bluuebunny/crossref_metadata_2025 huggingface dataset:
An autocrine motility factor secreted by the dunning R‐3327 rat prostatic adenocarcinoma cell subtype AT2.1
Authors: Evans Christopher P. , Walsh Douglas S. , Kohn Elise C.
Published: February 2007

Tumor cell locomotion is an integral part of the metastatic process. We present a new autocrine motility factor (AMF) derived from the serum‐free conditioned medium of the Dunning R‐3327 rat prostate adenocarcinoma AT2.1 tumor cell subline AT2.1‐AMF, prepared by concentration of components ≧30 kDa in size and washed free of low‐molecular‐weight growth factors, stimulated motility of AT2.1 cells in modified Boyden chamber migration assays. This stimulated migration was dose‐dependent, and by checkerboard analysis was both chernotactic and chemokinetic. AT2.1‐AMF activity was labile to heat, acid, base, reduction, oxidation, and proteases. Lyophilization and treatment with 6M urea caused a mild decrease (<20%) in migration‐stimulating capability. Tumor‐cell specificity was demonstrated for AMF of AT2.1 and AT3.1 Dunning sublines, and the A2058 human melanoma cell lines. AT2.1 cell migration to AT2.1‐AMF was inhibited by 2 hr pre‐treatment with cholera toxin (0.1 μg/ml) or forskolin (100 μM), but not altered by 2 hr pre‐treatment with pertussis toxin (1.0 μg/ml). This indicates that guanine nucleotide binding protein‐mediated regulation of CAMP is involved in modulating the AT2.1 cell response to its AMF. The AT2.1‐AMF belongs to a related family of tumor autocrine motility factors and represents a new model for understanding the role of tumor‐cell migration in the metastatic process of human prostate cancer.
Interleukin 6 is secreted by breast fibroblasts and stimulates 17β‐oestradiol oxidoreductase activity of MCF‐7 cells: Possible paracrine regulation of breast 17β‐oestradiol levels
Authors: Adams Eric F. , Rafferty B. , White M. C.
Published: February 2007

Previous studies have demonstrated that cultured human breast fibroblasts secrete a high‐molecular‐weight polypeptide which stimulates the ability of human breast‐cancer MCF‐7 cells to convert oestrone (E1) to the biologically more active 17β‐oestradiol (E2). This effect is mediated by an increase in reductive E2 oxidoreductase (EOR) activity. We have identified the fibroblast‐derived stimulatory factor as interleukin 6 (IL6) or an immunologically related peptide. Human breast fibroblasts in culture secreted up to 10 ng IL6/ml medium during 24 hr of incubation. The effects of IL6 and breast fibroblast conditioned medium (CM) on reductive EOR activity of MCF‐7 cells were similar; both CM and IL6 potently stimulated enzyme activity in a dose‐dependent manner, and both exerted synergistic stimulatory effects in combination with E2. A polyclonal neutralizing antibody to IL6 completely abolished the reductive EOR‐stimulating activity of CM. These results indicate that breast stromal fibroblasts may have a paracrine role in regulation of breast‐cancer‐tissue levels of E2, and that this effect is mediated by IL6 or a closely related peptide.
TGFβ1 and TGFβ2 are potential growth regulators for low‐grade and malignant gliomas in vitro: Evidence in support of an autocrine hypothesis
Authors: Jennings Mark T. , Maciunas Robert J. , Carver Robert , Bascom Charles C. , Juneau Patrick , Misulis Karl , Moses Harold L.
Published: February 2007

Low‐grade astrocytomas, anaplastic astrocytomas and glio‐blastomas in vitro were found to ubiquitously produce the mRNA of transforming growth factor‐β (TGFβ). TGFβ1 and TGFβ2 mRNA were expressed to a lesser degree among the hyperdiploid malignant gliomas. By radioreceptor assay of conditioned medium, TGFβ was secreted predominantly in latent form, in both latent and active form, or only in active form within a panel of low‐grade and malignant gliomas. The TGFβ receptor (types I, II and III) was evident among the glioma lines. Many near‐diploid gliomas were growth‐inhibited by TGFβ1 and TGFβ2. in vitro. Most hyperdiploid glioblastomas showed a positive mitogenic response to exogenous TGFβ1 and TGFβ2. A synergistic or additive mitogenic interaction with epidermal growth factor and insulin was observed among some. Under serum‐free conditions, anti‐TGFβ antibody neutralized the expected growth‐regulatory effect of endogenous TGFβ1 thus establishing the specificity of the response in vitro. TGFβ1 also enhanced the clonogenicity of certain gliomas which had been growth‐stimulated in monolayer. Thus, basic elements in support of an autocrine hypothesis have been demonstrated: TGFβ mRNA was expressed among low‐grade and malignant gliomas, TGFβ was secreted in latent and/or active form into conditioned media and appeared to serve as an endogenous regulator of glioma proliferation in vitro. The mitogenic response, either positive or negative, correlated with the degree of anaplasia and karyotypic divergence.
Mutational activation of c‐Ha‐ras genes in intraductal proliferation induced by N‐nitroso‐N‐methylurea in rat mammary glands
Authors: Sakai Hirotsuka , Ogawa Katsuhiro
Published: February 2007

Although administration of a single dose of N‐nitroso‐N methylurea (NMU) to young virgin rats induces a high rate of mammary carcinomas, precise histogenesis of the carcinomas has not been well characterized. In this study, we investigated the alterations of H‐ras gene in early focal lesions as well as carcinomas in the mammary glands of F344 rats treated with NMU. At 2 weeks after treatment, intraductal proliferation (IDP) was occasionally observed, and mammary carcinomas emerged at 12 and 36 weeks. The individual lesions of IDP and carcinomas were scooped out from the tissue sections under a stereomicroscope, and the DNA‐sequence‐spanning codon 12 of H‐ras gene was amplified from the tissue sections by polymerase chain reaction (PCR). The analysis of amplified DNA by oligonucleotide hybridization revealed that 65% (11/17) of IDP and 89% (16/18) of carcinomas had a point mutation (G‐to‐A transition) at the 2nd position of H‐ras codon 12. However, the DNA amplified from the areas, which appear histologically normal, never showed such mutation. These results indicate that IDP is a very early change for NMU‐induced mammary carcinogenesis.
Nutritional factors in colorectal cancer risk: A case‐control study in majorca
Authors: Benito E. , Stiggelbout A. , Bosch F. X. , Obrador A. , Kaldor J. , Mulet M. , Muñoz N.
Published: February 2007

The relationship between energy intake, selected nutrients and colorectal cancer was investigated in the population of Majorca, a Spanish island in the Mediterranean basin. A population‐based case‐control study using food frequency questionnaires was conducted during the period 1984‐1988 and included 286 cases of colorectal cancer, 295 population controls and 203 hospital controls. Food composition tables and ad‐hoc estimates of portion sizes were used to derive intake estimates of 29 nutrients and of total calories. Relative risks were calculated for quartiles of consumption of each specific nutrient after adjustment for total calorie intake. Colorectal cancer was found associated with dietary intake of total calories (RRs = 1.0, 1.6, 1.6, 2.6) and cholesterol (RRs = 1.0, 0.9, 1.7, 1.7) and a protective effect was associated with the intake of fibre from legumes (pulses) and folic acid. The associations and the trends were statistically significant. Among the main energy‐supplying nutrients, after adjustment for calories from other sources, increased risks were found for protein (RRs = 1.0, 1.1, 1.7, 2.5), notably animal protein, and carbohydrates (RRs = 1.0, 1.5, 1.4, 2.2), whereas no effects were found for increased consumption of lipids or saturated fats.
Active alpha2 and beta adrenoceptors in lymphocytes from patients with chronic lymphocytic leukemia
Authors: Goin Juan C. , Sterin‐Borda Leonor , Borda Enri S. , Finiasz Marta , Fernandez J. , De Bracco Maria M. E.
Published: February 2007

A single population of alpha2 adrenoceptors was characterized in intact B lymphocytes from patients with chronic lymphocytic leukemia (B‐CLL) by binding and saturation studies with 3H labelled yohimbine and by competition studies with alpha adrenergic antagonists. While the affinity of B‐CLL alpha2 adrenoceptors was low (KD: 9.81 nm‐20.98 nm), each cell expressed a large number of receptors. No binding of the alpha1 adrenoceptor antagonist prazosin was observed and the binding properties of beta adrenergic receptors (assayed with 3H‐labelled dihydroalprenolol), were similar to those described for normal lymphocytes. Reaction of B‐CLL with the beta adrenergic agonist isoproterenol raised the levels of cAMP in 11/13 patients tested, and in 8 of these, incubation with the alpha2 adrenergic agonist clonidine prevented the effect and reduced the basal cAMP levels. The presence of active alpha2 adrenoceptors on B‐CLL lymphocytes may be involved in the regulation of metabolic pathways that affect cell functions and favor neoplastic growth.
Depot‐medroxyprogesterone acetate (DMPA) and risk of edometrial cancer
Authors:   THE WHO COLLABORATIVE STUDY OF NEOPLASIA AND STEROID CONTRACEPTIVES, Cuevas Hector Rodriguez , Salazar Socorro Benavides , Palet Antonio , Ontiveros Patricia , Silpisornkosol Suporn , Pardthaisong Tieng , Charoeniam Viruch , Theetranont Shoti , Boosiri Banpot , Chutivongse Supawat , Virutamasen Pramuan , Wongsrichanalai Chansuda , Sindhvananda Sermsri , Koetsawang Suporn , Rachawat Duangdao , Kiriwat Orawan , Koetsawang Amorm , Scully Robert E. , Young Robert H. , Thomas David B. , Stanford Janet L. , Rosenblatt Karin A. , Noonan Elizabeth A. , Ray Roberta M. , Holck Susan , Farley Timothy M. M. , Stanford Janet L. , Thomas David B.
Published: February 2007

The use of depot‐medroxyprogesterone acetate (DMPA), a long‐acting progestational contraceptive, in relation to risk of epithelial ovarian cancer was examined in a hospital‐based case‐control study conducted in Mexico and Thailand. Women with histologically confirmed epithelial ovarian cancer (n = 224) diagnosed between 1979 and 1988 were compared with hospital controls (n = 1,781) matched on age, hospital and year of interview. Overall, 9.8% of cases and 12.9% of controls had ever used DMPA. The relative‐risk (RR) estimate in women who had ever used DMPA, controlling for the confounding effects of number of live births and oral contraceptive use, was 1.07 (95% CI 0.6, 1.8). No consistent patterns of increasing or decreasing risk were noted according to duration of use, time since first or most recent use or age at first use of DMPA. These results suggest that the risk of epithelial ovarian cancer is not altered by the use of DMPA.
Association of ki‐ras mutation with differentiation and tumor‐formation pathways in colorectal carcinoma
Authors: Laurent‐Puig P. , Olschwang S. , Delattre O. , Validire P. , Melot T. , Mosseri V. , Salmon R. J. , Thomas G.
Published: February 2007

The occurrence of a point mutation on the 12th and 13th codons of the Ki‐ras oncogene has been investigated in 99 colorectal carcinomas in relation to 3 histological parameters: extent of differentiation, occurrence of a mucinous component within the tumor, and presence of peripheral adenomatous polyp remnants. The mutation frequency increased with each parameter: from 13% (2/15) to 44% (37/84) with differentiation, from 33% (26/79) to 65% 13/20) with mucinous character, and from 27% (15/56) to 56% (24/43) with the presence of polyp remnants. The frequency was highest in well‐differentiated mucinous tumors with adenomatous remnants 83% (5/6). We suggest that Ki‐ras mutation is preferentially involved in carcinomas that have developed from adenoma and that the mutation preserves differentiation and much secretion in these cancer cells.
Differential susceptibility of balb/c and DBA/2 cells to plasmacytoma induction in reciprocal chimeras
Authors: Silva Santiago , Sugiyama Hiroyuki , Babonits Magdalena , Wiener Francis , Klein George
Published: February 2007

Reciprocal chimeras were generated between BALB/c and DBA/2 mice by inoculating newborn recipients of either strain with bone‐marrow (BM) cells of the other through the periorbital vein. DBA/2 mice inoculated with the BALB/c with proven chimerism will be referred to as C→D, the reciprocal as D→C. The BALB/c cells carried a Robertsonian 6;15 (Rb6;15) chromosome marker to facilitate identification. The chimeric mice contained between 5% and 70% of donor cells when examined at 4 to 5 weeks of age. Six of 10 C→D developed plasmacytomas (MPC) after 3 × 0.5 ml monthly pristane treatment (incidence 60%) and 8 of 25 (incidence 32%) after 2 to 3 × 0.5 ml pristane followed by Abelson virus (A‐MuLV) infection. Seven of 15 D→C developed MPC after pristane treatment (incidence 47%) and 4 of 17 after pristane + A‐MuLV (incidence 24%). All tumors that have arisen in both reciprocal chimeras originated from BALB/c cells independently of the degree of chimerism. All tumors contained an Ig/myc translocation. Among the C→D chimeras, 5 carried t(12;15) and 1 t(6;15) in the pristane‐treated group, while 4 carried t(12;15), 1 t(6;15) and 3 t(15;16) in the pristane + A‐MuLV. Among the D→C chimeras 6 carried t(12;15) and 1 t(6;15) in the pristane‐treated group, while 3 t(12;15) and 1 t(6;15) in the pristane + A‐MuLV. No tumors developed in 18 pristane‐ and 22 pristane + A‐MuLV‐treated DBA/2 mice nor in 15 pristane‐ and 17 pristane + A‐MuLV‐treated (BALB/c → DBA/2)F1 mice. The data indicate that BALB/c and DBA/2 cells differ in their propensity to transform into plasmacytoma in identical host environments after both pristane and pristane + A‐MuLV treatment. They also show that the oil granuloma can support MPC development in either type of chimeric host.
Invasion by WC5 rat cerebellar cells is independent of RSV‐induced changes in growth and adhesion
Authors: Brady‐Kalnay Susann M. , Boghaert Erwin R. , Zimmer Stephen , Soll David R. , Brackenbury Robert
Published: February 2007

The WC5 rat cerebellar cell line, which is infected with a Rous sarcoma virus that is temperature‐sensitive for pp60src transformation, shows temperature‐dependent expression of the neural‐cell‐adhesion molecule (N‐CAM) and glial fibrillary acidic protein (GFAP). We found that WC5 cells maintained at the non‐permissive temperature in both monolayer cultures and spheroids are subject to density‐dependent inhibition of growth, whereas cells maintained at the permissive temperature continued to grow. The movement of isolated WC5 cells at both temperatures was similar, while the migration of WC5 cells out of 3‐dimensional aggregates was faster at the non‐permissive temperature. We tested whether the RSV‐induced changes affect the invasion of the WC5 cells in 2 in vitro assays: the chorio‐allantoic‐membrane assay and the chick‐heart‐fragment assay. In both assays, WC5 cells grown at either temperature were invasive. These results indicate that growth rate is unrelated to invasion and that loss of N‐CAM‐mediated cell‐cell adhesion is not necessary for invasion.
Establishment of an IL‐2 independent, human T‐cell line possessing only the p70 IL‐2 receptor
Authors: Starkebaum Gordon , Loughran Thomas P. , Waters Cory A. , Ruscetti Francis W.
Published: February 2007

A continuous cell line was established from the blood of a patient (HH) with an aggressive cutaneous T‐cell leukemia/lymphoma who lacked antibodies to human T lymphotrophic virus, type 1. The immunophenotype of the cultured cells was CD2+, CD3+, CD4+, CD5+, CD8+, DR+ and CD25− (Tac, IL‐2 receptor α chain). Southern‐blot hybridization analysis of T‐cell‐receptor β chain DNA demonstrated the same rearrangement in freshly isolated blood cells and cultured cells, indicating that the cell line was derived from the patient's malignant clone. Since cultured T‐cells grew in complete medium without added IL‐2, we investigated whether HH cells could be producing and responding to IL‐2 in an autocrine fashion. However, no IL‐2 was detectable in supernatant from the cell line, while antibodies to IL‐2, or to the IL‐2 receptor α or β chains did not inhibit cell growth. In addition, no mRNA message for IL‐2 was detectable in these cells. The results appear to exclude an autocrine IL‐2‐dependent mechanism of cell growth for this T‐cell line. Although cultured HH cells lacked detectable IL‐2 receptor α chain, they did show increased proliferation to exogenous IL‐2. Binding studies with 125I‐IL‐2 demonstrated an intermediate affinity receptor for IL‐2, KD = 1.7nM, with 6400 binding sites per cell, suggesting the presence of an IL‐2 receptor β chain. Consistent with these findings 125I‐IL‐2 cross‐linking studies demonstrated a single receptor calculated to be 75kDa. Also, the β chain of the IL‐2 receptor was detected by immunofluorescence using specific monoclonal antibodies (MAbs). Nanomolar concentrations of an IL‐2‐diphteria toxin fusion protein inhibited cellular protein synthesis, an effect abrogated by native IL‐2. These findings indicate that the IL‐2 receptor β‐chain was functional. This novel mature T‐cell line may be useful in studies of IL‐2 receptor regulation and in analysis of the mechanism of T‐cell leukemogenesis.
Effect of combination treatment with analogs of luteinizing hormone‐releasing hormone (LH‐RH) or somatostatin and 5‐fluorouracil on pancreatic cancer in hamsters
Authors: Szepeshazi Karoly , Lapis Karoly , Schally Andrew V.
Published: February 2007

Ductal pancreatic cancers were induced with N‐nitrosobis(2‐oxopropyl)amine (BOP) in female Syrian golden hamsters. The animals were then treated for 2 months with 5‐fluorouracil (5‐FU) and with sustained delivery systems of the LH‐RH agonist D‐Trp‐6‐LH‐RH antagonist (Ac‐D‐Nal(2)1‐D‐Phe(4CI)2‐D‐Pal(3)3‐D‐Cit6, D‐Ala10)LH‐RH(SB:75) and somatostatin analog D‐Phe‐Cys‐Tyr‐D‐Trp‐Lys‐Val‐Cys‐Trp‐NH2, (RC‐160), and with some combinatfon; thereof: In the first experiment, the treatment with D‐Trp‐6‐LH‐RH plus 5‐FU resulted in 52% inhibition of tumorous pancreas weight, a smaller number of tumor nodules on histology, a marked increase of programmed cell death (apoptosis) and a reduced number of AgNOR (argyrophilic nucleolar organizer region) in tumor cells, as compared with controls. The inhibitory effects of this combination were greater than those obtained with 5‐FU and D‐Trp‐6‐LH‐RH treatment alone. In the 2nd experiment, a 76% inhibition of tumorous pancreas weight, a significant decrease in the number of tumor nodules, an increased amount of stroma, enhanced apoptosis and decreased AgNORs were observed after therapy with somatostatin analog RC‐160 plus 5‐FU. Most of these tumor inhibition parameters were superior to those in the group treated with 5‐FU alone, and in some cases slightly better than those treated with RC‐160 alone. Both LH‐RH antagonist SB‐75 and somatostatin analog RC‐160 caused a significant inhibition of tumors, and their combination had the strongest tumor inhibitory effect, with the best survival of animals, the lowest tumorous pancreas weight and the highest apoptosis index among groups. Our results suggest that the combinations of LH‐RH analogs with somatostatin analogs or of either type of analog with 5‐FU may be superior to single agents in the therapy of pancreatic cancer.
Involvement of leukocyte (β2) integrins (CD18/CD11) in human monocyte tumoricidal activity
Authors: Bernasconi Sergio , Peri Giuseppe , Sironi Marina , Mantovani Alberto
Published: February 2007

Appropriately activated mononuclear phagocytes mediate contact‐dependent tumoricidal activity. Adhesion structures involved in contact‐dependent tumor cytotoxicity have not been defined. The present study was aimed at identifying the adhesion structures involved in the tumoricidal activity of activated (IFN‐γ + LPS) human monocytes. Tumor cells of different histological origin were used as targets in a 48‐hr cytolysis assay. Anti‐CD18 (integrin β2 chain) monoclonal antibodies (MAbs) substantially (50–40%) inhibited human monocyte cytotoxicity. When the role of different a‐chains was studied, anti‐αL (CD11a, LFA1), anti‐αM (CD11b, Mac‐1) and anti‐αX (CD11c, p150.95) caused marginal inhibition, but the effect of the 3 combined was comparable to that of anti‐CD18. Anti‐CD 18 MAb did not affect the release of various cytotoxic molecules (e.g. TNF) by activated human monocytes. Activated monocytes showed augmented binding to target cells and anti‐CD18 MAb inhibited the binding of resting and activated monocytes to tumor target cells. While IFN‐γ alone augmented expression of leukocyte integrins and LPS had no effect, the 2 activation signals, combined for optimal stimulation of tumoricidal activity, resulted in no appreciable increase in these leukocyte adhesion molecules, as assessed by flow cytometry. Our results suggest that the augmented CD 18‐dependent binding of activated monocytes on tumor cells depends mainly upon changes in the adhesive properties of these molecules rather than upon increased numbers on the cell surface. Anti‐1CAM‐1 MAb significantly reduced monocyte cytotoxicity on tumor cells, which is consistent with a role of the CD11/CD18 adhesion pathway. These results implicate “activated”︁ leukocyte (β2) integrins (CD11 /CD18) as important adhesion molecules in the contact‐dependent tumoricidal activity of human monocytes.
Comparison of neutralization of BPV‐1 infection of C127 cells and bovine fetal skin xenografts
Authors: Ghim Shinje , Christensen Neil D. , Kreider John W. , Bennett Jenson A.
Published: February 2007

BPV‐I induces focus formation in murine C127 cells and fibropapillomas in bovine fetal skin xenografts. In this study, we compared the specificity of neutralization of BPV‐I in both assay systems, using sera and monoclonal antibodies (MAbs) selected to define neutralizing epitopes. Sera from rabbits and cattle, inoculated with intact BPV‐1 or BPV‐2 virions, neutralize BPV‐1 infectivity in both C127 cells and xenografts. Selected human sera and murine MAbs that react with intact BPV‐1 particles, serum of a rabbit immunized with denatured BPV‐1 particles, and sera from calves vaccinated with a recombinant L1 fusion protein did not neutralize BPV‐1 infection in either system. It was concluded that neutralization of BPV‐1 infection of C127 cells and bovine fetal skin xenografts by hyperimmune sera is specific and concordant for both assay systems, and involves conformational BPV‐1 capsid epitopes.
The receptor encoded by the human C‐MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors
Authors: Prat Maria , Narsimhan Radha P. , Crepaldi Tiziana , Rita Nicotra M. , Natali Pier G. , Comoglio Paolo M.
Published: February 2007

The human c‐MET oncogene encodes a transmembrane tyrosine kinase (p 190c‐met) with structural and functional features of a growth‐factor receptor. Monoclonal antibodies (MAbs) have been used to investigate the distribution of the c‐Met protein in human normal and neoplastic tissues. By immunofluorescence microscopy homogeneous expression was detected in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Positive staining was also found in epithelial cells of the endometrium and ovary, and in basal keratinocytes of esophagus and skin. By Northern blot analysis, high levels of c‐met messenger RNA were detected in specimens of liver, gastro‐intestinal tract and kidney. c‐met‐specific mRNA was also found in thyroid, pancreas and placenta, in which organs c‐Met protein was barely detectable by immunofluorescence. The antibodies revealed expression of c‐MET protein in hepatomas (11/14), carcinomas of colon and rectum (19/21), stomach (11/22), kidney (16/19), ovary (9/17) and skin (7/17). Carcinomas of the lung (13/20), thyroid (11/13) and pancreas (5/7) were also positive. In these last cases (lung, thyroid and pancreas) tumor cells were homogeneously stained by the antibodies, whereas in their normal counterparts staining was barely detectable. These data suggest that the receptor encoded by c‐MET plays a physiological role in epithelial cell growth and that its expression is altered in human carcinomas.
Herpes simplex virus type 2: A possible interaction with human papillomavirus types 16/18 in the development of invasive cervical cancer
Authors: Hildesheim Allan , Mann Valerie , Brinton Louise A. , Szklo Moyses , Reeves William C. , Rawls William E.
Published: February 2007

A case‐control study of 766 histologically confirmed incident cases of invasive cervical cancer and 1,532 hospital and community controls was conducted in Latin America to evaluate the etiologic role of herpes simplex virus type 2 (HSV‐2) and to examine whether HSV‐2 interacts with other risk factors. In addition to a personal interview, all subjects were asked to donate blood samples and cervical swabs for assessment of exposure to HSV‐2 and human papillomaviruses (HPVs) respectively. Ninety‐eight percent of cases and 91% of controls agreed to the interview and blood collection. Women testing positive for HSV‐2 antibodies were found to have a 60% increased risk of cervical cancer compared with seronegative women (95% CI = 1.3, 1.9). Control for education, sexual and reproductive behavior, prior Pap‐smear screening, smoking, oral contraceptive use, HPV‐6/11 DNA, or HPV‐16/18 DNA detection did not materially affect this estimate. No effect modification of HSV‐2 by age, HPV‐6/11 DNA, pregnancies, oral contraceptive use or cigarette smoking was observed. However, a significant interaction was detected between HSV‐2 and HPV‐16/18. Compared with women testing negative to both virus types, those positive for HSV‐2 alone had a RR of 1.2 (95% CI = 0.9, 1.6), those positive for HPV‐16/18 DNA alone had a RR of 4.3 (95% CI = 3.0,6.0), and those positive for both viruses had a RR of 8.8 (95% CI = 5.9, 13.0). These findings corroborate recent laboratory evidence of a possible biological interaction between HSV‐2 and HPV‐16/18 in the development of cervical cancer. Further confirmatory studies are needed, given concerns with potential misclassification of exposure by the laboratory assays utilized.
Cysteine endopeptidase activity levels in normal human tissues, colorectal adenomas and carcinomas
Authors: Shuja Sania , Sheahan Kieran , Murnane Mary Jo
Published: February 2007

We have assayed cysteine endopeptidase activities in 17 types of normal human tissue and in matched sets of colorectal mucosa, adenoma and carcinoma samples. Our data indicate that cathepsin B enzyme levels vary 70‐fold and cathepsin L enzyme levels vary 20‐fold from one normal tissue to another. Cathepsin B specific activity in normal tissues fell into 3 categories. High activity, with a mean of 156.7 ± 41.5 nmoles min−1 mg−1 protein, was measured in liver, thyroid, kidney and spleen; intermediate activity, with a mean of 60.2 ± 8.3 nmoles min−1 mg−1 protein, was measured in heart, colon, adrenal and lung; and low activity, with a mean of 18.4 ± 9.7 nmoles min−1 mg−1 protein, was measured in prostate, testis, nerve, stomach, pancreas, brain, skeletal muscle, skin and breast. Cathespin L specific activity fell into 2 categories. High activity, with a mean of 51.1 ± 4.9 nmoles min−1 mg−1 protein, was measured in thyroid, liver and kidney; and low activity, with a mean of 11.4 ± 5.5 nmoles min−1 mg−1 protein, was measured in spleen, colon, heart, adrenal, lung, testis, brain, nerve, skin, stomach, pancreas, skeletal muscle, prostate and breast. Our characterization of these enzyme levels provides a reference standard for normal cathepsin B and L activities in human tissues that should enhance the detection of their deregulation in disease states. For example, in studies of colorectal carcinoma and normal mucosa, we observed a significant tumor‐specific increase in cathepsin B and L activities with particularly high activity levels in earlier (Dukes′ A and B) compared to later (Dukes′ C and D) stages of colorectal cancer. In contrast, adenomas from colorectal cancer patients expressed normal levels of cathepsin B activity, providing evidence that the increase in expression of cathepsin B may be a sensitive marker for progression from the pre‐malignant to the malignant state in the development of colorectal cancer.
Expression of integrin receptors on 45 clinical neuroblastoma specimens
Authors: Favrot Marie C. , Combaret Valérie , Goillot Evelyne , Lutz Patrick , Frappaz Didier , Thiesse Philippe , Thyss Antoine , Dolbeau Dominique , Bouffet Eric , Tabone Eric , Philip Thierry
Published: February 2007

Immunohistological expression of integrins has been analyzed on 45 neuroblastoma specimens representative of the different clinical and histological forms of the tumor. None of the specimens expressed the α5 chain of the integrins. The β1 chain was expressed on all specimens, the α1 chain on 44 specimens and the α3 chain on 42; the 4 specimens which lacked α1 or α3 were stage‐4 neuroblastomas. The α2 chain was expressed on 18 specimens, and the α6 chain on 17;15 reacted with both. Their reactivity was related to the maturation of the tumor rather than the stage of the disease: they were expressed on lowgrade, well‐differentiated specimens; stage 3‐4 neuroblastoma specimens analyzed at diagnosis were negative, but usually expressed both chains when analyzed after in vivo differentiation by chemotherapy. αv reacted with 18 specimens and β3 with 12, without strict relation with the stage of the disease and/or its degree of differentiation; 9 well‐differentiated specimens expressed the β4 chain; only 4 well‐differentiated specimens expressed the α4 chain. The 4 specimens which lacked α1‐β1 or α3‐β1 expression had n‐myc amplification, whereas those which expressed either α4, β4, β3, or αv had no amplification. Furthermore, the expression of the 3 heterodimers α4‐β1, αv‐β3 and α6‐β4 was essentially observed on primary tumors which developed in the mediastinum. The expression of α2‐β1 and α6‐β1 was observed on both n‐myc‐positive and ‐negative specimens. β1 and α3, were diffusely expressed on all counterparts of these tumors, from undifferentiated neuroblasts to ganglion and Schwann cells. The α1 chain reacted with undifferentiated and intermediate neuroblasts as well as with Schwann cells, but ganglion cells were negative. α2 and α6 chains were negative on undifferentiated neuroblasts, variably expressed on intermediate neuroblasts, and restricted to Schwann cells in ganglioneuroma. The expression of α4 and β4 was restricted to Schwann cells. αv and β3 occasionally reacted with undifferentiated and intermediate neuroblasts; αv was strongly positive on Schwann cells but negative on ganglion cells, whereas β3 was positive on both neuronal and non‐neuronal populations.
Epidemiologic assessment of interactions of hepatitis‐C virus with seromarkers of hepatitis‐B and ‐D viruses, cirrhosis and tobacco smoking in hepatocellular carcinoma
Authors: Tzonou Anastasia , Trichopoulos Dimitrios , Kaklamani Evangelia , Zavitsanos Xenophon , Koumantaki Yvonni , Hsieh Chung‐Cheng
Published: February 2007

A recently introduced enzyme immunoassay procedure for antibodies against the hepatitis‐C virus (HCV) was used to test samples from 185 cases with hepatocellular carcinoma (HCC) and 432 hospital controls. The anti‐HCV results were examined in conjunction with previously reported data from this study concerning hepatitis‐B virus (HBV) serology, hepatitis‐D virus (HDV) antibodies, presence of cirrhosis and tobacco smoking. There was evidence for interaction between HBV and HCV in the causation of HCC: as previously reported, the rate ratio (RR) linking the presence of anti‐HCV to HCC among subjects positive for hepatitis‐B surface antigen (HBsAg) was substantially higher than the corresponding RR among those negative for this marker; furthermore, among HCC patients positive for HBsAg, a high proportion (33/61) of those who were positive for hepatitis‐Be antigen (HBeAg) or its antibody were positive for anti‐HCV, whereas among HBsAg‐positive controls who were also positive for HBeAg or its antibody, none was positive for anti‐HCV (0/18; p < 10−4. The anti‐HCV‐related RR for HCC was also higher among HCC patients with cirrhosis than among those without evidence of co‐existing cirrhosis (RR 11.4 vs. 4.4; p = 0.06). In addition, there was some evidence of interaction between tobacco smoking and HCV in the origin of HCC; after controlling for age, sex and HBsAg status, the RR for subjects positive for anti‐HCV was 6.8 among smokers but only 3.2 among non‐smokers (p = 0.26). By contrast, there was no suggestion of an interaction between anti‐HCV and anti‐HDV, in agreement with the presumed minimal role, if any, of HDV in HCC etiology. These results support the notion that HCV is involved in the etiology of HCC by advancing, through a chronic liver disease process, carcinogenesis initiated by other factors.
Epstein‐barr virus antibody patterns preceding the diagnosis of non‐hodgkin's lymphoma
Authors: Mueller Nancy , Mohar Alejandro , Evans Alfred , Harris Nancy L. , Comstock George W. , Jellum Egil , Magnus Knut , Orentreich Norman , Frank Polk B. , Vogelman Joseph
Published: February 2007

Immunosuppressed patients who develop non‐Hodgkin's lymphoma (NHL) have abnormal antibody responses against the Epstein‐Barr virus (EBV) prior to the diagnosis of malignancy. To see if this is also true of „spontaneous”︁ cases in the general population, we undertook a collaborative serologic case‐control study. From 4 serum banks containing specimens from over 240,000 persons, 104 subjects were identified for whom a blood specimen had been stored an average of 63 months before diagnosis of NHL, and 259 controls matched for age, sex, ethnic group and date of serum collection. The relative risks (RR) for subsequent development of NHL associated with elevated levels of IgG and IgM antibodies against viral capsid antigen were 2.5 (95% confidence interval = 1.1‐5.7) and 3.2 (1.3‐7.5), respectively; these associations increased with age at diagnosis. For the nuclear antigen, the distribution of titers for cases was more restricted than that of controls, with fewer cases having either elevated or low titers, RR = 0.5 (0.2‐1.4) and 0.5 (0.2‐1.2), respectively. Cases had significantly lower antibody titers against the cytomegalovirus, RR = 0.4 (0.2‐0.9). These findings suggest that, at least for some patients, NHL is preceded by an enhanced level of endogenous immunosuppression with resultant EBV activation. This observation supports the role of EBV either directly in the development of NHL or as a primary marker of immune dysfunction.
Expression of lymphocyte homing receptor gene is lost in multi‐drug‐resistant variants of human T‐lymphoblastoid CCRF‐CEM cells
Authors: Cianfriglia M. , Yassen A. , Tombesi M. , Samoggia P. , Barca S. , Caserta M.
Published: February 2007

The 2.2‐kb human cDNA clone PBL32, encoding for the lymphocyte homing receptor (LHR) was used to study the expression of this determinant in multi‐drug‐resistant (MDR) variants of human T‐lymphoblastoid CCRF‐CEM (CEM) cells. LHR is significantly associated with the drug‐sensitive phenotype, its expression being progressively and quantitatively reduced in MDR variants of CEM cells according to the extent of drug resistance.
Anti‐tumoral activity of L and D isomers of aspartic acid β‐hydroxamate on L5178Y leukemia
Authors: Thomasset Nicole , Hamedi‐Sangsari Farid , Tournaire Roselyne , Navarro Claudine , Malley Serge , Goetsch Liliane , Grange Jacques , Vila Jorge
Published: February 2007

D and L isomers of aspartic acid β‐hydroxamate (respectively DAH and LAH) were compared for their in vitro and in vivo activity against the murine leukemia L5178Y and their tolerance in vivo in DBA/2 mice. DAH and LAH displayed comparable cytotoxic activity against L5178Y leukemia in vitro. Death of leukemia cells was observed at concentrations above 1.2 mM for both DAH and LAH. High concentrations of L‐asparagine partially reversed the growth‐inhibitory effects of DAH and LAH on L5178Y cells for concentrations of DAH and LAH lower than 0.6 mM. Intraperitoneal administration of DAH and LAH to mice showed that the LD10, LD50 and LD90 of DAH was 3‐ to 4‐fold greater for DAH than for LAH. DAH was able to eradicate L5178Y tumors in mice without inducing toxic deaths, whereas LAH at comparable doses killed all the animals treated.
Establishment of a new human cancer cell line secreting protease nexin‐II/amyloid β protein precursor derived from squamous‐cell carcinoma of lung
Authors: Itoh Hiroshi , Kataoka Hiroaki , Koita Hiroyuki , Nabeshima Kazuki , Inoue Teruhiko , Kangawa Kenji , Koono Masashi
Published: February 2007

A new cell line (LC‐1/sq) of human lung squatnous‐cell carcinoma was established from a surgically resected specimen of primary lung cancer. Upon continuous propagation in serum‐free culture medium, it secreted trypsin inhibitors into the conditioned medium. The major fraction of the trypsin inhibitor (TI‐1) was purified to apparent homogeneity by anion‐exchange and gel‐filtration high‐performance liquid chromatography (HPLC) and sodium dodecyl sulfate polyacrylamide gel electro‐phoresis (SDS‐PAGE) followed by transblotting to Immobilon. TI‐1 effectively inhibited trypsin. Chymotrypsin, plasmin and kallikrein were inhibited to a lesser extent, but urokinase‐type plasminogen activator, elastase, thrombin and papain were not inhibited. The activity of TI‐1 was acid‐stable and heat‐resistant, and its molecular weight was 115 kDa by SDS‐PAGE. It exhibited single NH2‐terminal sequence, and its first 20 NH2‐terminal amino‐acid residues were identical with those of protease nexin‐II (PN‐II)/amyloid β‐protein precursor (APP). These characteristics of TI‐1 suggest that the major trypsin inhibitor secreted by LC‐1/sq is indistinguishable from PN‐II/APP. LC‐1/sq is the first lung squamous carcinoma cell line that secretes functionally active trypsin inhibitor, PN‐II/APP, in vitro and is useful for studying its biological significance in malignant tumor.
Recombinant human granulocyte colony‐stimulating factor inhibits the metastasis of hematogenous and non‐hematogenous tumors in mice
Authors: Matsumoto Y. , Saiki I. , Murata J. , Okuyama H. , Tamura M. , Azuma I.
Published: February 2007

We studied the effects of in vivo administrations of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) on the metastasis of murine hematogenous and non‐hematogenous tumors in spontaneous and experimental metastasis models. Spontaneous lung metastasis caused by intra‐footpad injections of B16‐BL6 melanoma and Lewis‐lung‐carcinoma (3LL) cells were inhibited by intravenous (i.v.) and subcutaneous (s.c.) injections of rhG‐CSF after excision of the primary tumors. Recombinant hG‐CSF significantly inhibited liver metastasis when administered i.v. after i.v. injection of L5178Y‐ML25 T‐lymphoma cells. Multiple i.v. administration of rhG‐CSF after the tumor inoculation prolonged the survival times of mice inoculated i.v. with L5178Y‐ML25 lymphoma cells. Recombinant hG‐CSF did not directly affect the growth of B16‐BL6 and L5178Y‐ML25 cells in vitro. During the administration periods, both i.v. and s.c. injections of rhG‐CSF increased the number of total white blood cells (WBC) in peripheral blood to approximately 3 times the normal level in normal and tumor‐bearing mice. We also found that the administration of rhG‐CSF stimulates neutrophils to become cytostatic against these tumor cells. Our results indicate that the injection of rhG‐CSF is effective in inhibiting lung and liver metastases by activating neutrophils and increasing cell number.
Inhibition by retinoic acid of hepatocarcinogenesis induced by N‐nitrosomorpholine and of expression of myc oncogene protein in sprague‐dawley rats
Authors: Baba Miyako , Iishi Hiroyasu , Yamamoto Reiko , Tatsuta Masaharu
Published: February 2007

The effects of all‐trans‐retinoic acid (RA) on hepato‐carcinogenesis induced by N‐nitrosomorpholine (NNM) and on the expression of myc p 110 proteins were investigated in male Sprague‐Dawlay rats. Rats received i.m. injections of RA twice week and, from the beginning of the experiment, were given drinking water containing NNM for 8 weeks. Pre‐neoplastic and neoplastic lesions staining positively for gamma‐glutamyl transpeptidase (GGT), glutathione‐S‐transferase placental type (GST‐P) or myc p 110 protein were examined histochemically. At week 18, quantitative histological analysis showed that prolonged administration of RA resulted in a significant reduction in the number, size and volume of GGT‐positive and GST‐P‐positive hepatic lesions. Administration of RA also caused significant increase in the proportion of myc p 110‐negative lesions to the total pre‐neoplastic lesions observed. Myc p 110‐negative lesions had a significantly lower mitotic index than myc p 110‐positive lesions. These findings indicate that RA inhibits hepatocarcinogenesis and suggest that this effect may be related to its influence in reducing the expression of myc gene proteins and its subsequent inhibition of cell proliferation pre‐neoplastic lesions.
Risk factors for cancer of the oesophagus in Kerala, India
Authors: Sankaranarayanan R. , Duffy Stephen W. , Padmakumary G. , Nair S. Muralidharan , Day Nicholas E. , Padmanabhan T. K.
Published: February 2007

A case‐control study of oesophageal cancer was carried out in Trivandrum, Kerala, involving 267 cases and 895 controls. Risk factors studied in males were pan (betel)‐tobacco chewing, bidi and cigarette smoking, drinking alcohol and taking snuff. Only pan‐tobacco chewing was investigated in females as very few indulged in the other habits. Among males significant associations with higher risk were observed for bidi smoking (p < 0.001), bidi plus cigarette smoking (p > 0.05) and drinking alcohol (p < 0.001). While a significant effect of duration of pan‐tobacco chewing (p < 0.005) was observed in males, there was no significant trend, the risk first falling then rising as duration of use increased. This was partly due to confounding with smoking. No effect of pan‐tobacco use was observed in females. A step‐wise model was fitted, retaining only those risk factors which were significant when adjusted for other factors; the risk factors included were duration of pan‐tobacco chewing, duration of bidi smoking, daily frequency of bidi and cigarette smoking and alcohol use (yes or no). An adjusted relative risk of 2.03 was observed for a pan‐tobacco habit of more than 40 years' duration, of 4.70 for more than 20 years of bidi smoking, of 4.80 for more than 20 bidis/cigarettes per day, and of 2.33 for regular alcohol use (in each category relative to a baseline of those never indulging in the relevant habit).
Indications of future decreasing trends in skin‐melanoma mortality among whites in the United States
Authors: Scotto Joseph , Pitcher Hugh , Lee John A. H.
Published: February 2007

Trends in skin melanoma death rates during a 35‐year period, 1950‐84, were analyzed according to age, sex, and birth cohort for whites in the United States. In contrast to upward trends observed for older men and women (i.e., over 40), downward trends were noted for younger age groups. The risk of dying from skin melanoma appears to have peaked for male cohorts born during the 1950s and for female cohorts born during the 1930s. Assuming no future environmental or lifestyle changes, the upward trend in age‐adjusted mortality rates, which averaged 2 to 3% per annum since 1950, is projected to discontinue and bend downward by the second decade of the 21st century. Skin melanoma incidence data, which was limited to a series of 12 years (1973‐84) and inadequate for cohort analyses, were included to demonstrate that trends in age‐specific rates were comparable with those observed for mortality during the overlapping time period. Incidence trends according to anatomical site are also described. These results indicate that baseline data necessary for assessing the potential effects on this disease from future depletions of the ozone layer, and predicted increases of solar ultra‐violet radiation exposure, would be improved with the inclusion of cohort data and age‐specific trend analyses.
The systemic complement activation caused by interleukin‐2/lymphokine‐activated killer‐cell therapy of cancer causes minimal systemic neutrophil activation
Authors: Moore Francis D. , Schoof Deric D. , Rodrick Mary , Eberlein Timothy J.
Published: February 2007

Twenty‐three cancer patients undergoing therapy with interleukin‐2 and lymphokine‐activated killer cells were studied for evidence of complement activation and systemic neutrophil activation occurring during the course of therapy. Patient plasma samples demonstrated evidence of marked complement activation, with 3‐fold elevations of C3a desArg concentrations by the 8th day of therapy. Concentrations of C4a desArg were also elevated by the end of therapy. In vitro chemotaxis of patients' neutrophils both to C5a and to the synthetic peptide chemotaxin, FMLP, was initially normal and then fell progressively to 60% of normal by the end of treatment. Mean neutrophil cell‐surface expression of complement receptor Type 1 and complement receptor Type 3 increased in inverse temporal relationship to the deficit in chemotaxis, but showed no consistent pattern for individuals and was only doubled at maximum. Thus, despite a degree of complement activation which should have produced pronounced neutrophil activation, the response of the circulating neutrophils was diminished. In view of this discrepancy, the toxicity of this therapy may not be mediated by activation of circulating neutrophils.
Dietary factors and stomach cancer in Spain: A multi‐centre case‐control study
Authors: González Carlos A. , Sanz J. Miguel , Marcos Guillermo , Pita Salvador , Brullet Enric , Saigi Eugeni , Badia Asunción , Riboli Elio
Published: February 2007

A multi‐centre case‐control study of diet and gastric cancer was carried out in 4 regions of Spain (Aragon, Castile, Catalonia and Galicia). We selected 354 cases of pathologically confirmed gastric adenocarcinoma from 15 hospitals, representative of nearly all those in the study areas. A control for each case, matched by age, sex and area of residence, was selected from the same hospital as the case. Habitual diet was investigated by the dietary history method, and past diet by means of frequency questionnaire. The results regarding consumption of food items are presented here. With respect to habitual diet, an increase in risk was associated with consumption of preserved fish, cold cuts and oleaginous fruits. A high intake of cooked green vegetables, fresh noncitrus fruit and dried fruit showed an inverse association with the risk of gastric cancer. Simultaneous intake of 2 groups of food which increase or decrease the risk of cancer strengthens the respective individual effect. The intake of protective food items seems to neutralize the effects of food items which increase risk. With reference to past diet, possible a protective effect was observed for daily consumption of fresh fruit and green vegetables.
Survival of breast cancer patients in relation to factors which affect the risk of developing breast cancer
Authors: Ewertz Marianne , Gillanders Sonya , Meyer Lesley , Zedeler Karin
Published: February 2007

In order to evaluate the prognostic significance of risk factors for developing breast cancer, a population‐based study was conducted of 2,445 breast cancer patients diagnosed in Denmark, 1983‐1984. Data on clinical and pathological characteristics of breast cancer were derived from the Danish Breast Cancer Cooperative Group and data on risk factors from self‐administered questionnaire. Among 1,744 patients (71%) with complete information, survival was determined primarily by size of the tumour, skin invasion, number of positive lymph nodes and grade. No significant association was found between survival and reproductive or hormonal risk factors, dietary variables, alcohol consumption and smoking. Low current body weight and weight loss indicated a poor prognosis, independent of the clinical characteristics of the tumour.