA‐MB‐231, HBL‐100) mammary tumor cell lines. The cells also reacted differently on the different lipoproteins offered in the medium. Human low‐density lipoproteins (LDL) exhibited a marked stimulation of the growth of hormone‐independent cell lines but no or only toxic effects upon the hormone‐sensitive lines. Human high‐density lipoproteins (HDL) stimulated the proliferation of all cell lines in a dose‐dependent manner but hormone‐independent cells showed a higher response. These findings point towards different utilizations of nutrients in hormone‐dependent and hormone‐independent cells.
Role of glucose‐6‐phosphate dehydrogenase on enhanced proliferation of pre‐neoplastic and neoplastic cells in rat liver induced by n‐nitrosomorpholine
Authors: Baba Miyako , Yamamoto Reiko , Iishi Hiroyasu , Tatsuta Masaharu , Wada Akira
Published: February 2007

The relationship between G6PD and the number and size of pre‐neoplastic and neoplastic lesions in rat liver was examined. Male Sprague‐Dawley rats were given drinking water containing 250 mg/l of NNM for 8 weeks. Pre‐neoplastic and neoplastic lesions with positive staining of GT were classified histochemically into G6PD‐positive and G6PD‐negative lesions. At week 24, quantitative analysis showed that the incidence and number of G6PD‐positive lesions were significantly higher than those of G6PD‐negative lesions. Histologically, hepatocellular carcinomas were more frequent and larger in G6PD‐positive lesions than in G6PD‐negative ones. Statistical analysis of the quantitative data also showed that the number and volume of G6PD‐positive hepatocellular carcinomas were significantly higher than in G6PD‐negative carcinomas. The G6PD‐positive pre‐neoplastic lesions had a significantly higher labelling index than G6PD‐negative ones. These findings revealed a considerable difference in the growth of these 2 populations of the lesions, and indicate that G6PD activity may be closely related to proliferation of the pre‐neoplastic and neoplastic cells in the liver.
Correlations of dihydropyrimidine dehydrogenase, thymidine phosphorylase and thymidine kinase activities in strongly and weakly malignant cultured murine neuroblastoma cells
Authors: Williams Christopher S. , Tuchman Mendel
Published: February 2007

The C‐1300 neuroblastoma tumor which arises spontaneously in the A/J mouse has been maintained in this mouse strain. Two different cell populations have been recognized in cultured C‐1300 mouse neuroblastoma (MNB): (1) round, “neuroblast‐like” cells, growing in suspension (poorly attached), that have a highly malignant behavior when injected into the A/J mouse (T1 cells); and (2) flat, “epithelioid” cells that attach well to surfaces and show low malignancy towards the inoculated animals (T2 cells). The specific activities of the pyrimidine metabolizing enzymes thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and thymidine kinase (TK) were examined in both MNB cell lines by a new radiochromatographic method. Enzymatic activities of TP and DPD in the cytosols of T2 (weakly malignant) cells were up to 15 times higher than those of T1 (strongly malignant) cells, whereas the mean TP/DPD activity ratio was 16 in either cell line. TP and DPD activity levels increased with time of growth in culture in T2 cells while no such increase was seen in the T1 cells. Maximal TK activity was similar in both cell lines but dropped more rapidly in the T2 cells as cell densities increased. The enzymatic activity levels of TP and DPD but not of TK correlated inversely with neoplastic expression of MNB cells. The observed patterns of pyrimidine metabolizing enzymes in MNB cells could result in an increased thymidine pool in T1 cells whenever TK activity is suppressed, whereas such conditions would favor the generation of thymine in the T2 cells.
A survey of in vivo growth characteristics and spontaneous metastasizing potentials of C3H mouse mammary tumors
Authors: Vaage Jan
Published: February 2007

This investigation examined the relationship between spontaneous metastasizing potential, immunogenicity and growth rate in 34 C3H/He mammary carcinomas. The main purpose of our studies was to examine the hypothesis that a tumor's metastasizing potential is affected by its immunogenicity. The tumors were studied during serial intra‐mammary transplantations, starting with tissue from autochthonous, spontaneous pulmonary metastases. The results show that there was no correlation between metastasizing potential and tumor immunogenicity, and no correlation between metastasizing potential and tumor growth rate. Moreover, metastasizing potential was not related to invasive behavior, because histological examination showed that all of the metastases grew extensively within pulmonary vessels and displayed no tendency to active extravasation.
Inhibition of dmba‐induced mammary tumorigenesis by caloric restriction in rats fed high‐fat diets
Authors: Klurfeld David M. , Welch Carrie B. , Lloyd Lisa M. , Kritchevsky David
Published: February 2007

Most previous studies on the inhibiting effect of caloric restriction during promotion of DMBA‐induced mammary carcinogenesis have used low to moderate levels of dietary fat, i.e., about 4 to 14% by weight. The current study was designed to test whether a moderate degree of caloric restriction, 25%, would inhibit tumor growth in rats fed the equivalent of 20% dietary fat which approximates human consumption in affluent countries. Rats were fed diets ad libitum that contained 5, 15 or 20% corn oil. Groups of rats were pair‐fed to the last 2 groups, but subjected to a 25% caloric restriction. These groups were fed 20 or 26.7% corn oil so that absolute fat intake in the paired groups was identical. Significant inhibition of tumor incidence, tumor weight, tumor burden, body fat deposition, and fasting serum insulin were observed in the 2 calorically restricted groups. We conclude that moderate caloric restriction is significantly more effective in inhibiting tumor growth than is the promoting effect of diets high in fat. Total body weight, body fat and serum insulin concentrations may be better correlates of risk of developing mammary tumors than is dietary fat.
Presence of nerve growth factor‐like immunoreactivity in carcinoid tumour cells and induction of a neuronal phenotype in long‐term culture
Authors: Ahlman Håkan , Wigander Anneli , Möulne Johan , Nilsson Ola , Karlsson Jan Erik , Theodorsson Elvar , Dahlström Annica
Published: February 2007

Mid‐gut carcinoid tumour cells expressed a neuronal phenotype, observed and characterized immunocytochemically in long‐term culture. Initially the culture contained a main population of spherical tumour cells with granules immuno‐positive for serotonin (5‐HT) and tachykinins (TK). Production and secretion of these substances into media was verified biochemically. Cytoplasmic granules with 5‐HT‐like immuno‐reactivity (5‐HT‐LI) were markedly reduced during culture, while granules with TK‐LI were unchanged in number, corresponding to the biochemical findings. After a few days in culture, tumour cells were flattened and fine neurite‐like processes extended. After 2‐3 weeks many endocrine tumour cells had converted to neuron‐like cells with slender cell processes containing granules with TK‐LI. Varicose enlargements and apparent growth cones were observed. When neurites were extended, 50‐80% of the neuron‐like cells were positive with antisera against the neurofilament triplet. Cells of both endocrine and neuronal phenotypes were positive with antisera against tetanustoxin, Thy I‐antigen, neuron‐specific enolase, synapsin and a synaptic vesicle protein (p 38) supporting the concept of these tumour cells as para‐neurons. Intermediate filaments, studied with monoclonal anti‐vimentin, were found in all cells. Filaments were also observed ultrastructurally. Initially, nerve growth factor (NGF)‐LI was found in granules of all spherical tumour cells. When neuritic processes were extended, the cells appeared to lose these granules. After 40 days in culture, NGF‐LI was absent or very sparse. The studies indicate autocrine secretion of a growth factor, reacting with the NGF antiserum, by cultured midgut carcinoid tumour cells inducing a neuronal phenotype with enhanced NF and TK synthesis and suppressed 5‐HT synthesis. In bioassay systems the culture media caused a delayed neurite reaction on PC12 cells, but no reaction on chick ciliary ganglion cells, indicating that the factor is not authentic NGF.
Risk factors for oral cancer in Brazil: A case‐control study
Authors: Franco Eduardo L. , Kowalski Luiz P. , Oliveira Benedito V. , Curado M. Paula , Pereira Raimunda N. , Silva M. Estela , Fava Antonio S. , Torloni Humberto
Published: February 2007

A case‐control study of risk factors for carcinomas of the tongue, gum, floor, and other specified parts of the mouth was conducted in 3 metropolitan areas in Brazil: São Paulo (South‐east), Curitiba (South), and Goiãnia (Central‐West). We analyzed information on demographics, occupational history, environmental exposures, tobacco smoking and alcohol drinking habits, as well as diet, oral and other health characteristics obtained from interviews with 232 cases and 464 hospital non‐cancer controls matched for 5‐year age‐group, sex, hospital catchment area and trimester of admission. Tobacco and alcohol consumption were the strongest risk factors irrespective of the anatomical site. The adjusted relative risks (RR) for ever vs. never smokers were: 6.3, 13.9, and 7.0, for industrial‐brand cigarettes, pipe, and hand‐rolled cigarettes, respectively. A strong correlation was seen between number of pack‐years and risk. The RR for the heaviest vs. the lowest consumption categories (>100 vs. <1 pack‐years) was 14.8. Risk levels generally decreased to those of never smokers after 10 years had elapsed since stopping smoking. The risk associated with alcohol was mostly evident for wine (cancer of the tongue) and “cachaça” (all sites), a hard liquor distilled from sugar cane. Other important risk factors were drinking “chimarrão” (a type of maté), use of a wood stove for cooking, and frequent consumption of charcoal‐grilled meat and manioc. Oral hygiene characteristics represented correlates of disease risk. A significant protective effect was observed for consumption of carotene‐rich vegetables and citric fruits, but not for green vegetables in general.
in vivo effects of combination treatment with recombinant interferon‐gamma and ‐alpha in metastatic melanoma
Authors: Osanto Susanne , Jansen Rumo , Naipal Albert M. I. H. , Gratama Jan‐Willem , Van Leeuwen Aad , Cleton Frans J.
Published: February 2007

The toxicity and therapeutic efficacy of the combination of recombinant interferon gamma (rIFN‐γ) and alpha (rIFN‐α) was investigated in 15 patients with metastatic melanoma. Patients were treated with an escalating dose of rIFN‐γ and a fixed dose of rIFN‐α administered s.c. 3 times a week. The maximum dose was well tolerated. The median survival time of the patients was 7 months; no clinical remissions were observed. In the majority of cases, expression of HLA class‐I and ‐II antigens on the patients' peripheral blood lymphocytes and monocytes increased markedly during treatment. An increase in HLA‐DR expression of peripheral blood T lymphocytes was correlated with a longer survival time. This suggests that activation of T lymphocytes may have a favourable influence on the course of metastatic disease. The in vitro anti‐proliferative activity of IFNs on melanoma cell lines isolated from melanoma metastases during treatment of 3 patients was determined. In contrast to the lack of in vivo anti‐tumour effect in patients, both rIFN‐γ and rIFN‐α inhibited DNA synthesis of these melanoma cell lines in vitro, combined IFNs acting synergistically. Anti‐proliferative activity observed in vitro occurred at IFN concentrations below the peak serum levels achieved in vivo.
Relationship between clinical stage, histopathology and antibody titers against the second epstein‐barr virus nuclear antigen (EBNA‐2) in non‐Hodgkin's lymphoma patients
Authors: Masucci G. , Mellstedt H. , Henle G. , Henle W. , Rymo L. , Masucci M. G. , Ernberg I. , Klein G.
Published: February 2007

Non‐Hodgkin lymphoma (NHL) patients with centroblastic (Cb) or centroblastic‐centrocytic (Cb/Cc)‐diffuse lymphomas, immunocytoma (IC) and chronic lymphocytic leukemia (CLL) in clinical stages III‐IV and with active disease (highly malignant group) were compared to NHL patients with CLL, IC, and centrocytic (Cc) or centroblastic‐centrocytic (Cb‐Cc)‐diffuse/follicular lymphomas, in clinical stages I‐II and with inactive disease (low malignant group) based on the presence of antibodies to Epstein‐Barr virus (EBV) nuclear antigen I (EBNA‐I) and 2 (EBNA‐2). In the highly malignant group, anti‐EBNA‐1 geometric mean titers (GMT) were 13.2 (range <2‐80) and anti‐EBNA‐2 60.6 (range: 20‐320). The ratio between the logarithms of anti‐EBNA‐1 and anti‐EBNA‐2 antibody titers was <1.0 (mean: 0.32) in all the patients examined. In 6 out of 8 patients of the low malignant group, anti‐EBNA‐I titers were higher (mean: 30.1; range 10‐160) than anti‐EBNA‐2 titers (mean: 4.3; range <2‐80) and the EBNA 1/2 ratio was >1.0. In healthy EBV‐seropositive individuals, anti‐EBNA‐I GMT were 49 (range: 10‐320) and only 5 out of 17 individuals had detectable anti‐EBNA‐2 titers (GMT: 3; range <5‐20). The EBNA‐1/2 ratio was in all cases >1. Among patients of the highly and low malignant groups, patients with follicular‐cell‐derived lymphomas had elevated antibody titers against the restricted component of early antigens (EAR), whereas all patients with IC and 2 out of 4 CLL patients had elevated antibody titers against the diffuse component of early antigens (EA‐D). The results indicate that the ratio between anti‐EBNA‐1 and anti‐EBNA‐2 antibody titers may be of diagnostic importance in patients with immunodeficiencies.
A case‐control study of diet and invasive cervical cancer
Authors: Verreault René , Chu Joseph , Mandelson Margaret , Shy Kirk
Published: February 2007

A population‐based case‐control study was conducted to assess the relation of diet, especially intake of vitamins A, C and E and of folic acid, to the risk of invasive cervical cancer. Cases were 189 women diagnosed with cervical carcinoma between 1979 and 1983 in 3 counties of the Seattle area. Controls (N = 227) were selected through random digit dialling. Diet during the year preceding diagnosis was assessed by interview, using a food frequency questionnaire covering the intake of 66 food items. After adjustment for known risk factors, frequent consumption of dark green or yellow vegetables and of fruit juices was related to a reduced risk of cervical cancer. Similarly, high dietary intake of carotene was associated with a lower risk of the disease, especially of the squamous‐cell type. There was an inverse relationship between vitamin C intake and the risk of cervical carcinoma. The adjusted relative risk (RR) was 0.5 (95% confidence interval: 0.2‐1.0) for the highest quartile of intake compared to a RR of 1.0 for the first quartile. High vitamin E intake was also related to a reduced risk, the risk for women in the highest quartile being only one‐third of the risk for those in the first quartile. Intake of pre‐formed vitamin A and of folic acid was not related to the risk of cervix cancer. Thus, our study suggests that the risk of invasive cervical carcinoma might be influenced by some aspects of diet.
The cost‐effectiveness of breast cancer screening
Authors: Van Der Maas Paul J. , De Koning Harry J. , Van Ineveld B. Martin , Van Oortmarssen Gerrit J. , Habbema J. Dik F. , Lubbe Koos Th. N. , Geerts Ada T. , Collette Hubertine J. A. , Verbeek André L. M. , Hendriks Jan H. C. L. , Rombach Jan J.
Published: February 2007

The costs and effects of different invitation schedules of breast cancer screening are compared. The effect estimates are based on trials from the USA, Sweden and the Netherlands. The cost estimates use registration data, file studies and organization charts. The calculations were performed with the MISCAN computer simulation package, which is developed especially for the evaluation of mass screening programmes. Screening women of 50–70 years at 2‐yearly intervals is a relatively cost‐effective schedule. In a real population, it will reduce breast cancer mortality by 12%. Screening of women under 50 is probably far less cost‐effective. Screening induces a considerable shift towards breast‐conserving therapy. Although a 12% mortality reduction may seem low, in absolute numbers this represents more than the total mortality from, e.g., cervical cancer. Moreover, cost per death prevented or per life‐year saved is much lower than for most other medical interventions for which cost‐effectiveness ratios are known, screening for cervical cancer included.
Marker profile of mesothelial cells versus ovarian carcinoma cells
Authors: Van Niekerk C. C. , Jap P. H. K. , Thomas C. M. G. , Smeets D. F. C. M. , Ramaekers F. C. S. , Poels L. G.
Published: February 2007

We investigated the marker profile of human ascitic and cultured mesothelial cells, and compared it to that of ovarian carcinoma cells which are related in terms of their histogenesis, unrelated colon carcinomas being used as reference. Mesothelial and ovarian carcinoma cells could not be distinguished by (intermediate) filament typing, using monoclonal antibodies (MAbs) to keratins, vimentins and desmins. Colon carcinomas differed from mesothelial cells and ovarian carcinomas by the absence of keratin‐7 filaments. The epithelial marker BW 495/36 was completely negative on mesothelial cells and positive on all ovarian and colon carcinoma cells. While CEA was found on about 85% of all colon carcinomas, CEA expression on mesothelial cells and ovarian carcinoma cells was below 20%. The ovarian carcinoma markers (OV‐TL 3, OV‐TL 10, OC 125, MOV 18) were strongly positive on ovarian carcinomas and negative on colon carcinomas (or limited to traces of immunofluorescence on some samples). Although the mesothelial cells showed weak or negative reactivity with these markers, OC 125 antigen was found by immunoelectron microscopy on the surface of cultured mesothelial cells, and was shed in the culture supernatant at concentrations of 50, 28, and 25 CA 125 U/ml/104 positive cells. This suggests that mesothelial cells may be responsible for the synthesis of CA 125 in ascitic fluid. The data indicate that ovarian carcinomas, mesothelial cells and colon carcinomas can be distinguished using a combination of anti‐keratin antibodies with BW 495/36 and anti‐ovarian carcinoma markers.
Formation of multinucleated cells in a Hodgkin's‐disease‐derived cell line
Authors: Drexler Hans G. , Gignac Suzanne M. , Hoffbrand A. Victor , Minowada Jun
Published: February 2007

The proliferative potential of multinucleated Reed‐Sternberg‐like cells and the process of multinuclear formation were studied on the Hodgkin's‐disease‐derived cell line HDLM‐2. No difference in surface antigen expression was found between mono‐ and multinucleated cells as determined by immunolabelling with characteristic markers. After sorting and reculture of purified mononucleated cells, polykaryons emerged subsequently in these cultures, indicating that mononucleated cells give rise to multinucleated variants. The morphological observation of mitotic figures and immunostaining with the cell cycle indicators Ki‐67 and BrdU provided evidence of DNA synthesis and nuclear division in multinucleated cells. The presence of mitotic figures demonstrated that multinucleated cells are able to undergo synchronous nuclear division. However, while polykaryons were clearly mitotically active and capable of DNA synthesis, the absence of telophases and the failure of active replication suggest a disturbed cytokinesis. Co‐cultivation of BrdU‐labelled and unlabelled populations did not lead to hybrid polykaryons with negative and positive nuclei. Therefore, multinucleated giant cell formation of HDLM‐2 cells appears to involve nuclear endomitosis without cell division rather than cell fusion.
The Mr 140,000 fibronectin receptor complex in normal and virus‐transformed human fibroblasts and in fibrosarcoma cells: Identical localization and function
Authors: Ylänne Jari , Virtanen Ismo
Published: February 2007

We studied the function and localization of the fibronectin receptor complex in cultured normal and SV40‐transformed human fibroblasts and in human fibrosarcoma cells by using monoclonal antibodies (MAbs) against the β sub‐unit of the receptor. Immunoprecipitation, fibronectin fragment affinity chromatography and immunoblotting results suggested that all the cells studied had similar amounts of the receptor. In normal fibroblasts MAbs additionally immunoprecipitated a smaller polypeptide, revealed as the precursor for the β subunit and another polypeptide shown to be the α sub‐unit of the VLA‐1 complex. The emergence of vinculin‐positive focal adhesion sites and actin stress fibers was slower in the malignant cells than in normal fibroblasts when the cells were plated on non‐coated glass‐substrate in serum‐free conditions and the fibronectin receptor complex did not become located to focal adhesions in any of the cells studied. Added substratum‐bound but not soluble fibronectin mediated assembly of the fibronectin receptor complex to the focal adhesions in both normal and malignant cells. On fibronectin‐coated growth substrate stress fibers also emerged as rapidly in the malignant cells as in normal fibroblasts. In all the cells the receptor complex, however, became largely dissociated from the focal adhesions within 48 hr. In cell adhesion conditions MAb against the α sub‐unit of VLA‐1 complex revealed an even cell‐surface labelling in normal fibroblasts and lack of labelling in malignant cells.
Effects of dimethylsulfoxide on friend erythroleukemic cell proliferation and on the activity of enzymes involved in this process
Authors: Liotti F. S. , Menghini A. R. , Guerrieri P. , Bianchi R.
Published: February 2007

Variations in catalase, glutathione peroxidase (GP) and adenylate cyclase (AC) activity in murine erythroleukemic (MEL) cells were studied during multiplication and dimethylsulfoxide (DMSO)‐induced differentiation. The results demonstrated that, although DMSO favors the incorporation of 3H‐thymidine into DNA of treated cells, it slows down cell multiplication. Increased incorporation was also observed in superoxide dismutase (SOD)‐treated cells. DMSO also determined an early and significant drop in AC activity and a late fall in catalase activity, whereas there was no significant variation in GP activity in parallel with the decreased cell multiplication that accompanied cell differentiation. We hypothesize that DMSO and SOD favor 3H‐thymidine incorporation by neutralizing the reactive forms of oxygen and that the reduction in catalase and AC activity is closely related to the mitotic activity of MEL cells.
Direct and serial transplantation of Ph1‐positive acute lymphoblastic leukemia into nude mice
Authors: Miyagi T. , Kubonishi I. , Ohtsuki Y. , Ohyashiki J. H. , Toyama K. , Miyoshi I.
Published: February 2007

A new Philadelphia chromosome (Ph1‐positive acute lymphoblastic leukemia (ALL) cell line was established in nude mice by direct and serial transplantation of peripheral blood leukemia cells from an adult patient. Although the patient's leukemia cells did not grow in vitro, they were successfully transplanted for 8 serial passages, giving rise to progressive growth of tumors with frequent involvement of lymph nodes, liver, spleen, bone marrow, and meninges. The tumor cells could also be passaged in an ascites form. This in vivo cell line, designated PALL‐1, retained the Ph1 chromosome, t(9;22) (q34;q11), and pre‐B‐cell phenotype (SmIg−, CpIg−, CD10+, CD19+, OKIal+, and CD38+), like the original leukemia cells. Molecular genetic analysis of PALL‐1 cells revealed neither bcr rearrangement nor 8.5‐kb abl‐related mRNA that is characteristically seen in Ph1‐positive chronic myelogenous leukemia (CML). Thus, the PALL‐1 cell line is genetically distinct from CML. It may provide a useful model for an understanding of the cellular and molecular biology of Ph1‐positive ALL without classical bcr rearrangement.
Polyoma t‐antigen‐derived synthetic peptides induce polyoma‐virus‐specific macrophage migration inhibition
Authors: Reinholdsson Git , Ramqvist Torbjörn , Sziget Robert , Dalianis Tina
Published: February 2007

Synthetic peptides, 2 derived from the sequence common to small, middle and large T‐antigen, and I derived from the sequence unique for middle T, activated lymphocytes from polyoma‐virus‐immunized, but not from control mice, to release the lymphokine migration inhibitory factor (MIF). In contrast, purified, bacterially grown, full‐length small T‐antigen and a middle T‐antigen mutant Py 1387T MT (lacking 37 C‐terminal amino acids) did not induce lymphokine release, although they were capable of inducing an antipolyoma TSTA response in vivo.
Influence of shear stress on tumor‐cell adhesion to endothelial‐cell extracellular matrix and its modulation by fibronectin
Authors: Bastida Eva , Almirall Lourdes , Bertomeu M. Cruz , Ordinas Antonio
Published: February 2007

The interaction of malignant cells with blood‐vessel endothelial cells and their underlying basement membrane is an important step in the development of secondary metastases. We investigated the interactions of highly metastatic human tumor cells, the A‐549 adenocarcinoma of the lung, with cultured endothelial cells (EC) and their extracellular matrix (ECM). We studied the adhesion patterns of the A‐549 tumor cells to EC and ECM under static and flow conditions. Our results provide evidence that tumor‐cell adhesion depends not only on the characteristics of the tumor cells themselves, but also on the properties of the EC and ECM. Our results also indicate that tumor‐cell adhesion to ECM is shear‐rate‐dependent, and that it is partially modulated by fibronectin. Moreover, our results suggest that the arg‐gly‐asp (RGD) common adhesion receptor site is also involved in the adhesion of the A‐549 cells to EC and ECM.
Co‐inoculation of tumorigenic rat prostate mesenchymal cells with non‐tumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals
Authors: Chung Leland W. K. , Chang Shi‐Ming , Bell Carol , Zhau Haiyen E. , Ro Jae Y. , Von Eschenbach Andrew C.
Published: February 2007

Co‐inoculation of NbF‐I and NbE‐I s.c. into either adult male syngeneic rats or athymic nude mice induced the development of tumors that resembled carcinosarcoma on histopathologic evaluation. These tumors were composed of a mixture of adenocarcinoma and fibrosarcoma and were induced by the mixtures of NbF‐I and NbE‐I cells at a ratio ranging from 0.001 to 3.2; inoculation of NbF‐I alone resulted in the development of fibrosarcoma. Flow‐cytometric analysis showed that the epithelial cells subcloned from the carcinosarcoma had a DNA profile like that of their parental cell line and remained non‐tumorigenic. When co‐inoculated with the tumorigenic fibroblasts in syngeneic hosts, however, the subcloned epithelial cells again formed carcinosarcomas. Our results indicate that cell fusion between epithelial cells and fibroblasts is an unlikely explanation for tumorigenicity. We propose that prostatic fibroblasts exert a directive influence on their adjacent epithelial cells through a paracrine mechanism that determines epithelial growth and tumorigenicity in vivo.
A novel derivative of the chelon desferrioxamine for site‐specific conjugation to antibodies
Authors: Pochon S. , Buchegger F. , Pélegrin A. , Mach J.‐P. , Offord R. E. , Ryser J. E. , Rose K.
Published: February 2007

We describe the preparation of the modified chelator aminooxyacetyl‐ferrioxamine, and the replacement of its iron atom by 67Ga at high specific activity. The aminooxy function of this compound was allowed to react with the aldehyde groups generated by the periodate oxidation of the oligosaccharide of a mouse IgG1 monoclonal antibody (MAb) directed against carcino‐embryonic antigen (CEA). The use of the aminooxy group allowed a stable bond to be formed between the chelon and the antibody with no need for reduction. Iron was removed from the ferrioxamine moiety and replaced by 67Ga either before or after conjugation of the chelon to the antibody. In either case the labelled antibody was injected into nude mice bearing a human colon carcinoma having the appropriate antigenicity. Unoxidized antibody, labelled with 125I by conventional methods, was co‐injected as an internal control. Additional control experiments were carried out with a non‐immune IgG using the same 67Ga‐labelled modified chelon as above. The in vivo distribution of the modified antibodies was evaluated at various times between 24 and 96 hr after injection. The methods used were gamma‐camera imaging and, more quantitatively, gamma‐counting of the various organs after dissection. Interestingly, with the metal‐chelonlabelled antibody, the intensity and specificity of tumor labelling was comparable and in some cases superior to the results obtained with radio‐iodinated antibody. In particular, there was almost no increase in liver and spleen uptake of radioactive metal relative to radio‐iodine, contrary to what has been observed with most antibodies labelled with 111In after conjugation with DTPA.