bluuebunny/crossref_metadata_2025 huggingface dataset:
Intake of foods and nutrients and cancer of the exocrine pancreas: A population‐based case‐control study in the Netherlands
Authors: De Mesquita H. B. Bueno , Maisonneuve P. , Runia S. , Moerman C. J.
Published: February 2007

During 1984–88 a population‐based case‐control study was carried out in the Netherlands In collaboration with the International Agency for Research on Cancer in order to investigate the role of diet in exocrine pancreatic carcinoma. A semi‐quantitative food‐frequency questionnaire was used to comprehensively assess usual diet about I year prior to diagnosis of 164 cases or interview of 480 controls. More than half of the cases were directly interviewed. After controlling for age, gender, response status, life‐time cigarette consumption and dietary intake of total energy, monotonic, significantly inverse dose‐response effects with estimates of daily consumption of vegetables were found. The significant inverse effect of total cooked vegetables was primarily concentrated in cruciferous vegetables. Consumption of fresh vegetables was also significantly and inversely related to risk. A monotonic, positive dose‐response gradient was seen for the consumption of eggs, while consumption of fish was significantly related to risk as well. Among direct respondents, significantly inverse relationships were found for the consumption of legumes, tomatoes, cheese and fermented milk products. Inverse associations with consumption of (subgroups of) fruits were observed in women only. The monotonic, significantly inverse relationship for consumption of low‐fibre vegetables and the somewhat weaker, inverse association for high‐fibre vegetables in directly interviewed subjects only, may point to protective agents other than vegetable fibre. Although intake of dietary fibre and beta‐carotene were both inversely related to risk, simultaneous estimation suggested that beta‐carotene or other as yet unknown correlated constituents, rather than dietary fibre, might explain the inverse relationships. A significant protective effect of vitamin C was demonstrated in women but not in men. Our study suggests that, independent of smoking and dietary intake of total energy, low consumption of specific vegetables and possibly fermented milk products and high consumption of eggs and fish may have influenced the development of exocrine pancreatic cancer.
Constitutive expression and secretion of proteases in non‐metastatic SP1 mammary carcinoma cells and its metastatic sublines
Authors: Korczak Bozena , Kerbel Robert S. , Dennis James
Published: February 2007

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over‐expressed in a simultaneous or co‐ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady‐state levels of mRNA coding for uroklnase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue‐specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non‐metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15‐ to 20‐fold, while TIMP transcripts were decreased 3‐fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5–3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
Effect of macrophages on interleukin‐2 (IL‐2)‐ and IL‐4‐induced murine lymphokine‐activated killer activity
Authors: Tunru Insan S. , Suzuki Hidehiko , Yano Saburo
Published: February 2007

The enhancing effect of macrophages on interleukin‐2 (IL‐2)‐ and IL‐4‐induced murine lymphokine‐activated killer (LAK) activity was investigated in this study. Peritoneal macrophages significantly enhanced LAK activity generated from accessory cell‐depleted splenic lymphocytes in both IL‐2 and IL‐4 cultures. This effect was dependent on the number of macrophages and was not replaced by a factor derived from macrophages or lymphocytes. Macrophages enhanced IL‐2‐ and IL‐4‐induced LAK activity against both natural killer (NK)‐sensltive (YAC‐1, P388D1) and NK‐resistant (P815) tumor cells. Negative selection or cells with antibodies and complement showed no differences in surface markers between IL‐2 LAK effectors and IL‐4 LAK effectors generated in the presence of macrophages. These results suggest that the same LAK effector subsets can be enhanced by macrophages In either IL‐2 or IL‐4 cultures.
Suppression of the translocated myc gene and expression of intracisternal A‐particle genes in tumorigenic and non‐tumorigenic hybrids between murine myeloma and normal fibroblasts
Authors: Laskov Reuven , Sharir Hava , Tzieger‐Dickbuch Sara , Hijazzi Mohammad , Greenberg Aviva , Ber Rosalie
Published: February 2007

We have studied the tumorigenlc potential of a series of Independent intraspecies hybrid clones derived from fusion of murine myeloma (BALB/c) and normal fibroblasts (C3H). All of these hybrids grew as adherent cells and thus resembled the fibroblast phenotype. As judged by chromosome enumeration, these hybrids appear to retain the full complement of their parental cells. Three out of 4 hybrids tested were able to form colonies in soft agar and to grow as tumors in either nude or (BALB/c ± C3H) F1 mice, albeit at a reduced rate. The 4th hybrid did not grow in agar, was non‐tumorigenic and may have had a 2:1 fibroblast to myeloma genomic equivalence ratio. In contrast to the parental myeloma cells, all the hybrids exhibited restricted growth rates in serum‐free medium. As in our previous sets of hybrids formed between myeloma and L‐cells, expression of the Ig genes was inhibited in the new hybrids and the derived tumors. The constitutive expression of the translocated myc gene in the myeloma parental cells was decreased in the hybrids and in all their derived tumors. In contrast, all of the hybrid cell lines and the tumors express high levels of the intracisternal A particle mRNAs. Our results show that the tumorigenic phenotype of myeloma cells is either fully or partially suppressed in myeloma ± fibroblast hybrids and that this may be due to the fact that expression of the translocated c‐myc is suppressed. We suggest that, in addition to the translocated myc gene, myeloma cells contain other activated oncogene(s), and that the latter are responsible for the residual tumorigenic potential of the myeloma × fibroblast hybrids.
Pharmacokinetics and intracellular distribution of the tumor‐targeted radiopharmaceutical m‐iodo‐benzylguanidine in SK‐N‐SH neuroblastoma and PC‐12 pheochromocytoma cells
Authors: Smets Lou A. , Janssen Manon , Rutgers Marja , Ritzen Karin , Buitenhuis Corine
Published: February 2007

Radioiodinated meta‐iodobenzylguanidine (MIBG) is increasingly used for the diagnosis and targeted radiotherapy of neuro‐adrenergic tumors. We have investigated various conditions for specific tumor loading and prolonged retention of this radiopharmaceutical in poorly differentiated SK‐N‐SH neuroblastoma and highly differentiated PC‐12 pheochromocytoma cells. At a constant value of drug concentration × incubation time, short incubations were superior to protracted incubations for maximal cell loading. This effect was most pronounced in the SH‐N‐SH neuroblastoma cells. In highly differentiated pheochromocytoma cells, the levels of MIBG storage remained high and unchanged during incubations up to 46 hr in label‐free medium, while primitive SK‐N‐SH cells lost 40–50% of accumulated drug by diffusion. In PC‐12 cells, susceptibility of stored MIBG to exocytotic release induced by acetylcholine or K+ was similar to that of natural norepinephrine (NE) and prevented by the Ca++ ‐channel blockers verapamil and nifedipine. Conversely, granule‐poor SK‐N‐SH cells were insensitive to exocytotic release of MIBG. Uptake and retention capacities were minimally impaired by an externally delivered radiation dose of 5 Gy to mimic the radiobiologicaf effect of 131I‐MIBG in tumors. In pre‐irradiated cultures, drug uptake was even stimulated, probably due to enrichment in non‐proliferating cells. An autoradiographic comparison of the (sub)cellular distributions of 3H‐noreplnephrine and 125I‐MIBG showed that routine conditions of cell fixation and sample processing do not yield reliable results regarding localization of MIBG.
Pigmentary and cutaneous risk factors for non‐melanocytic skin cancer—A case‐control study
Authors: Kricker Anne , Armstrong Bruce K. , English Dallas R. , Heenan Peter J.
Published: February 2007

The roles of ethnic origin, pigmentray traits, sun sensitivity and other cutaneous characteristics as risk factors for basal‐cell carcinoma (BCC) and squamous‐cell carcinoma (SCC) were examnied in a case‐control study of prevalent and incident cases of histopathologically confirmed skin cancers. Two hundred and twenty six confirmed cases of BCC, 45 of SCC and 1,015 controls with no lesions were identified in a population‐based survey of skin cancer in 1987 in Geralditon, Western Australia. The risk of both cancers was higher in nativeborn Australians than in migrants. The risk of BCC decreased with increasing age at arrival in Australia. Southern European ancestry was strongly protective against BCC (for any southern European grandparents) and SCC (no case of SCC had any granparetns of southern European origin). Inability to tan was the strongest pigmentary risk factor for both BCC and SCC. Among Factors that incorporated a measure of sun exposure as well as sun sensitivity, freckling on the arm in childhood was important for both cancers, the number of moles on the back was important for BCC, and forearm skin colour and having a permanent colour difference between the neck and adjacent protected areas were important for SCC. Among measures of sun damage to the skin, solar elastosis of the neck was a strong risk factor for both BCC and SCC, loss of fine texture of the sink of the back of the hands (as measured by cutaneous microtopography) was important for BCC and telangiectasia of the face for SCC. When all important variables for each cancer were examined together in a single model with age, sex, migrant status or age at arrival in Australia, and ethnicity, inability to tan, solar elastosis of the neck, and the number of moles on the back were independently significant risk factors for BCC and solar elatosis of the neck and having a permanent colour difference between the neck and adjacent protected areas were independently sifnificant risk factors for SCC. The effects of age at arrival or migrant status and ethnic origin remeained important on the models incorporating these factors. A history of ever having acne and a history of warts were protective for BCC and a history of acne was protective for SCC.
Prognostic significance of nuclear DNA content in human neuroepithelial tumors
Authors: Danova M. , Giaretti W. , Merlo F. , Mazzini G. , Gaetani P. , Geido E. , Gentile S. , Utti G. B. , di Vinci A. , Riccardi A.
Published: February 2007

The relationship between survival and flow cytometric DNA‐ploidy and other prognostic factors such as histological subtype, anatomical tumor site, patient sex and age was investigated in 153 patients with intracranial neuroepithelial tumors who underwent surgical treatment. We found a trend toward poorer survival from anaplastic astrocytomas and glioblastomas with respect to low‐grade (I and II) astrocytomas (which did not differ significantly); accordingly, patients were grouped into these 3 histologic subgroups. Thirty‐seven of the 153 tumors (24.2%) were aneuploid with a median DNA‐index (DI) of 1.3 (range: 1.2–2.0). DNA‐ploidy correlated with histology, since anaplastic astrocytomas and glioblastomas were significantly (p = 0.041) more frequently aneuploid (around 30%) than low‐grade astrocytomas (around 10%). Patients with DNA‐aneuploid tumors (i.e., with DI # 1.00) survived for a shorter time (31.4 weeks) than patients with DNA diploid tumors (75.1 weeks) (p< 0.001). This difference was confirmed by Cox's multivariate analysis. Aneuploid tumors were associated with a poorer survival (p = .0002) when compared with diploid tumors, resulting in a relative risk point estimate (RR) of 2.41, 95% confidence interval (CI) = 1.55–3.74. Histological subtype was also significantly associated with survival (p< 0.0001), with RRs of 2.09, 95% CI = 1.13–3.86 and 3.59, 95% Cl = 1.96–4.59 for anaplastic astrocytomas and glioblastomas, respectively, compared to low‐grade astrocytomas. We therefore suggest that the flow cytometric measurement of DNA‐ploidy has relevant significance in predicting survival in patients treated for intracranial neuroepithelial tumors.
Differential expression of thymosin genes in human tumors and in the developing human kidney
Authors: Hall Alan K.
Published: February 2007

Thymosins β4 and β10 are 2 structurally related polypeptides originally defined in the rat immune system. To date, no truly unambiguous functions have been formally ascribed to these small (<4.9 kDa) acidic proteins. Previous research has demonstrated relationships between expression of these genes and cell growth/differentiation. These observations prompted the present study which has used cDNA and synthetic oligonucleotide probes in combination with high‐performance liquid chromatography (HPLC) to examine the differential expression of these 2 genes in normal and neoplastic human tissues and in the developing human kidney. Low levels of β4 and β10 mRNA species prevailed in normal tissues; in contrast, these gene transcripts were notably more abundant in malignant renal tumors and in the normal human embryonic kidney. These findings show that the thymosin β4 and β10 genes are constitutively expressed at higher levels in embryonic/neoplastic as compared to normal/benign tissues and that thymosin in β10 in particular may be a new molecular marker for renal‐cell carcinoma as well as other malignancies.
Occurrence of antibodies TO L1, L2, E4 and E7 gene products of human papillomavirus types 6b, 16 and 18 among cervical cancer patients and controls
Authors: Köchel Heinrich G. , Monazahian Masyar , Sievert Kai , Höhne Michaela , Thomssen Christoph , Teichmann Alexander , Arendt Peter , Thomssen Reiner
Published: February 2007

Sera from 118 women of 33 to over 90 years of age, with or without a history of cervical squamous‐cell carcinoma, were examined for the presence of antibodies to HPV‐6b, HPV‐16 and HPV‐18 L1, L2, E4, and E7 gene products by the use of bacterially derived β‐Gal fusion proteins and Western‐blot analysis. Among the cervical cancer patients, 29/46 (63.0%) were positive for antibodies to E4 and/or E7 of HPV‐16 and/or E7 of HPV‐18. In contrast, only 2 of 31 (6.5%) non‐genital cancer patients and 4 of 41 (9.8%) healthy individuals were antibody‐positive for HPV‐16 E4 or E7, while antibodies to the homologous proteins of HPV‐18 could not be detected. Prevalence rates of antibodies to the HPV‐16/18 late proteins were 25/46 (54.3%) in the cervical carcinoma group, 13/31 (41.9%) among women with non‐genital cancer types, and 18/41 (43.9%) among normal, healthy individuals. Antibodies to HPV‐6b late gene products ranged between 6.5% and 12.2% in the different patient groups. Antibodies to HPV‐6b E4 and E7 were detected only once. By studying an additional control group of 207 women with a different age distribution, age‐dependence of antibodies to HPV gene products could be ruled out. Whereas antibodies to late proteins may indicate that, regardless of clinical stage, HPV infections are widespread among the female population, the striking difference between the prevalence rates of antibodies to early proteins of HPV‐16 and HPV‐18 among cervical cancer patients and controls (p < 0.001) supports the idea of the involvement of these virus types in carcinogenesis of the cervix.
Expression of cholecystokinin forms by medullary thyroid cancer
Authors: Poston G. J. , Draviam E. J. , Seitz Patricia K. , Rajaraman S. , Alexander R. W. , Cooper C. W. , Townsend C. M. , Thompson J. C.
Published: February 2007

We have studied the production and release of cholecystoklnin (CCK) forms by rat medullary thyroid cancer (MTC) in vivo. MTC cells were inoculated s.c. into 8 Wag‐Rij rats. One month later, after i.v. injection of calcium plasma levels of CCK, calcitonin and tissue contents of gastrln and calcitonin were determined by radioimmunoassay (RIA), immunocyto‐chemistry, and high‐pressure liquid chromatography (HPLC). The tumors were passed 4 times to 8 rats in 1‐month intervals fasting levels of CCK in control rats were unaffected by calcium stimulation, and in tumor‐bearing rats, plasma CCK was elevated in 3 out of 4 passages, falling to normal levels at the end of passage 4. Hypercalcemia had no effect on plasma levels of CCK in tumor‐bearing rats, but did stimulate the release of calcitonin in both control and some tumor‐bearing rats in later passages. CCK‐8 sulfate was found in all 4 tumor passages but not CCK‐33/39. We conclude that rat MTC synthesizes and releases CCK‐8, but unlike calcitonin, release of CCK appears unresponsive to calcium stimulation.
Growth inhibition of two solid tumors in mice, caused by polyamine depletion, is not attended by alterations in cell‐cycle phase distribution
Authors: Hessels J. , Kingma A. W. , Muskiet F. A. J. , Sarhan S. , Seiler N.
Published: February 2007

We studied the effect of polyamine depletion on growth and cell cycle characteristics of subcutaneously grown Lewis lung carcinoma (LLC) and fibrosarcoma (FIO 26) in mice. Polyamine depletion was achieved by inhibition of ornithine decarboxylase using 2‐(difluoromethyl)ornithine, limitation of exogenous polyamines by administration of a polyamine‐poor diet and decontamination of the gastrointestinal tract, and inhibition of endogenous polyamine reutilization by N, N'‐bis‐(2,3‐butadienyl)putrescine (MDL 72527). Determination of S‐phase cells was performed in tumor‐cell suspensions by flow cytometry and in tumor tissue sections by microscopy, following In vivo labelling with 5‐bromo‐2′‐deoxyuridine (BUdR). DNA synthesis rate was estimated from the Incorporation of in vivo‐injected [3H]‐thymidine (3H‐TdR). Both solid tumors almost completely stopped growing after access to polyamines was blocked. Growth inhibition was, however, not attended by changes in cell‐cycle‐phase distribution. Paradoxically, we measured increased in vivo 3H‐TdR incorporation rates and unaltered BUdR‐linked staining intensity in treated tumors. Injection of putrescine into treated LLC‐bearing mice resulted in an increase in intracellular putrescine and spermidine concentrations, a slight increase in the number of S‐phase cells and a marked drop in DNA synthesis rate within the following 9 hr.
HLA‐class‐I and‐class‐II expression on renal tumor xenografts and the relation to sensitivity for α‐IFN, γ‐IFN and TNF
Authors: Beniers A. J. M. C. , Peelen W. P. , Debruyne F. M. J. , Schalken J. A.
Published: February 2007

In this study we evaluated the usefulness of the histocom‐patibility leucocyte antigen (HLA) class‐I and class‐II expression on renal‐cell carcinoma (RCC) xenografts as predictive markers for response to cytokine therapy. Eight different RCC xenografts growing in BALBC nu/nu mice were treated with 0.5 or 5.0 ng/g recombinant human at‐or γ‐interferon (If N), or 500 ng/g recombinant human tumor necrosis factor (TNF). Modulation of HLA class‐I,‐II expression was evaluated immunohistochemically using the monoclonal antibodies (MAbs) W6.32 and B8.11.2 and at the mRNA level using the plasmids pDP001 and DR alpha 120. HLA class‐I expression in all lines was upregulated by α‐and γ‐IFN and was highest in the high‐IFN‐dose‐treated tumors. TNF also stimulated HLA‐class‐I expression and up‐regulated class‐I expression still further when combined with IFN. Highest up‐regulation of HLA‐class‐I in all tumors was measured in the alpha‐IFN‐5.0/TNF‐500‐ng/g‐treated mice, although this was not necessarily the treatment regimen resulting In the most pronounced effect on tumor growth. Hence, maximum up‐regulation of class‐I antigens at a given regimen was not always indicative for the highest achievable anti‐tumor effect. HLA‐class‐II expression which was present on only 3 of the untreated tumors was up‐regulated by both a and γ‐IFN. TNF itself did not up‐regulate class‐II expression but enhanced the class‐II expression on the α‐IFN‐treated tumors but not on the γ‐IFN‐treated tumors. Irrespective of the basic expression level, inducibility of both HLA‐class‐I and‐class‐II antigens appear to be correlated to the direct effects on growth of renal‐tumor xenografts towards α‐IFN, γ‐IFN and TNF. Modulation of HLA antigens was studied in the nude mouse, hence T‐cell‐mediated effector mechanisms cannot explain the good correlation between inducibility and response. Nonetheless, our studies indicate that the extent of modulation of HLA‐class‐I and‐II can serve as predictive marker for response to cytokine therapy, which may serve as a valuable criterion for inclusion of patients in cytokine treatment regimens.
Characterization of a cathepsin‐H‐like enzyme from a human melanoma cell line
Authors: Tsushima Hirofumi , Ueki Ayako , Matsuoka Yasuo , Mihara Hisashi , Hopsu‐Havu Väinö K.
Published: February 2007

A cathepsin‐H‐like enzyme has been isolated from cultured human melanoma cells (G 361 cell line). The enzyme is similar to cathepsin H(s) of normal tissues in molecular weight, enzymatic characteristics (substrates, inhibitors, pH optima, Km values), and immunoreactivity. The inactive form of the enzyme with a molecular mass of 40 kDa has been found in the culture medium. The inactive enzyme is activated by acid pH, pepsin, and cathepsin‐D‐like enzyme treatments and converted into a form with a molecular mass of 28 kDa. The activated extracellular cathepsin‐H‐like enzyme and the active intracellular enzyme exhibit the same characteristics. The melanoma‐derived cathepsin‐H‐like enzyme degrade fibrinogen and fibronectin, but not laminin or type‐IV collagen. We conclude that the extracellular cathepsin‐H‐like enzyme may have important functions, together with other proteinases, in the destruction of extracellular matrix components, thus enabling proliferation, migration, and metastasis to occur.
Results and conclusions of the national toxicology program's rodent carcinogenicity studies with sodium fluoride
Authors: Bucher John R. , Hejtmancik Milton R. , Toft John D. , Persing Ronald L. , Eustis Scot L. , Haseman Joseph K.
Published: February 2007

The US National Toxicology Program (NTP) has conducted toxicity and carcinogenicity studies with sodium fluoride administered in the drinking water to F344/N rats and B6C3F1 mice. The drinking water concentrations used in the 2‐year studies were 0, 25, 100, or 175 ppm sodium fluoride (equivalent to 0, 11, 45 or 79 ppm fluoride). Survival and weight gains of rats and mice were not affected by fluoride treatment. Animals receiving sodium fluoride developed effects typical of dental fluorosis, and female rats given 175 ppm had increased osteosclerosis. There were no Increases in neoplasms in female rats or in male or female mice that were attributed to sodium fluoride administration. There was equivocal evidence of carcinogenic activity of sodium fluoride in male rats based on the occurrence of a small number of osteosarcomas in treated animals.
Protein kinase C activity as marker for colorectal cancer
Authors: Sakanoue Youichirou , Hatada Takuya , Kusunoki Masato , Yanagi Hidenori , Yamamura Takehira , Utsunomiya Joji
Published: February 2007

Protein kinase C (PKC) activity was measured in normal‐appearing colonic mucosa from patients undergoing colonic resection. Comparisons were made between cases with and without colorectal cancers. PKC activity in cytosolic and particulate fractions was significantly reduced in patients with colorectal cancer: 40 ± 9 and 114 ± 29 (pmol/min/mg) respectively, compared with patients without cancer; 129 ± 11 and 250 ± 38 (pmol/min/mg) (p < 0.05). Normal‐appearing colonic mucosa in patients with cancer showed significantly decreased total PKC activities in the cytosolic and particulate fractions compared with those In patients without cancer (10 ± I and 20 ± 3 vs. 30 ± 2 and 33 ± 6) (pmol/min/g tissue) (p < 0.05). The cellular distribution (% particulate fraction) of PKC activity in normal‐appearing mucosa in patients with cancer (64%) was higher than in patients without cancer (49%) (p < 0.05). Our data suggest that PKC activity may be used as a biological marker of risk of developing colorectal cancer or risk of bearing an asymptomatic tumor.
Spontaneous and induced abortions and risk of breast cancer
Authors: Parazzini Fabio , Negri Eva , La Vecchia Carlo
Published: February 2007

The relationship between spontaneous or induced abortion and the risk of breast cancer was analyzed in a case‐control study conducted in the greater Milan area on 2,394 cases of breast cancer and 2,218 controls in hospital for a spectrum of acute conditions, not gynecological, hormonal or neoplastic. No consistent relationship emerged between spontaneous or induced abortion and breast cancer: compared with women reporting no abortions (spontaneous or induced), the multivariate relative risk (RR) was 1.0 (95% confidence interval, Cl, 0.9 to 1.2) in those reporting one abortion and 0.9 (95% Cl 0.7 to 1.0) in those reporting two or more. This lack of association was consistent in strata of age and parity, including younger women. We further analyzed the risk of breast cancer associated with an abortion before and after full‐term pregnancy. Compared with parous women reporting no induced or spontaneous abortions, those who had an abortion before their first full‐term pregnancy had about a 20% higher risk of breast cancer. This finding, however, was not statistically significant (RR 1.2, 95% Cl 0.9 to 1.7). No increased risk was observed in women who had had a first abortion after a full‐term pregnancy (RR 0.9, 95% Cl 0.8 to 1.0). This study does not support the hypothesis that spontaneous or induced abortion appreciably Influences subsequent breast‐cancer risk.
Monoclonal antibodies against Galα 1 −4Galß 1 −4Glc(Pk, CD77) produced with a synthetic glycoconjugate as immunogen: Reactivity with carbohydrates, with fresh frozen human tissues and hematopoietic tumors
Authors: Oosterwlik Egbert , Kalisiak Angela , Wakka Jeannette C. , Scheinberg David A. , Old Lloyd J.
Published: February 2007

The purpose of this study was to isolate mouse monoclonal antibodies (MAbs) recognizing Galα I ‐4Galβ I −4Glc (Pk. CD77), which has been described as a Burkitt's‐lym homa‐associated using a synthetic glycoconjugate as immunogen and a filter immunoplaque screening assay. One MAb (PK67) was characterized by immuno‐thin‐layer chromatography, ELISA and competition assays using neutral glycolipids from various sources and a variety of carbohydrates and glycoproteins. Epitope analysis showed that all 3 carbohydrate moieties are required in PK67 binding. No cross‐reactivity was observed with closely related carbohydrate structures, with the exception of Galα I ‐4Ga1β I ‐4GlcNAc. However, the reactivity with this structure was several orders of magnitude lower than with Pk. lmmunohistochemical analysis of fresh‐frozen tissue specimens showed that Gb3, is widely expressed: prominent staining was observed in many normal tissues, e.g., kidney and gastric tissue and on capillary endothelial cells. In lymph nodes, very weak staining of a few B cells was observed. Flow cytometric analysis of hematopoietic neoplasms showed Gb, expression on B‐cell neoplasms, particularly those with committed 8‐cell phenotype indicating that, in addition to earlier reports of Gb3, expression on Burkitt's lymphoma, Gb3, is present on other committed B‐cell neoplasms.
Relationships between epithelial basement membrane staining patterns in primary colorectal carcinomas and the extent of tumour spread
Authors: Hewitt Robert E. , Powe Desmond G. , Griffin Nicholas R. , Turner David R.
Published: February 2007

In colorectal cancer an association has been found between lack of epithelial basement membrane (EBM) immunostaining in the tumour centre and more extensive malignant spread. Interestingly, ultrastructural investigations suggest that EBM loss at the tumour periphery may be part of an invasive mechanism. To further assess the significance of EBM deficiencies in different tumour areas, we carried out a detailed study of the basement membrane laminin immunostaining patterns in 130 cases of colorectal carcinoma. We find that discontinuous EBM staining in the tumour centre is associated with poor tumour differentiation (p < 0.005). presence of lymph‐node metastases (p < 0.02), and more advanced Dukes stage (p < 0.02). The latter association is strengthened by excluding cases in which numerous polymorphonuclear leukocytes (PMNs) are present adjacent to EBM breaks, suggesting that these inflammatory cells are a confounding factor. Discontinuous EBM staining is more frequently observed in tumour deep to muscularis propria than in submucosal tumour (p < 0.02). indicating intra‐tumoral variation. At the tumour periphery, extensive EBM discontinuity shows no association with lymph‐node involvement, but is linked with deeper local invasion (p < 0.05). While EBM staining patterns around central and peripheral tumour glands are related (p < 0.001). staining around peripheral glands is almost invariably more discontinuous. However, EBM lack at the tumour periphery is not as absolute as previously suggested, since in 18% of tumours fewer than 25% of peripheral tumour glands show EBM breaks. This appears consistent with the hypothesis that invasive changes at the tumour periphery are temporary and reversible.
Glutathione and cellular response of ACNU‐resistant rat glioma sublines to drugs and radiation
Authors: Saito Yuji , Hotta Takuhiro , Mikami Takasi , Kurisu Kaoru , Yamada Kenji , Kiya Katuzou , Kawamoto Keiichi , Uozumi Tohru , Nakada Yosihiro
Published: February 2007

Three ACNU‐resistant sublines (R1, R3 and R12) from rat glioma 9L cells showed cross‐resistance to vinblastine, adriamycin, and VP‐16. Among these, the R3 subline also acquired radioresistance under aerobic conditions. Total glutathione levels In these sublines were elevated 2‐to 3‐fold. Treatment of the cells with BSO, a specific inhibitor of GSH synthesis, resulted in decreased intracellular total glutathione levels in all 4 cell lines to about 10% of control levels. However, sensitivity to radiation or to chemicals did not change accordingly. Treatment of 9L cells with OTZ, a precursor of cystelne, resulted in a rise in intracellular GSH levels but it did not correlate with sensitivity to X‐ray or to ACNU. These results suggest that, in terms of cellular sensitivity to radiation or ACNU, total glutathione level alone cannot serve as a predictive indicator.
Effect of N1,N14‐bis‐(ethyl)‐homospermine (BE‐4–4‐4) on the growth of U‐251 MG and SF‐188 human brain tumor cells
Authors: Basu Hirak S. , Pellarin Malgorzata , Feuerstein Burt G. , Deen Dennis F. , Marton Laurence J.
Published: February 2007

We studied the effects of the spermine analogue N,N14‐bis‐(ethyl)‐homospermine (BE‐4–4‐4) on growth, survival and polyamine levels in cultured U‐251 MG and SF‐188 human brain tumor cells. After 48 hr of treatment at concentrations of 1 μM or higher, BE‐4–4‐4 accumulated in cells with a concomitant decrease in intracellular putrescine, spermldine and spermine concentrations. Growth inhibition by 10 μM BE‐4–4‐4 began at 6 hr and peaked between 16 and 24 hr. The analogue was also increasingly cytotoxic with doses between 1 and 10 μM and with treatment times between 16 and 48 hr. Polyamines added 1 day after BE‐4–4‐4 lowered the intracellular concentrations of the analogue but did not reverse its growth‐inhibitory activity. When added simultaneously with the analogue, however, polyamines caused a decrease in analogue concentration that was accompanied by a block to the growth Inhibition. BE‐4–4‐4 has a higher affinity for DNA than spermine has, but is less able to aggregate DNA. Its growth‐inhibitory and cytotoxic effects support our hypothesis that polyamine analogues that enter cells and replace natural polyamines at DNA binding sites, without fulfilling their biologic functions, should act as antiproliferative agents.
Immunological characterization of the epstein‐barr virus phosphoprotein pp58 and deoxyribonuclease expressed in the baculovirus expression system
Authors: Chen Hai‐Feng , Sauter Marlies , Haiss Peter , Müller‐Lantzsch N.
Published: February 2007

The open reading frames of the phosphoprotein pp58 (BMRF1) and the deoxyribonuclease (BGLF5) of the Epstein‐Barr‐virus (EBV) strain M‐ABA were cloned in the baculovirus expression vectors pAc373 and pAc360 and expressed in the Spodoptera frugiperda (SF158) insect cells. The recombinant phosphoprotein pp58 expressed in SF158 cells was recognized by the anti‐pp58 rabbit anti‐sera which were generated by immunizing rabbits with a TrpE‐BMRF1 fusion protein expressed in E. coli. DNA‐cellulose chromatography showed that the recombinant pp58 exhibited DNA‐binding activities. Immunofluorescence, immunoblot and ELISA analysis indicated that sera from patients with nasopharyngeal carcinoma (NPC) contained antibodies against pp58. The recombinant EBV DNase expressed in SF158 cells was recognized by the anti‐EBV DNase rabbit anti‐sera which were generated by immunizing rabbits with a TrpE‐C‐termlnal part of BGLF5 fusion protein expressed in E. coli. The anti‐EBV DNase rabbit anti‐sera recognized also a protein of about 52 kDa in the EBV‐harboring human B‐cell lines Raji, Jijoye, 895–8, M‐ABA and BL74 induced by TPA and n‐butyrate. The recombinant EBV DNase exhibited exonuclease and endonuclease activities, a requirement for magnesium, and a high pH optimum (8.0). Its enzyme activities could be inhibited by sera from NPC patients and anti‐EBV DNase rabbit anti‐sera. Comparable studies of Raji EBV‐DNase and recombinant EBV‐DNase implied that recombinant EBV‐DNase could also be used in the enzyme activity assay for the detection of NPC. In contrast to the enzyme inhibition test, immunofluorescence and immunoblot analysis demonstrated that the recombinant EBV DNase exhibited only a weak immunological reaction with NPC sera.
Natural killer‐cell activity under conditions reflective of tumor micro‐environment
Authors: Loeffler David A. , Heppner Gloria H. , Juneau Paul L.
Published: February 2007

Natural‐killer(NK) activity was examined in the presence of low oxygen tension, low glucose concentration and acidic pH, to determine whether physical conditions present in the tumor micro‐environment could play a role in down‐regulating cytolytic activity of tumor‐infiltrating lymphocytes with NK phenotype. Anoxia (0% O2), but not hypoxia (1% O2), significantly reduced NK activity, as did acidic pH (6.4 or 6.7). Low glucose concentration (6 mg/dl) did not impair NK activity. Combinations of either moderate (1% O2, 26 mg/dl glucose, pH 6.7) or extreme (0% O2, 6 mg/dl glucose, pH 6.4) alteration of physical conditions significantly reduced NK activity. This study indicates that the physico‐chemical conditions present within solid tumors are capable of down‐regulating NK activity.
A recombinant vaccinia virus expressing human carcinoembryonic antigen (CEA)
Authors: Kaufman Howard , Schlom Jeffrey , Kantor Judy
Published: February 2007

Carcinoembryonic antigen (CEA) is a 180‐kDa glycoprotein expressed on most gastrointestinal carcinomas. A 2.4‐kb cDNA clone, containing the complete coding sequence, was isolated from a human colon tumor cell library and inserted into a vaccinia virus genome. This newly developed construct was characterized by Southern blotting, DNA hybridization studies, and polymerase chain reaction analysis. The CEA gene was stably integrated into the vaccinia virus thymidine kinase gene. The recombinant was efficiently replicated upon serial passages in cell cultures and in animals. The recombinant virus expresses on the surface of infected cells a protein product recognized by a monoclonal antibody (COL‐1) directed against CEA. Immunization of mice with the vaccinia construct elicited a humoral immune response against CEA. Pilot studies also showed that administration of the recombinant CEA vaccinia construct was able to greatly reduce the growth In mice of a syngeneic murine colon adenocarcinoma which had been transduced with the human CEA gene. The use of this new recombinant CEA vaccinia construct may thus provide an approach in the specific active immunotherapy of human G1 cancer and other CEA expressing carcinoma types.
Radiation leukemia virus (RadLV)‐induced leukemogenesis is associated with an increased number and activity of thymic macrophages
Authors: Messika E. , Gallily R. , Yefenof E.
Published: February 2007

The radiation leukemia virus (RadLV) is a chronic leukemia retrovirus that induces thymlc lymphomas in C57BL/6 mice after a latency of 3 to 6 months. During the pre‐leukemic (PL) period, the number of thymic macrophages gradually increased up to 100 fold. Of the cells in a RadLV‐induced lymphoma, 0.3% were large macrophages packed with infected lymphoma cells. These thymic lymphoma macrophages (TLM) also ingested RadLV‐induced lymphoma cells in vitro. red RadLV‐induced lymphoma lines could activate and fix C3 fragments through the alternative complement pathway (ACP). C3‐bound lymphoma cells elicited an oxidatlve burst (OB) response in TLM but not in bone‐marrow macrophages (BMM). However, IL4 treatment of BMM rendered them capable of responding with an OB following triggering by C3‐opsonized cells. Thymic macrophages (TM) responded moderately with OB to C3‐opsonized cells and this response was elevated If the TMs were treated by rlL4. The OB reaction of the TLMs could be partially inhibited by anti‐LFA‐1 or anti‐MALA‐2 antibodies, and was completely inhibited by antl‐CR3 antibodies. These results suggest that IL4 can prime macrophages for triggering an OB reaction and that the interaction between C3‐opsonized cells and IL4‐primed macrophages is mediated primarily through CR3.
Reactivity against herpes simplex virus in patients with head and neck cancer
Authors: Larsson P‐A. , Edström S. , Westin T. , Nordkvist A. , Hirsch J. M. , Vahlne A.
Published: February 2007

The relation between herpes simplex virus (HSV) and head and neck cancer was examined. A total of ninety patients were analyzed for IgG antibodies against HSV. Antibody titers were established with an enzyme‐linked immunosorbent assay and antibodies against specific HSV‐antigens were analyzed by Western blot. These patients' seroreactivity was compared to that of an age‐matched control group of patients with arteriosclerotic disease in their lower limbs, a disease also closely related to heavy tobacco consumption. Prevalence of antibodies against HSV was around 90% and did not differ significantly between cancer patients and controls, but antibody titers against HSV were significantly higher in the cancer patients. The cancer patients also reacted more constantly (80%) in Western blot analysis against the early immediate protein, ICP‐4, than controls (50%). This suggests a different course of an earlier herpetic infection in these patients with a prolonged exposure to early immediate HSV‐proteins which may be related to an increased risk of developing head and neck cancer. We propose that heavy smoking may contribute to this phenomenon.
Increased expression of laminin receptors during myeloid differentiation
Authors: Federico M. H. H. , Maria D. A. , Sonohara S. , Yamamoto M. , Katayama M. L. H. , Brentani M. M.
Published: February 2007

Variation of laminin receptor levels (LNR) during myeloid‐cell differentiation and in acute leukemia were investigated by 125I‐laminin‐binding determination during HL60 cell differentiation and in cells of patients with different types of leukemia, characterized according to the FAB classification. LNR levels in HL60 cells increased during differentiation, being significantly higher in cells exposed to phorbol myristate acetate (PMA) and ethanol (55,391 ± 27,845 and 29,314 ± 6,435 sited cell respectively) as compared with HL60 controls (8,549 ± 4,000 siteskell). The control cells do not adhere to laminin‐coated surfaces, but differentiation with PMA results in their rapid adherence on this substratum. Short treatment with PMA does not increase the number of adherent cells or the receptor expression. Granulocytes also presented equally high LNR concentration (29,739 ± 13,516 sites/cell). The lymphoid cells (lymphocyte, acute lymphoid leukemia and chronic lymphocytic leukemia) shared low LNR numbers (<6,500 sites/cell). Myeloid cells displayed a wide range of LN receptors with higher levels being associated with the more differentiated FA9 subgroups. 125I‐laminin binding to lymphoid or myeloid leukemic cells was mainly inhibited by P1 fragments, whereas granulocytes and differentiated HL60 cells displayed a dual binding pattern for laminin fragments P1 and E8. These results were confirmed by assays using 125I‐labelled P1 and E8 fragments. We conclude that magnitude of LNR levels and variation in expression of P1 and E8 receptors appear to be linked to lineage and maturation status in hematopoietic cells.
Pooled analysis of 3 european case‐control studies of ovarian cancer: II. Age at menarche and at menopause
Authors: Franceschi Silvia , La Vecchia Carlo , Booth Margaret , Tzonou Anastasia , Negri Eva , Parazzini Fabio , Trichopoulos Dimitrios , Beral Valerie
Published: February 2007

The role of age at menarche and at menopause on epithelial ovarian cancer risk was re‐assessed in a combined analysis of 3 hospital‐based case‐control studies conducted in Italy, the United Kingdom and Greece, which produced a total of 1, 140 cases and 2,724 controls. In the overall dataset, there was no evidence of an association with age at menarche: compared with women whose menarche occurred at age I5 or over, the relative risk (RR) estimates were 1.0[95% confidence interval (CI) 0.8 to 1.2] for those with menarche at ages 12 to 14, and 1.0 (95% CI 0.8‐1.2) for those with menarche below age 12. There was no consistent interaction between age at menarche and study centre or age at diagnosis. In relation to age at menopause, compared with women whose menopause occurred at age 44 or earlier, the RR was 1.4 between 45 and 49, 1.6 between 50 and 52 and 1.9 above 52. The strength of the association was apparently (but not significantly) greater in the British than in the Greek or Italian dataset. The effect of age at menopause tended to be long‐lasting and, if anything, to increase across subsequent age‐groups. The large dataset, and the replication of results in different studies, provide more definite and precise information than previously available on the absence of appreciable effect of age at menarche on subsequent ovarian cancer risk in developed countries. For age at menopause, there was a direct and consistent trend in risk, but the association was relatively weak, with RRs below 2 even between extreme categories.
Roles of ovaries and testes in hepatocellular tumorigenesis induced in mice by 3′‐methyl‐4‐dimethylaminoazobenzene
Authors: Yamamoto Reiko , Iishi Hiroyasu , Tatsuta Masaharu , Tsuji Motomu , Terada Nobuyuki
Published: February 2007

The roles of gonads in tumorigenesis induced in mouse liver by 3′‐methyl‐4‐dimethylaminoazobenzene (3′‐Me‐DAB) were investigated. C57BL/6 × DS‐F1 mice which were 10, 12, 14, 16 and 18 days old were treated i.p. with 3′‐Me‐DAB. Nodular lesions induced in the liver were classified into adenomatous nodules and hepatocellular carcinomas. Adenomatous nodules were composed of a mixture of eosinophilic, basophilic, vacuolated and foamy hepatocytes in various proportions and compressed the adjacent parenchyma. These adenomatous nodules were of monoclonal origin. Carcinomas had a trabecular structure. The incidence, numbers per mouse and areas of adenomatous nodules and carcinomas in male and female mice aged 16‐64 weeks were compared. Adenomatous nodules were first detected in males and females aged 24 and 52 weeks, respectively, and their incidences were much higher in males than in females of the same age. The number of adenomatous nodules per mouse and their size were also higher in males. The first carcinoma was found in a 52‐week‐old male, but no carcinomas were found in females even at 64 weeks of age. The effects of castration 23 days after birth on the appearance of nodular lesions in the livers of 32‐ to 64‐week‐old mice were examined. Castration of males did not affect the incidence of adenomatous nodules, but reduced the incidence of carcinomas. It also decreased the number of adenomatous nodules per mouse. Castration of females reduced the time before appearance of adenomatous nodules and increased their incidence, number per mouse, and area. A carcinoma appeared in a 64‐week‐old castrated female, but no similar lesion was found in intact females of the same age. These results indicate that tumorigenesis induced in mouse liver by 3′‐Me‐DAB is enhanced by the testes and suppressed by the ovaries.
Butyric monosaccharide ester‐induced cell differentiation and anti‐tumor activity in mice. Importance of their prolonged biological effect for clinical applications in cancer therapy
Authors: Pouillart Philippe , Cerutti Italina , Ronco Gino , Villa Pierre , Chany Charles
Published: February 2007

The interest of butyric salts is based on their capacity to promote differentiation of malignant cells and inhibition of tumor development. The phenotypic modifications are rapidly reversible and require the continuous presence of butyric salts in the target area, which raises problems for therapeutic applications. We show here that the covalent binding of n‐butyric acid on natural polyhydroxylated compounds such as monosaccharides, especially 3‐ or 6‐O‐butanoyl‐ 1,2‐O‐iropro‐pylidene‐α‐D‐glucofuranose, retains the majority of the biological properties of n‐butyric acid. The delayed degradation of these covalent compounds is associated with an improved maintenance of cell differentiation and anti‐tumor protection in mice. These butyric complexes thus seem potentially useful for therapeutic applications.