bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities of the EGF receptor system in human thyroid neoplasia
Authors: Lemoine Nicholas R. , Hughes Christine M. , Gullick William J. , Brown Christopher L. , Wynford‐Thomas David
Published: February 2007

The epidermal‐growth‐factor receptor (EGF‐r) and its ligands are involved in the control of proliferation of both normal and neoplastic thyroid epithelium. Autocrine stimulation of growth involving this receptor system has been identified in several types of human neoplasia and we were interested to determine whether it might occur in human thyroid tumours. We have therefore examined an archival series of thyroid tumours and non‐neoplastic pathologies for expression of the EGF‐r and 2 of its ligands, transforming growth factor alpha (TGF‐α) and epidermal growth factor (EGF), using immunohistochemistry. We found evidence of expression of both the EGF‐r and the TGF‐α in the majority of thyroid tumours, with a trend to higher expression in more malignant neoplasms. We also found variable levels of expression of EGF‐r and TGF‐α in all cases of thyroiditis examined. We conclude that there is a potential autocrine loop involving the EGF‐r system in both neoplastic and non‐neoplastic conditions of the human thyroid.
Combined in vitro modulation of adriamycin resistance
Authors: Meijer C. , Mulder N. H. , Timmer‐Bosscha H. , Petfrs W. H. M. , de Vries E. G. E.
Published: February 2007

In a P‐glycoprotein‐negative cell line, GLC4‐Adr90, a 75‐fold acquired Adriamycin (Adr) resistance coincided with a reduced cellular Adr level, an increased detoxifying capacity (glutathione (GSH) and glutathione S‐transferase (GST) elevated), and a reduced topoisomerase‐II (topo‐II) activity compared with the parent cell line GLC4. The effect on Adr resistance of buthionine sulfoximine (BSO, GSH synthesis inhibitor), was studied alone or in combination with verapamil (drug‐efflux inhibitor), docosahexaenoic acid (membrane lipid domain affector), ethacrynic acid (GST inhibitor), aphidicolin (DNA‐ polymerase‐α inhibitor) or novobiocin (NOV, topo‐II inhibitor). Cytotoxicity was tested using a microculture tetrazolium assay. In GLC4‐Adr90, BSO and NOV increased Adr‐induced cytotoxicity 12.9‐fold and 1.8‐fold respectively. The combination of BSO plus NOV showed an additive effect, decreasing the Adr resistance factor from 75 to 2.7. Combination of modulators of Adr resistance directed at different resistance mechanisms appears promising in vitro.
Induction of multiple‐drug resistance during anti‐neoplastic chemotherapy in vitro
Authors: Licht Thomas , Fiebig Heinz‐Herbert , Bross Klaus J. , Herrmann Friedhelm , Berger Dietmar P. , Shoemaker Robert , Mertelsmann Roland
Published: February 2007

Induction of P‐glycoprotein‐related multi‐drug‐resistance (MDR) has been shown innormal and malignant tissues to result from environmental stresses such as heat shock, exposure to carcinogens or X‐ray irradiation. To identify conditions under which MDR is enhanced during anti‐neoplastic chemotherapy, a cell line showing low‐level intrinsic MDR was investigated. In the pleural mesothelioma cell line, PXF1118, < 1% of cells ex‐ pressed P‐glycoprotein (P‐gp), as shown by immunocytochemical staining with monoclonal antibody (MAb) MRK16. Exposure of PXF1118 to vincristine, vindesine, vinblastine or doxorubicin for 2‐3 weeks led to an increase in the MDR cell fraction of up to 15‐28% during 2 to 3 weeks. For doxorubicin and vindesine, dose‐dependence was observed: drug concentrations not capable of eliciting cytotoxicity failed to induce significant P‐gp expression. Nutrient starvation in aging medium, exposure to activated cyclophosphamide (even at high concentrations) or cisplatin caused only negligible MDR induction. After exposure to vindesine for 6 weeks, tumor colonies exhibited highly enhanced resistance to Vinca alkaloids, doxorubicin, etoposide and dacarbacine, whereas their sensitivity to mitomycin, activated cyclophos hamide or cisplatin remained unchanged. As determined by [3H]‐thymidine uptake and proliferation antigen expression, induction of MDR phenotype was observed at minimal proliferative activity with no change in cell count during exposure to anti‐cancer drugs, thus suggesting that the drug treatments changed the phenotype of the cells rather than selecting for a resistant sub‐population. In addition, changes in cell differentiation were observed during MDR induction. Induction of P‐gp during exposure to anti‐cancer drugs thus provides a model for MDR development during initially successful chemotherapy.
Ethnic differences in the anatomical location of colorectal adenomatous polyps
Authors: Offerhaus G. Johan A. , Giardiello Francis M. , Tersmette Kasper W. F. , Mulder Jan‐Willem R. , Tersmette Anne C. , Moore G. William , Hamilton Stanley R.
Published: February 2007

The ratio of right‐ to left‐sided colonic cancer is increasing, but data on the distribution of its usual precursor lesion, the colorectal adenoma, are contradictory. Therefore, we investigated the prevalence of right‐ and left‐sided colorectal adeno‐matous polyps from January I, 1970, to September 30, 1989, using the study design of „epidemiologic necropsy”︁ and the autopsy files of The Johns Hopkins Hospital.

Compared with the decade of the 1970's, the 1980's showed a slight decrease in the overall prevalence of right‐sided adenomas (6.4 per 1,000, 95% confidence limits 4.7‐8.8 vs. 5.1 per 1.000, 95% CL 3.6‐6.5), but a marked decrease occurred in left‐sided adenomas (11.8 per 1,000,95% CL 9.3‐14.3 vs. 6.7 per 1,000, 95% CL 4.8‐8.6). As a result, the ratio of right‐sided to left‐sided adenomas increased from 0.55 in the 1970's to 0.77 in the 1980's. This increased ratio occurred in both sexes, although prevalences were lower in females, and in whites. Unexpectedly, blacks had a ratio of right‐sided to left‐sided adenomas greater than unity in both the 1970's and 1980's (1.19 vs. 1.79) due to a relatively high prevalence of right‐sided adenomas (5.8 per 1,000, 95% CL 3.6‐8.0 in 1970's; 5.8 per 1,000, 95% CL 3.3‐8.3 in 1980's), but low prevalences of left‐sided adenomas (4.9 per 1,000, 95% CL 3.0‐6.8 in 1970's; 3.2 per 1,000, 95% CL 1.2‐5.2 in 1980's). The overall adenoma prevalence in blacks was lower than in whites.

We conclude that the right‐sided predominance of colorectal adenomas in blacks suggests ethnic differences in the pathogenesis of colorectal adenomas. This observation may have important implications for secondary prevention of colorectal cancer.
Tissue concentrations of prostate‐specific antigen in prostatic carcinoma and benign prostatic hyperplasia
Authors: Pretlow Thomas G. , Pretlow Theresa P. , Yang Bin , Kaetzel Charlotte S. , Delmoro Carrie M. , Kamis Sheryl M. , Bodner Donald R. , Kursh Elroy , Resnick Martin I. , Bradley Edwin L.
Published: February 2007

Prostate‐specific antigen (PSA), as measured in peripheral blood, is currently the most widely used marker for the assessment of tumor burden in the longitudinal study of patients with carcinoma of the prostate (PCA). Studies from other laboratories have led to the conclusion that a given volume of PCA causes a much higher level of PSA in the peripheral circulation of patients than a similar volume of prostate without carcinoma. We have evaluated PSA in the resected tissues immunohistochemically and in extracts of PCA and of prostates resected because of benign prostatic hyperplasia (BPH) with an enzyme‐linked immunosorbent assay. Immunohistochemical results were less quantitative than but consistent with the results of the ELISA of tissue extracts. Immunohistochemically, there was considerable heterogeneity in the expression of PSA by both PCA and BPH both within and among prostatic tissues from different patients. While the levels of expression of PSA in these tissues overlap broadly, PSA is expressed at a lower level in PCA than in BPH when PSA is expressed as a function of wet weight of tissue (p = 0.0095), wet weight of tissue/% epithelium (p < 0.0001), protein extracted from the tissue (p = 0.0039). or protein extracted/% epithelium (p < 0.0001).
Association of C‐erbB‐2 protein over‐expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long‐term survival in breast cancer
Authors: Kallioniemi Olli‐P. , Holli Kaija , Visakorpi Tapio , Koivula Timo , Helin Heikki H. , Isola Jorma J.
Published: February 2007

C‐erbB‐2 protein over‐expression was studied immunohis‐tochemically in 319 paraffin‐embedded breast carcinomas representing 89% of all breast‐cancer cases operated in the Tampere University Hospital between 1977 and 1981. The immunohistochemical evaluation of c‐erbB‐2 was optimized using protease pre‐treatment and verified using antibodies for both the external and the internal domains of the protein. c‐erbB‐2 over‐expression was found in 72 (23%) of the 319 cases and was associated with high histological and nuclear grade (p< 0.0001), DNA aneuploidy (p= 0.003), high tumor S‐phase fraction (p< 0.000l), and lack of estrogen (p< 0.0001) and progesterone (p= 0.03) receptors. Overall, breast‐cancer patients with c‐erbB‐2 over‐expression had about 2.2‐fold relative risk (RR) of death (p< 0.001) as compared with those without over‐expression. According to a multivariate analysis, c‐erbB‐2 over‐expression was an independent prognostic factor in the whole material as well as in the node‐negative sub‐set. In node‐negative breast‐cancer tumor size, S‐phase and c‐erbB‐2 status defined a large patient group with only 4% 5‐year and 15% 10‐year mortality rate without adjuvant therapy. In comparison with c‐erbB‐2‐negative tumors, those with over‐expression of this gene metastasized 3 times more often (p= 0.0002) to the lungs, liver and brain and 3 times less often to the bone. Our findings suggest that the prognostic value of c‐erbB‐2 over‐expression may be related not only to increased cell proliferation rate but also to a distinctive pattern of metastasis.
Allelic loss on the short arm of chromosome 11 in non‐small‐cell lung cancer
Authors: Ludwig Christian U. , Raefle Gaby , Dalquen Peter , Stulz Peter , Stahel Rolf , Obrecht Jean‐Paul
Published: February 2007

Forty‐eight samples of primary non‐small‐cell lung cancer (nsclc) and normal tissue from the same patients were analyzed for allelic deletions on chromosome 11p. five polymorphic loci were assessed to determine the incidence of 11 p sequence deletions and to define hot‐spots of deletions. information was obtained from all patients in at least one locus. our data show that the deletions observed were not randomly scattered over the short arm of chromosome i i. rather, 2 hot‐spots of deletions were observed: one in the area of the genes for catalase and β‐fsh corresponding to band ii p13, the other close to the igf‐ii locus corresponding to band ii p15. a high incidence of loss of heterozygosity (loh) was found with the probe for catalase (21/29), a locus flanking the centromeric region of the wilms' tumor locus. most of the samples exhibiting loh of one or more of the alleles analyzed remained heterozygous for at least one other chromosome iip allele. furthermore, duplication of the intensity of the remaining allele was rarely observed. our results indicate that loh on the short arm of chromosome ii is a common event in nsclc and that the chromosomal region containing the wilms' tumor locus is most commonly involved.
Distribution of collagenase and tissue inhibitor of metalloproteinases (TIMP) in colorectal tumours
Authors: Hewitt Robert E. , Leach Iain H. , Powe Desmond G. , Clark Ian M. , Cawston Tim E. , Turner David R.
Published: February 2007

Increased collagenase activity in colorectal carcinomas has recently been shown to be associated with increased malignant potential. To determine the tissue distribution of collagenase and its specific inhibitor, tissue inhibitor of metalloproteinases (TIMP), we carried out an immunohistochemical study on colorectal carcinomas (n = 20), adenomas (n = 7) and normal mucosa (n = 6). We found increased staining for collagenase in the connective tissue stroma of carcinomas, as compared with adenomas and normal mucosa. Little evidence of epithelial cell staining for collagenase was seen in any tissue. In carcinomas, both stromal fibroblasts and collagen fibres stained strongly and stromal staining was strongest close to neoplastic glands. Vascular staining was more prominent in neoplastic than normal tissues, perhaps reflecting the increased proteolytic activity during tumour angiogenesis. The pattern of TIMP immunostaining was similar to that of collagenase, although basement membrane staining for TIMP was generally more intense. Another difference was that, unlike TIMP, staining for collagenase was often increased at the invasive edge of carcinomas, perhaps reflecting increased collagenase activity at this location.
Inhibitory effect of maternal antibody on mother‐to‐child transmission of human T‐lymphotropic virus type I
Authors: Takahashi Kazuo , Takezaki Toshiro , Oki Toshitaka , Kawakami Kiyoshi , Yashiki Shinji , Fujiyoshi Toshinobu , Usuku Kouichiro ,   THE MOTHER‐TO‐CHILD TRANSMISSION STUDY GROUP, Mueller Nancy , Osame Mitsuhiro , Miyata Kouichiro , Nagata Yukihiro , Sonoda Shunro
Published: February 2007

In order to evaluate the protective role of the maternal antibody against mother‐to‐child transmission of HTLV‐I, we followed a total of 780 children born to HTLV‐I carrier mothers by investigating the level of anti‐HTLV‐l antibody transferred in utero, decline of the maternal antibody and seroconversion in post‐natal life. The anti‐HTLV‐1 antibody was positively detected within the first 3‐6 months of life and declined at 6‐12 months after birth in all children. After the maternal antibody declined, seroconversion occurred in some of the children following either breast feeding or bottle feeding. The seroconversion rates of short‐term (≦6 months) and long‐term (≧7 months) breast feeders were 4.4% (4/90 cases) and 14.4% (20/139 cases), and the rate of bottle feeders was 5.7% (9/158 cases). Long‐term breast feeding yielded more seroconverters than short‐term breast feeding; 14.4% (20/139 cases) vs. 4.4% (4/90 cases), RR = 3.68, p = 0.018. The seroconversion rate of short‐term breast feeders was nearly equal to that of bottle feeders; 4.4% (4/90 cases) vs. 5.7% (9/158 cases), RR = 0.770, p = 0.471. When neonatal lymphocytes were cultured with breast milk cells of HTLV‐I carrier mothers, the in vitro infection of HTLV‐I was inhibited by the addition of HTLV‐I‐seropositive cord‐blood plasma. Our results suggest that the maternal antibody may inhibit HTLV‐I infection by short‐term breast feeding but not by long‐term breast feeding after decline of the maternal antibody.
Synergistic cytotoxicity of different alkylating agents for epithelial ovarian cancer
Authors: Lidor Y. J. , Shpall E. J. , Peters W. P. , Bast R. C.
Published: February 2007

Alkylating agents have been used individually and in combination to treat epithelial ovarian carcinoma. In this study, the cytotoxicity of 7 alkylating agents has been measured using a serial dilution clonogenic assay. When individual agents were evaluated, markedly different activity was observed against several ovarian cancer cell lines. Among 4 cell lines tested, OVCA 432 was the most sensitive to cisplatin, thiotepa and melphalan. When alkylating agents were used in combination against OVCA 432, synergistic activity was observed with cisplatin and each of several other alkylating agents including thiotepa, melphalan, 4‐hydroperoxycyclophosphamide (4HC) and carboplatin. The combination of cisplatin and thiotepa also exerted synergistic activity against the OVCA 420, 429 and 433 cell lines, but had only additive or subadditive activity against the NIH:OVCAR‐3 cell line. Sequential treatment of tumor cell lines with the different alkylating agents was as effective as simultaneous treatment. Synergistic anti‐tumor activity in cell culture is consistent with clinical observations that alkylating agents in combination appear more effective than single agents for treatment of advanced epithelial ovarian cancer. In addition, our study suggests that cisplatin in combination with thiotepa, 4HC or melphalan might prove useful for high‐dose therapy with autologous bone‐marrow support.
Pentoxifylline enhances lung colonization and alters cell adhesion and glycosaminoglycan synthesis by metastatic B16 melanoma cells
Authors: Edward Michael , Mackie Rona M.
Published: February 2007

The effect of pentoxifylline on B16 melanoma cell lung colonization, synthesis and properties of glycosaminoglycans (GAGS), and adhesion to and degradation of subendothelial extracellular matrix was examined. Pentoxifylline inhibited cell growth, cell numbers being reduced by 50% following incubation for 4 days in the presence of 250 μg/ml pentoxifylline, while the treated cells appeared more flattened, possessed numerous but short dendritic processes, and exhibited greatly enhanced tyrosinase activity and melanin synthesis. Pentoxifylline treatment increased the cells' ability to colonize the lungs of syngeneic C57BL mice following tail‐vein injection of 105 cells. The number of lung tumours increased from 16.7 ± 6.1 to 52.2 ± 17.8. In addition, pentoxifylline‐treated cell GAG synthesis was reduced by 36%, and the charge density of chondroitin sulphate reduced, while tumour‐cell aggregation and adhesion to subendothelial extracellular matrix was increased, as was the tumour‐cell‐mediated release of 35SO4, from radiolabelled subendothelial matrix. The observed changes in GAG synthesis may contribute toward the increased cell adhesiveness which, in addition to increased degradation of certain components of the subendothelial extracellular matrix, may account, at least in part, for the enhancement of lung colonization.
Adaptation to 5‐fluorouracil of the heterogeneous human colon tumor cell line ht‐29 results in the selection of cells committed to differentiation
Authors: Lesuffleur Thécla , Kornowski Anne , Luccioni Catherine , Muleris Martine , Barbat Alain , Beaumatin Jacqueline , Dussaulx Elisabeth , Dutrillaux Bernard , Zweibaum Alain
Published: February 2007

The HT‐29 cell line contains a small proportion of differentiated polarized, enterocytic and mucus‐secreting cell types (< 95%) which can be selected under various pressure conditions, e.g., glucose deprivation or methotrexate. The purpose of the present work was to investigate whether this also applies to 5‐fluorouracil (FUra). Stepwise adaptation of exponentially growing cells to 1, 5, 10 and 20 μM FUra results, after a phase of high mortality, in the emergence of adapted sub‐populations with stable growth rates and curves, and IC50 6, 18, 37, and 110 times higher than in untreated cells respectively. FUra‐adapted cells are all differentiated, according to 2 phenotypes: (1) polarized dome‐forming cells which express carcinoembryonic antigen at their apical surface and (2) goblet cells which secrete a mucus of colonic immunoreactivity. These phenotypes are present in the parental population and are different from those selected e.g., by glucose deprivation or methotrexate. This differentiation pattern is maintained when the cells are sub‐cultured in drug‐free medium. Resistance to FUra is acquired through gene amplification as substantiated by a 4‐ to 6‐fold increase of thymidylate synthase gene copies in cells stably adapted to the drug. Whether the same mechanism or others are responsible for the first steps of resistance to FUra remains to be elucidated. Altogether, these results support the hypothesis that some of the cells which are present in the parental line and are committed to differentiation possess advantages which allow them to immediately resist and secondarily adapt to FUra. Comparison of the differentiation characteristics of FUra‐adapted cells with those from cells selected under other pressure conditions suggests that resistance and adaptation to either type of pressure may depend on the differentiated phenotype to which the cells are committed.
The lipoxygenase metabolite 12(S)‐hete induces a cytoskeleton‐dependent increase in surface expression of integrin αiibβ3 on melanoma cells
Authors: Chopra Hemi , Timar Jozsef , Chen Yong Q. , Rong Xianhui , Grossi Irma M. , Fitzgerald Laurence A. , Taylor John D. , Honn Kenneth V.
Published: February 2007

Integrin receptors are mediators of cell‐extracellular matrix and cell‐cell interactions. Biochemical and immunocytochemical evidence shows that the platelet integrin receptor αIIbβ3 is present on the cell surface, at focal adhesion plaques and in the perinuclear region of metastatic B16a murine melanoma cells. Antibody to the fibronectin receptor α5β1, inhibits basal adhesion by approx. 30%, whereas antibodies to αIIbβ3 are ineffective. The surface immunoreactivity of tumor cells for αIIbβ3 can be enhanced by pre‐treatment (5 min) with a lipoxygenase metabolite of arachidonic acid [i.e. 12‐(S)‐HETE] in a dose‐dependent manner (max. effect approx. 0.1 μM). Other lipoxygenase metabolites are ineffective. B16a cells possess a large intracellular pool of αIIbβ3, from which the receptor complex translocates to the cell surface following 12‐(S)‐HETE pre‐treatment. This pre‐treatment of tumor cells enhances their adhesion to fibronectin, which is mediated exclusively by αIIbβ3 receptors. 12‐(S)‐HETE also facilitates the redistribution of αIIbβ3 in the plasma membrane with localization at the focal adhesion plaques. The cytoskeleton of the B16a cell is characterized by an absence of distinct microtubules in interphase cells and the presence of prominent microfilaments and vimentin intermediate filaments. In B16a cells, the disruption of intermediate filaments and/or microfilaments prevents the 12‐(S)‐HETE‐induced increase in plasma membrane αIIbβ3, and enhanced tumor‐cell adhesion to fibronectin. The microtubule‐disrupting agent, colchicine, is ineffective in both respects. We conclude that the lipoxygenase metabolite of arachidonic acid, 120‐(s)‐HETE, regulates the surface expression and function of the αIIbβ3, integrin in B16a cells. Further, these data support the hypothesis that microfilaments and intermediate filaments have a profound role in regulating the expression of a multifunctional integrin in B16a tumor cells.
Mucin production by colon cancer cells cultured in serum‐free medium
Authors: Real Francisco X. , Egea Gustavo , Francí Clara , Schüssler Martina H. , Xu Mai , Welt Sydney
Published: February 2007

Although many colon cancer cell lines are available for study, few of them exhibit differentiated properties. When cultured in medium containing fetal bovine serum, WiDr cells (WiDr‐FBS) show an undifferentiated phenotype: growth as a multilayer of cells adherent to plastic and lack of polarization, brush border, and much vacuoles. In contrast, WiDr cells cultured in a chemically‐defined serum‐free medium containing insulin, transferrin and selenium (WiDr‐ITS) grow as clusters of non‐adherent cells with abundant desmosomes and tight junctions, microvilli and electron‐lucid vacuoles. As WiDr‐FBS cells, WiDr‐ITS are not polarized. WiDr‐ITS cells show a marked enhancement in mucin synthesis as demonstrated by: periodic acid‐Schiff and Alcian blue stains, electron microscopy, immunohistochemistry using monoclonal antibodies (MAbs) reactive with mucin‐associated epitopes, immune electron microscopy and immunochemical analysis using Western blots. In comparison with WiDr‐FBS cells, WiDr‐ITS cells showed strong expression of Tn, sialyl‐Tn, blood group A and CEA. When mouse MAbs were used, higher levels of the MUCI gene product were detected in WiDr‐ITS than in WiDr‐FBS cells. The full spectrum of phenotypic changes was observed after 1 month of culture in ITS medium, and transfer of WiDr‐ITS cells to FBS medium was accompanied by a partial phenotypic reversal, suggesting that these phenotypic changes result from an adaptative–rather than selective–process.
Cancer in migrants to Argentina
Authors: Matos Elena L. , Khlat Myriam , Loria Dora I. , Vilensky Marta , Parkin D. Maxwell
Published: February 2007

Mortality rates from different cancers in migrants to Argentina from II individual countries and 6 groups of countries were compared with those in the Argentina‐born population and their countries of origin. Almost all countries of origin had higher mortality rates from gastric cancer than Argentina, but the risk declines in migrants, and for European migrants becomes similar to that of the Argentina‐born. In contrast, mortality from oesophageal cancer is significantly lower in European countries than in Argentina. For cancer of the colon and breast, most countries have lower mortality rates than the Argentina‐born, the exceptions being Uruguay and Germany, and migrants demonstrate a convergence of risk towards that of Argentina‐born. These results suggest that migrants to Argentina undergo changes in some environmental exposure, probably dietary, which give rise to substantial alterations in cancer risk within their lifespan.
Life‐time history of smoking and exocrine carcinoma of the pancreas: A population‐based case‐control study in the Netherlands
Authors: Bueno de Mesquita H. B. , Maisonneuve P. , Moerman C. J. , Runia S. , Boyle P.
Published: February 2007

From 1984 to 1988 a population‐based case‐control study was carried out in the Netherlands in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between habitual, life‐time consumption of varieties of tobacco and exocrine pancreatic carcinoma in 176 cases and 487 controls. An interviewer‐administered questionnaire was used to list major life events and obtain estimates of usual frequency of tobacco consumption throughout life. About 58% of patients were interviewed directly.

After adjustment for age, gender, response status, energy intake and consumption of vegetables compared with never‐smokers, a positive dose‐response effect of smoking of life‐time number of total cigarettes, i.e. non‐filter and filter, emerged (OR 1.00, 1.35, 1.40 and 2.10, p‐value trend < 0.05). Results of simultaneous estimation of the effects of life‐time smoking of non‐filter and filter cigarettes suggest that the effect was present primarily in non‐filter cigarettes. The dose‐response relationship was present in current smokers only. Compared with never‐smokers, the risk pattern among relatively recent quitters, i.e. 2 to 14 years previously, still suggested a positive effect of past smoking (OR for low smokers 1.99, 95% CI 0.79‐4.99 and for high smokers 1.69, 95% CI 0.63‐4.58). The risk of quitting 15 years or more could be examined in the low smoking group only and was no different from those who had never smoked (OR 1.02,95% CI 0.47‐2.20).

In brief, our results suggest that, independent of usual past intake of energy and vegetables, life‐time smoking of cigarettes influences the development of exocrine pancreatic cancer, whereas cessation of smoking of cigarettes for 15 years or more reduces the risk to the levels found among those who have never smoked.
Positive correlation between parity and incidence of thyroid cancer: New evidence based on complete Norwegian birth cohorts
Authors: Kravdal øystein , Glattre Eystein , Haldorsen Tor
Published: February 2007

We have examined the effect of parity on the incidence of thyroid cancer within a hazard model framework, using individual data on all (1.1 million) Norwegian women born 1935‐1969. This unique data source was established by linking information from the Cancer Registry with maternity histories derived from the Central Population Register of Norway. The relative effects on the total incidence of thyroid cancer, net of age, place residence and birth cohort, are 1.00 for the childless (arbitrarily chosen baseline group), 1.13 for parity I, 1.30 for parity 2, 1.39 for parity 3 and 1.46 for parity 4+. The latter 3 figures are significantly higher than 1.00. The effects are larger for follicular carcinoma, and for this type of thyroid cancer there are also indications of a recent‐pregnancy effect. Among women with 2 or more children, those who became pregnant less than 45 months previously have a higher cancer incidence than others at the same parity. Moreover, we have found that parity has virtually the same effect at all ages, in all birth cohorts and in both parts of the country. Age at first birth as well as the length of the interbirth interval appear to be unrelated to the thyroid‐cancer risk. Our findings are consistent with previous case‐control studies from other countries.
Expression of β1‐integrins, H‐CAM (CD44) and LECAM‐1 in primary gastro‐intestinal B‐cell lymphomas as compared to the adhesion receptor profile of the gut‐associated lymphoid system, tonsil and peripheral lymph node
Authors: Möller Peter , Eichelmann Anette , Mechtersheimer Gunhild , Koretz Karin
Published: February 2007

β1‐Integrins (VLA‐1 to ‐6) are cell‐surface molecules binding to matrix molecules such as collagen, fibronectin and laminin. VLA‐4 is the human homologue to the murine Peyer's patch homing receptor mediating cell/cell adhesion required for lymphocyte extravasation or “homing”. Other structures which have a homing‐receptor function through recognition of venular endothelium are H‐CAM (CD44) and LECAM‐1 (LAM‐ 1, human MEL‐14 equivalent). In order to elucidate whether these adhesion receptors are expressed in primary gastro‐intestinal malignant B‐cell lymphomas (GI BmL) which, in this case, might contribute to the initial confinement to this extranodal site, 31 extensively characterized tumors were examined together with reactive lymphoid tissues from small and large intestine, tonsil and lymph node using monoclonal antibodies (MAbs) against these receptors. All types of adhesion receptors were differentially expressed in the cytologically and microtopographically defined B‐cell subsets [follicular center cells (FC), mantle‐zone cells (MZ), extrafollicular cells (EF) and plasma cells (PC)] of the normal B‐cell system. With the exception of differences in LECAM‐1 levels among EF and PC of intestinal vs. nodal vs. tonsillar sites, receptor profiles were almost identical in different lymphoid organs. The expression pattern of these molecules in GI BmL was markedly heterogeneous, mimicking to some extent the receptor equipment of their reactive cellular counterpart. Thus, we failed to find a unifying adhesion receptor profile indicative of a tissue‐specific homing of reactive and neoplastic B‐cells.
A novel 21‐kDa protein as a serum marker for benign and malignant urogenital tumors: Preliminary communication
Authors: Shalitin C. , Epelbaum R. , Valansi C. , Segal R. , Mekori T. , Lover B. , Robinson E.
Published: February 2007

A novel 21‐kDa protein (p21) was isolated from auto‐immune complexes, found in sera of 14 patients with malignant urogenital tumors and isolated on Protein A‐Sepharose. Isolated complexes were analyzed in 15% polyacrylamide‐SDS minigels. After staining with Coornassie blue R, the bands were scanned with a clinical densitometer. The level of p21 in sera of cancer patients was 3 times higher than that found in normal individuals. An attempt was made to correlate consecutive levels of p21 in the sera of these cancer patients with the clinical course. In 4 cases a significant decrease (57‐75%) in the level of p21 was observed in parallel with response to treatment. In 9 of 10 cases where no response or tumor progression was observed, the relative abundance of p21 increased or remained unchanged. Thus, the level of p21 was indicative of progression or regression of the disease in 13 out of 14 patients. Similar high levels of p21 in sera were also found in 22 patients with benign hyperplasia of prostate. The p21 protein was not immunoreactive with known anti‐ras antibodies such as Y13‐259, 142‐24E05 and anti‐rap1. Partial amino acid analysis of this protein showed no complete homology to any known protein, but a partial homology to known bacterial proteins involved in DNA replication or transcription was observed. Monitoring of the novel p21 levels before and after treatment may be useful in follow‐up of cancer patients, providing evidence of response to treatment.
Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma
Authors: Rosenblatt Karin A. , Thomas David B.
Published: February 2007

The relationship between the strength of the estrogenic and progestational components of combined oral contraceptives and risk of endometrial carcinoma was examined in a multinational hospital‐based case‐control study comparing 220 cases from 7 countries with 1,537 age‐ and hospital‐matched controls. Oral contraceptives were classified according to their relative content of estrogen and progestin. The risk was not altered in women who used preparations containing high‐dose estrogen/low‐dose progestin compounds [odds ratio (OR) = 1.10, 95% CI = 0.13‐9.96]. In contrast, the risk among users of low‐dose estrogen/high‐dose progestin oral contraceptives was greatly decreased (OR = 0,95% CI = 0‐1.08). Risks observed for users of high‐dose estrogen/high‐dose progestin (OR = 0.15, 95% CI = 0.045‐0.50) and low‐dose estrogen/low‐dose progesterone (OR = 0.59,95% CI = 0.26‐1.30) preparations were intermediate between those for users of the 2 other types of preparation. A significantly lower risk was observed for high‐dose progestin users than for low‐dose users [ratio of odds ratios (ROR) = 0.21, 95% CI = 0.05‐0.84]. Although the numbers are small, findings from this study suggest that combined oral contraceptives with varying strengths of estrogen and progestin have different effects on the risk of endometrial carcinoma.
Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver
Authors: Oudejans Joost J. , Slebos Robert J. C. , Zoetmulder Frans A. N. , Mooi Wolter J. , Rodenhuis Sjoerd
Published: February 2007

To study the possible role of ras oncogene activation in the dissemination of colon cancer, we determined point mutations in codons 12, 13 and 61 in K‐ and N‐ras in 3 groups of tumors: (A) primary tumors of patients who had undergone surgery for Dukes' B (early‐stage) colon cancer, (B) primary tumors and metastases from patients undergoing resection of isolated lung metastases and (C) primary tumors and metastases from patients undergoing resection of isolated liver metastases. In 129 samples from 93 patients, 54 (42%) were positive for point mutations in either K‐ or N‐ras. Most mutations (89%) were found in the K‐ras gene. In group A (n = 50) ras point mutations were detected in 16 cases (32%) (15 in K‐ras and 1 in N‐ras). Thirteen out of 23 cases in group B (57%) were positive for a ras point mutation: 10 in K‐ras and 3 in N‐ras. In group C (n = 20), point mutations in codon 12 of K‐ras, but none in H‐ or N‐ras, were found in 10 cases (50%). In 31 cases the primary tumors from the metastases in groups B and C were available for analysis and 15 contained a ras point mutation (48%). Not all mutations were present in both the primary tumor and the metastasis. In 3 instances, a mutation was detected in the metastasis but not in the primary tumor, whereas in 1 case a mutation was found in the primary tumor.
Adult T‐cell leukemia: Structures and expression of the p53 gene
Authors: Sugito S. , Yamato K. , Sameshima Y. , Yokota J. , Yano S. , Miyoshi I.
Published: February 2007

Experiments were undertaken to investigate a genetic event involved in leukemogenesis in adult T‐cell leukemia (ATL). For this purpose, the p53 gene was chosen for study, since alteration of the gene has been found in a wide variety of human cancers. Structures and expression of the p53 gene in ATL cells were investigated by Southern and Northern blot analyses and a polymerase‐chain‐reaction single‐strand conformation‐polymorphism (PCR‐SSCP) analysis. Either subtle alterations of the p53 gene or the absence of detectable level of p53 mRNA were found in 2 of 3 acute ATL cell lines and 2 of 12 acute ATL fresh samples. In contrast, no mutation was detected in 4 cases with less aggressive types of ATL (3 chronic and I smoldering ATL cases). Mutations found in acute ATL cells occurred in regions highly conserved in evolution and all the cells carrying p53 mutation showed loss of the other p53 allele. These results suggests that alteration of the p53 gene may contribute to progression of the disease in some cases of ATL.
Morphometric analysis and identification of infiltrating leucocytes in regressing and progressing shope rabbit papillomas
Authors: Okabayashi Masafumi , Angell Michael G. , Christensen Neil D. , Kreider John W.
Published: February 2007

Spontaneous regressions of papillomavirus lesions frequently occur in both human and animal infections. The mechanism by which this occurs is currently unknown. Mononuclear infiltrates are found in regressing human and rabbit papillomas. To assess the potential functional role of these infiltrates in regression, we have characterized and quantitated the cell types present in regressing rabbit lesions.

Forty New Zealand white rabbits were inoculated with cottontail rabbit papillomavirus (CRPV) at 2 sites on the dorsal skin. All tumors on 6 rabbits markedly decreased in volume within 6 to 8 weeks of inoculation. Tumors on 4 of these 6 regressor rabbits were studied by immunohistochemistry. Regressor papillomas had conspicuous leucocytic infiltrates, most concentrated at the epithelial basement membrane, and often obliterating the basal cells of the germinal layer. Infiltrating leucocytes were also concentrated in the subjacent dermis immediately beneath the basement membrane. The infiltrates gradually lessened at increased depths in the dermis. In contrast, progressor papillomas contained fewer leucocytes, which were randomly distributed in the dermis. The phenotype of the infiltrating leucocytes was examined in 4 regressing and 12 progressing papillomas. In regressing papillomas, infiltrating leucocytes were predominantly T cells (68.0%), with relatively few B cells (7.4%). Progressing papilloma dermis contained fewer T cells and B cells than regressing papillomas. Most of the infiltrating T cells in regressing papillomas were labelled with a rabbit MHC‐class‐II‐specific monoclonal antibody (MAC) (2C4), in contrast to only a small number in progressing papillomas. In addition to the leucocytic infiltrates, keratinocytes in regressing, but not in progressing, papillomas, frequently exhibited strong 2C4 staining. These results demonstrate that infiltration with T cells expressing rabbit class II is characteristic of regressing Shope papillomas and strengthens the assertion that cell‐mediated immunity is the mechanism of Shope papilloma regression.
Integrin expression in human melanoma cell lines: Heterogeneity of vitronectin receptor composition and function
Authors: Marshall John F. , Nesbitt Stephen A. , Helfrich Miep H. , Horton Michael A. , Polakova Katarina , Hart Ian R.
Published: February 2007

Ten human melanoma cell lines were examined for integrin‐receptor expression using a panel of antibodies directed against different integrin subunits. Considerable heterogeneity was detected for levels of expression of 7 integrins, including the αvβ3 vitronectin receptor where a correlation between tumorigenic capacity in athymic nude mice and αvβ3 levels was found. Detailed analysis of the vitronectin receptor on these lines revealed heterogeneity of composition. In one cell line, VUP, an αvβ1 association was detected and, by antibody‐inhibition studies, this receptor was shown to bind vitronectin as its ligand. In another line, DX3, evidence was obtained which indicated that apart from the qfi, receptor the αv was able to associate with another β subunit which was not β3. The existence of these alternative forms of the vitronectin receptor in this small sample of tumours of common origin might explain why the capacity to bind to fibrinogen and vitronectin substrates by these cells did not necessarily correlate with αvβ3 levels.
Estradiol and EGF requirements for cell‐cycle progression of normal human mammary epithelial cells in culture
Authors: Colomb Evelyne , Berthon Philippe , Dussert Christophe , Calvo Fabien , Martin Pierre‐Marie
Published: February 2007

The purpose of our study was to show the feasibility of accurately investigating the factors likely to control cell proliferation of normal human mammary epithelial (HME) cells, using a scanning cytometric method. The methodology was previously developed with the SAMBA 200 cell image processor to characterize in situ the cell‐cycle phases of HME cells. Since various compartments constitute the mammary epithelium, cells obtained after reduction mammoplasty were cultured in a medium with a low calcium content (0.06 mM) to provide proliferating normal HME cells while maintaining their differentiation characteristics. Estradiol and EGF requirements for cell‐cycle phase progression of these cells were examined. Then, we showed that 2 normal HME cell cultures displaying different phenotypic characteristics may differently progress through the cell cycle under the same hormonally defined conditions. Cell‐cycle progression of the epithelial cells presenting luminal phenotype was induced only by sequential stimulation/pre‐treatment with estradiol followed by EGF treatment; this progression was enhanced when estradiol was maintained during EGF treatment. This definite order demonstrated that estradiol could have a permissive effect on EGF mitogenic activity. In contrast, epithelial cells likely to be localized in the basal position in the mammary gland showed the same proliferating activity whatever the estradiol and EGF treatment. These cells progressed profusely in cell cycle, independent of exogenous estradiol and EGF contribution, but they remained sensitive to estradiol regarding EGF‐receptor detection. Our results suggest autonomous proliferation of these cells through an autocrine pathway, in the absence of negative regulators.
Dipeptidyl peptidase iv expression identifies a functional sub‐population of breast fibroblasts
Authors: Atherton Amanda J. , Monaghan Paul , Warburton Michael J. , Robertson David , Kenny A. John , Gusterson Barry A.
Published: February 2007

The immunocytochemical distribution of the cell‐surface enzyme dipeptidyl peptidase IV (DPP IV) has been studied in the human breast at the light and ultrastructural level. The presence of the enzyme was demonstrated on the cell membranes of interlobular fibroblasts, whilst intralobular fibroblasts were DPP‐IV‐negative. A fluorograph, after immunoprecipitation of 35S‐methionine‐labelled proteins of fibroblasts from primary breast cultures with an anti‐serum to DPP IV, demonstrated a band at 135 kDa consistent with the presence of the enzyme. The clear delineation of 2 functionally distinct sub‐populations of breast fibroblasts was maintained in benign fibro‐adenomas and cystosarcoma phyllodes, both tumour types having growth characteristics of intralobular stroma. This observation has important implications for both normal breast biology and for breast carcinogenesis.
Oesophageal mucosa in a population at risk of oesophageal cancer: Post‐mortem studies
Authors: Jaskiewicz Kaz , Banach Lech , Mafungo Victor , Knobel Gideon J.
Published: February 2007

We performed post‐mortem studies of oesophageal mucosa from 513 consecutive autopsies of cases who died from unnatural causes or from diseases not related to the oesophagus. Of these, 170 cases were rural blacks from endemic high‐risk areas, 98 were urban blacks at high risk, 158 were coloureds at moderate risk and 87 whites at low risk for oesophageal carcinoma. Oesophagi were studied macroscopically and histologically to determine malignant and precursor lesions. A prevalence of 1.0 to 1.8% of squamous carcinoma and 7 to 7.5% of mucosal dysplasia was detected in cases older than 30 years from high‐risk urban and rural population groups. These results are in accord with our previous cytological and endoscopical screening studies. No significant differences in the prevalence of oesophagitis, glycogenic acanthosis and atrophy were found in the groups studied. A study of oesophageal melanocytes showed a 3% prevalence, unrelated to dysplastic and malignant lesions, and suggested that these cells were of little if any practical significance as precursor lesions.
Intramural metastasis of thoracic esophageal carcinoma
Authors: Kato Hoichi , Tachimori Yuji , Watanabe Hiroshi , Itabashi Masayuki , Hirota Teruyuki , Yamaguchi Hajime , Ishikawa Tsutomu
Published: February 2007

Of 393 patients with squamous‐cell carcinoma in the thoracic esophagus, 60 were found by histologic examination to have intramural metastasis. Metastases in 50 of these were identified by gross inspection. There appeared to be no preference for location proximal to the primary lesion. Eighteen patients had metastasis to the gastric wall, which suggested the existence of communicating lymphatic channels between the wall of the esophagus and the stomach. All 60 primary tumors invaded beyond the submucosa. These 60 patients (group A) were compared with a group of matched control patients without intramural metastasis (group B). The tumor size in group A was significantly larger than in group B (p< 0.01). The number of patients with lymph‐node metastasis was significantly higher in group A (p< 0.01), and the average number of positive nodes in group A was greater than in group B (p< 0.01). Recurrent disease in the mediastinal lymph nodes and in the liver is characteristic of group A. The survival curve for patients in group A was significantly lower than that for group B (p< 0.001). Conventional radiotherapy or chemotherapy after surgery were ineffective in improving prognosis. These results indicate that the presence of intramural metastasis is an important factor to consider when evaluating the prognosis of patients with squamous‐cell carcinoma of the esophagus.
Effects of interferons on the expression of the proto‐oncogene her‐2 in human ovarian carcinoma cells
Authors: Marth Christian , Cronauer Marcus V. , Doppler Wolfgang , Öfner Dietmar , Ullrich Axel , Daxenbichler Günter
Published: February 2007

The over‐expression of the proto‐oncogene HER‐2 (c‐erb B‐2/ neu) in ovarian, endometrial and mammary carcinoma is an important indicator for poor prognosis. We have previously shown in 3 out of 4 ovarian carcinoma cell lines an interferon‐gamma (IFN‐γ)‐mediated reduction in HER‐2 specific protein and RNA levels. The oncogene expression was lowered only in the ovarian carcinoma cell lines but not in 3 IFN‐γ‐sensitive human breast cancer cell lines. We extended our observations also to IFN type I, α and ω. The expression of the oncogene was measured by both the p185HER‐2 ELISA and in selected cases by a living cell radioimmunoassay using the monoclonal antibody (MAb) 4D5 against the extracellular domain. Both IFN types reduced the expression of HER‐2 in the ovarian carcinoma cell lines OVCAR‐3, HTB‐77, 2774 and SKOV‐6, and in the SKUT‐2 endometrial carcinoma cells. In contrast, SKOV‐8 human ovarian carcinoma cells were sensitive for both IFN types regarding proliferation, but only IFN‐γ reduced proto‐oncogene expression. In the SKBR‐3 human mammary carcinoma cells, neither IFN type had an effect on HER‐2 expression. The antibodies 4D5, 7C2, 3E8, and 3H4 which bind to the extracellular domain of p185HER‐2 protein specifically inhibited anchorage‐independent growth of SKBR‐3 and HTB‐77 cells. Expression of the oncogene HER‐2 is the leading prognostic factor in ovarian cancer. Its modulation might represent a mechanism by which IFNs inhibit cell proliferation.