bluuebunny/crossref_metadata_2025 huggingface dataset:
Lung cancer following Hodgkin′s disease: A case‐control study
Authors: Kaldor J. M. , Day N. E. , Bell J. , Clarke E. A. , Landmark F. , Karjalainen S. , Band P. , Pedersen D. , Choi W. , Blair V. , Henry‐Amar M. , Prior P. , Assouline D. , Pompe‐Kirn V. , Cartwright R. A. , Koch M. , Arslan A. , Fraser P. , Sutcliffe S. B. , Host H. , Hakama M. , Stovall M.
Published: February 2007

It is recognized that survivors of Hodgkin's disease are at a substantially increased risk of lung cancer. A collaborative group of population‐based cancer registries and major treatment centers carried out a case‐control study, in which 98 cases of lung cancer were identified in patients who had survived at least 1 year following a diagnosis of Hodgkin's disease. A total of 259 matched controls were selected from patients with Hodgkin's disease who did not develop subsequent lung cancer, and for both cases and controls detailed information was abstracted from medical records concerning stage and treatment of Hodgkin's disease. Patients treated with chemotherapy alone had about twice the risk of developing lung cancer than those treated by radiotherapy alone or both modalities. There was no increase in risk with cumulative number of cycles of chemotherapy. Among patients treated with radiotherapy alone, there was an increase in risk related to estimated radiation dose to the lung. There was also a strong association between cigarette smoking and the risk of lung cancer. The finding of a higher risk following chemotherapy than following radiotherapy was unexpected, but could not be explained by any identified methodological flaws. A plausible inference from the study is that all forms of Hodgkin's disease therapy are carcinogenic to the lung and that, in particular, chemotherapy is associated with an increase in risk which is at least comparable to and perhaps higher than the risk produced by radiotherapy. © 1992 Wiley‐Liss, Inc.
Viral CO‐infections in human papillomavirus‐associated anogenital lesions according to the serostatus for the human immunodeficiency virus
Authors: Bernard Catherine , Mougin Christiane , Madoz Laurence , Drobacheff Christine , van Landuyt Hervé , Laurent Rene , Lab Michel
Published: February 2007

In HIV‐infected men, human papillomavirus (HPV) infection is strongly linked with the development of anogenital lesions but is not a sufficient factor to explain the neoplastic transformation of such lesions. We investigated the association between HPV and herpesvirus infections in penile and anal lesions from 54 HIV‐seronegative and 54 HIV‐seropositive men by means of colposcopy, histopathology andin situhybridization. Our patients showed condyloma acuminata (39%), papular warts (35%) and macular warts (26%). High‐grade lesions were predominant in the HIV+men, whereas low‐grade lesions were more frequent in the HIV−men. In the HIV+group, potential oncogenic HPV were the most frequently detected (83.4%) whereas the “low‐risk” HPV were found chiefly in HIV−men (62.1%). The CD4 number was lower in patients showing “high‐risk” HPV than in men showing lesions without HPV or with non‐oncogenic HPV. HPV types 6/11 were found mainly associated with koilocytosis or with AIN(PIN)I. Oncogenic HPV were more often detected in AIN(PIN)II‐III. The herpesviruses DNA detection revealed a higher prevalence of HSV1 and ‐2 than CMV and EBV in the studied biopsies. The frequency of HSV and CMV detection was higher in the HIV+than in the HIV−men. A link was found between the “high‐risk” HPV and the CMV detection whatever the population considered. The detection in HPV lesions of other sexually transmitted viral agents could therefore represent an important means of preventing progression of the anogenital disease, especially in immuno‐suppressed patients. © 1992 Wiley‐Liss, Inc.
Suppression of basal, PMA‐and IFN‐α‐, but not IFN‐γ‐induced expression of HLA class I in v‐myc‐transformed U‐937 monoblasts
Authors: Larsson L.‐G. , Öberg F. , Stöckbauer P. , Masucci M. G. , Nilsson K.
Published: February 2007

Recent studies have suggested that certain oncogenes, in particular members of the myc family, may be involved in the down‐regulation of HLA class‐1 antigen expression observed in many types of tumor. We report that constitutive expression of an OK 10 v‐mye gene in human monoblastic U‐937 cells results in a reduced expression of HLA class‐1 cell‐surface expression and decreased levels of HLA class‐1 protein and mRNA. All class‐1 alleles, with the possible exception of HLA A3, were affected, as shown by one‐dimensional isoelectric focusing (ID‐IEF). Basal expression of the β2m chain was also reduced, although to a lesser extent. In addition, we show that the PMA‐, and at least partially the IFN‐α‐induced increase in HLA class‐1 antigen expression, was inhibited in U‐937‐myc cells both at the protein and the mRNA level. In contrast, the response to IFN‐γ was normal. Another important difference in the response to IFN‐γ and a was that, while IFN‐γ abrogated the v‐myc block of PMA‐induced differentiation of U‐937 cells, as previously reported, IFN‐α did nat. Our data show that v‐myc negatively affects the regulation of both basal and inducible HLA class‐1 antigen expression. © 1992 Wiley‐Liss, Inc.
Regulation of androgen receptor gene expression by steroids and retinoic acid in human breast‐cancer cells
Authors: Hall Rosemary E. , Tilley Wayne D. , McPhaul Michael J. , Sutherland Robert L.
Published: February 2007

Although the androgen receptor (AR) has been detected by ligand‐binding assays, there is little known about the expression and regulation of the AR gene in human breast‐cancer cells. AR mRNA, measured by Northern analysis in 18 cell lines, was found to be expressed predominantly in oestrogen‐ and progesterone‐receptor‐positive (ER+, PR+) lines as a single species of approximately 10.5 kb but was also comparatively abundant in I ER‐ and PR‐negative cell line, MDA‐MB‐453. Dexamethasone (Dex), Organon 2058 (Org 2058), dihydrotestosterone (DHT), and all‐trans‐retinoic acid (RA) down‐regulated AR mRNA levels in T‐47D (ER+, PR+) cells 6 hr after treatment, whereas oestradiol (E2) had no effect. In MDA‐MB‐453 (ER−, PR−) cells, regulation of AR mRNA by RA differed from the other cell lines: RA increased the level of AR mRNA. DHT‐binding assays indicated a corresponding increase in AR protein. Transfection of the androgen‐responsive mouse mammary tumour virus long‐terminal repeat (MMTV LTR) linked to a chloramphenicol acetyltransferase (CAT) reporter gene was used to examine the effect of altered AR levels on androgen action. The increased level of AR following RA pre‐treatment in MDA‐MB‐453 cells resulted in enhanced induction of CAT activity by DHT and, conversely, a decrease in the level of AR following RA pretreatment in T‐47D cells resulted in reduced induction of CAT activity by DHT. These data demonstrate that AR is expressed predominantly in ER+ and PR+ cell lines and its expression is regulated by ligands also known to regulate ER or PR, including progestins and retinoids. Androgen responsiveness measured by a transfected reporter gene was altered according to the extent of up‐ or down‐regulation of AR expression, demonstrating that responsiveness is dependent on receptor concentration. © 1992 Wiley‐Liss, Inc.
Inhibition by 6‐hydroxydopamine of enhanced gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in spontaneously hypertensive rats
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Baba Miyako , Taniouchi Haruo
Published: February 2007

The effects of chemical sympathectomy induced by 6‐hydroxydopamine (6‐OHDA) on the enhanced induction of gastric carcinogenesis by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) in spontaneously hypertensive rats (SHR), and the norepinephrine (NE) concentrations in their gastric wall and the labeling index of gastric epithelial cells were investigated. SHR rats and normotensive Wistar Kyoto rats (WKY) as controls were given MNNG (25 μ/ml) in their drinking water for 25 weeks and then i.p. injections of 6‐OHDA (42 mg/kg twice within 24 hr, and then 105 mg/kg every 2 weeks from I week later). In control group (WKY rat + NaCI), gastric cancers were found in 2 (11%) of 18 rats examined in week 52. In SHR rats treated with NaCI solution only, the incidence of gastric cancers significantly increased, to 53% compared with that in control WKY rats. Treatment of SHR rats with 6‐OHDA significantly decreased its incidence to 12% compared with the value in SHR rats treated with NaCI solution only. Prolonged administration of 6‐OHDA to SHR rats significantly reduced the NE concentration in the antral portion of the gastric wall and the labeling index of antral epithelial cells. These findings indicate that prolonged i.p. treatment with 6‐OHDA attenuated the normally higher incidence of MNNG‐induced gastric cancer in SHR rats. © 1992 Wiley‐Liss, Inc.
Expression and function of VLA‐α2, ‐α3, ‐α5 and ‐α6‐integrin receptors in pancreatic carcinoma
Authors: Weinel R. J. , Rosendahl A. , Neumann K. , Chaloupka B. , Erb D. , Rothmund M. , Santoso S.
Published: February 2007

The expression of the VLA‐integrins α2, α3, v5 and α6 was studied immunohistochemically in tissue samples from ductal pancreatic cancer, chronic pancreatitis, normal pancreas and in 8 cell lines of ductal human pancreatic cancer. Furthermore, adhesion assays on purified extracellular matrix (ECM)‐compounds were used to define the function of α2, α3, α5 and α6in pancreatic cancer cells. Immunohistochemically, VLA α2 and VLA α6 were moderately to strongly expressed on the basal surface of ductal and acinar cells in normal pancreatic tissue, while centro‐acinar cells predominantly expressed VLA α3 and VLA α5. Pancreatic carcinoma showed intense staining for VLA α2 and VLA α6 with a diffuse distribution on the cell surface. The redistribution of VLA α2 and VLA α6 may reflect a loss of spatial arrangement of tumor cells and their ability to interact randomly with extracellular matrix structures during invasion and metastasis. Expression of VLA α3 and VLA α5 in pancreatic carcinoma was heterogeneous, ranging from moderate to weak, and was lost in about 50% of the cells. Two pancreatic carcinoma cell lines (PC 3, PC 44) were further investigated in adhesion assays. Monoclonal antibodies (MAbs) against α2 (Gl 9, 10‐G‐11) were able to inhibit tumor‐cell adhesion to collagen IV (59%‐72%) in both cell lines. A MAb against α6 (GoH3) inhibited tumor‐cell adhesion to laminin (52%‐86%) in both cell lines. These results suggest that α2 is a collagen‐binding site and α6 a laminin‐binding site in pancreatic cancer cells. The anti‐α5‐MAb SAM I inhibited adhesion of PC3 to fibronectin (76%), being without effect in PC44. Adhesion of both cell lines to fibronectin was almost completely inhibited by RGDS (85%‐88%). Thus, α5is a functionally important fibronectin binding site in some pancreatic carcinoma cells, suggesting further RGD‐dependent fibronectin binding sites in other pancreatic carcinoma cells. © 1992 Wiley‐Liss, Inc.
Cell kinetics evaluation of colorectal tumors after in vivo administration of bromodeoxyuridine
Authors: Roncucci Luca , Pedroni Monica , Scalmati Alessandra , Bormioli Maria Luisa , Sassatelli Romano , Fante Rossella , Losi Lorena , di Gregorio Carmela , Petocchi Benedetta , de Leon Maurizio Ponz
Published: February 2007

Although several biomarkers have been tested, Dukes' (or TNM) stage at diagnosis is still considered the only prognostic factor of clinical relevance in colorectal cancer. Among the various biomarkers, the fraction of cells engaged in DNA synthesis has been extensively investigated as an indicator of tumor aggressiveness. Bromodeoxyuridine (BUdR) is a non‐radioactive thymidine analogue which is incorporated into DNA during the S‐phase of cycling cells. In order to evaluate the relationships between cell kinetics and morphologic variables, 500 mg of BUdR were given i.v. to 46 patients with colorectal cancer prior to surgery. After operation, a large tumor sample was taken and processed for immunohistochemical detection of BUdR‐labeled cells in various regions of the neoplasm and in normal colorectal mucosa. Smaller superficial tumor specimens were also incubated with 3H‐thymidine (3H‐TdR) for the autoradiographic identification of labeled cells. In the 43 evaluable tumors, the overall BUdR labeling index (BLI, percent of labeled cells) was significantly higher in carcinoma (20.30 ± 0.86%, SEM) than in normal colonic mucosa (6.51 ± 0.49%). BLIs in central and peripheral regions of carcinoma were closely correlated (r = 0.48, p = 0.003). In 21 neoplasms a high correlation between overall BUdR and 3H‐TdR labeling index in the same tumor was observed (r = 0.57, p = 0.007). No evident association between overall BLI and clinical or morphologic parameters of the tumor was seen, including number of capillaries and ras‐p2l protein expression. We conclude that BUdR immunostaining after in vivo administration of BUdR is a simple method for studying cell kinetics in various regions of colorectal cancer. BUdR labeling data are comparable to those obtained with in vitro incorporation of 3H‐TdR. © 1992 Wiley‐Liss, Inc.
Antibody against p58 surface antigen of RA‐2 rat rhabdomyosarcoma cells inhibits their metastatic activity
Authors: Guzhova Irina V. , Margulis Boris A. , Kaminskaya Elena V.
Published: February 2007

Antibodies generated against the whole membrane preparation isolated from rhabdomyosarcoma RA‐2 cells were shown by immunoblotting and immunoaffinity chromatography to recognize 58‐kDa polypeptide, p58. The latter was confirmed to be a surface molecule in a test of radioiodination of RA‐2 membrane by lodogen. The antibodies added to a suspension of RA‐2 cells before their inoculation into rats decreased metastatic activity 50‐fold without any noticeable influence on RA‐2 proliferation level and viability. The data indicate that masking of p58 surface antigen by antibodies could make RA‐2 cells unable to form experimental metastases in lung. We suggest that p58 may participate in the specific recognition by RA‐2 of lung endothelial cells. © 1992 Wiley‐Liss, Inc.
VLA‐4 integrin on sarcoma cell lines recognizes endothelial VCAM‐1. Differential regulation of the VLA‐4 avidity on various sarcoma cell lines
Authors: Mattila Pirkko , Majuri Marja‐Leena , Renkonen Risto
Published: February 2007

Osteosarcomas and rhabdomyosarcomas are vigorously invading tumors. Before they can extravasate to the parenchymal organs and form metastases, they have to adhere to the endothelial cells lining the blood vessels and then penetrate through the endothelium. We show that several human sarcoma cell lines, osteosarcomas HOS, MG‐63, U2‐OS, and a rhabdomyosarcoma RD, express VLA‐4 molecule on their surface and bind to the VCAM‐1 ‐expressing activated endothelial cell line Ea.hy 926. The increased sarcoma‐cell adhesion could be abolished by treating the sarcoma cells with monoclonal antibodies (MAbs) VLA4 (both α‐ and β‐chain, HP2/1 and 4B4 respectively) or treating endothelial cells with VCAM‐1 antibody (4B9). Furthermore, we show that sarcoma cells adhere to recombinant soluble VCAM‐1 protein. On the other hand, these sarcoma cell lines do not express marked amounts of other ligands (such as CD11/18 or sialyl‐Lex) for other endothelial adhesion molecules (ICAM‐1, ICAM‐2, E‐ and P‐selectin) indicating that the VLA‐4‐VCAM‐1 dependent pathway might be of major importance in sarcoma extravasation. VLA‐4 is not always in an avid form and therefore the expression of VLA‐4 does not directly predict adherence to VCAM‐1. The avidity of VLA‐4 (measured by adherence to soluble VCAM‐1) of MG‐63 and U2‐OS cells could be increased by a 30‐min PMA treatment, whereas the avidity of VLA‐4 on HOS cells increased only after 48 hr of PMA induction. Our results show that sarcoma cell lines (HOS, MG‐63, U2‐OS and RD) adhere to stimulated endothelium via VLA‐4‐VCAM‐1 adhesion molecules and that VLA‐4 avidity on sarcoma cells can be differentially modulated by PMA. © 1992 Wiley‐Liss, Inc.
Protection by muscimol against gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in spontaneously hypertensive rats
Authors: Tatsuta Masaharu , Iishi Hiroyasu , Baba Miyako , Uehara Hiroyuki , Nakaizumi Akihiko , Taniguchi Haruo
Published: February 2007

The effects of prolonged administration of the gamma‐aminobutyric acid receptor agonist muscimol on enhanced induction of gastric carcinogenesis by N‐methyl‐N′‐nitro‐N‐nitrosoguanid ine (MNNG) in spontaneously hypertensive rats (SHR), and on the norepinephrine concentration in the gastric wall and the labeling index of gastric mucosa were investigated. SHR and normotensive Wistar Kyoto (WKY) rats as controls were given a solution of MNNG (25 fig/ml) for 25 weeks and then i.p. injections of 0.5 mg/kg body weight of muscimol every other day. In control WKY rats, gastric cancers were found in I (7%) of 14 rats examined at week 52. In SHR treated with NaCI solution only, the incidence of gastric cancers was significantly increased to 50% compared with that in control WKY rats. However, treatment of SHR with muscimol significantly increased its incidence to 12% compared with the value in SHR treated with NaCI solution only. The norepinephrine concentration in the gastric wall and the labeling index of the gastric mucosa were significantly greater in SHR than in WKY rats. Prolonged administration of muscimol to SHR significantly reduced the norepinephrine concentration in the antral portion of the gastric wall or the labeling index of the antral epithelial cells. These findings indicate that long‐term treatment of SHR with muscimol attenuated the enhancement of gastric carcinogenesis in SHR. © 1992 Wiley‐Liss, Inc.
Second‐messenger pathways involved in the regulation of survival in germinal‐centre B cells and in burkitt lymphoma lines
Authors: Knox Kirstine A. , Finney Michael , Milner Anne E. , Gregory Christopher D. , Wakelam Michael J. O. , Michell Robert H. , Gordon John
Published: February 2007

Spontaneous apoptosis in germinal‐centre (G.C) B cells can be prevented by treatment with anti‐immunoglobulin (Ig). By contrast, susceptible group‐l Burkitt lymphoma (BL) cells can be driven to apoptosis by anti‐lg. The second‐messenger pathways involved in the regulation of apoptosis in GC B lymphocytes and in BL cell lines were studied using pharmacological agonists or inhibitors of intracellular calcium ([Ca2+],) and protein kinase C (PKC). Anti‐lg was found to mobilize Ca2+ in group‐l cells. Pre‐incubation with the Ca2‐ chelator EGTA partially reduced apoptosis induced by anti‐lg or by Ca2+ionophore in group‐l BL cells. Activation of PKC with phorbol ester reduced such Ca2+‐driven programmed cell death (PCD) to control levels of apoptosis. Apoptosis in group‐l BL cell lines could also be triggered by the kinase inhibitors staurosporine and Ro‐31 ‐8220 at concentrations selective for PKC activity. Expression of the bcl‐2 protein in BL group‐l cells following gene transfer affords protection from apoptosis induced by ionomy‐cin or anti‐lg. In the present study, bcl‐2 was additionally found to protect from apoptosis driven by staurosporine. The high levels of spontaneous apoptosis exhibited fay normal GC 6 cells were reduced, but not abrogated, by co‐culture with phorbol ester. These results indicate that, in group‐l BL cells, imbalance in the phosphoinositide pathway of signalling, in favour of [Ca2+], and away from PKC, results in apoptosis: constitutive phosphorylation of key proteins by PKC may therefore suppress apoptosis in BL as well as in GC B cells. © 1992 Wiley‐Liss, Inc.
p53 mutations and aflatoxin B1 exposure in hepatocellular carcinoma patients from thailand
Authors: Hollstein Monica C. , Wild Christopher P. , Bleicher Françoise , Chutimataewin Sopa , Harris Curtis C. , Srivatanakul Andpetcharin , Montesano Ruggero
Published: February 2007

The prevalence and type of mutations in the p53 tumoursuppressor gene have been determined in 15 hepatocellular carcinomas (HCC) originating from Thailand. Direct sequencing of exons 5‐8 revealed 2 mutations, an AGG to AGT (Arg → Ser) transversion at codon 249, and an ATC → AAC (lle → Asn) transversion at codon 254. Samples from the Thai patients were analyzed for the presence of aflatoxin‐liver DNA and aflatoxinserum albumin adducts, and all but one were found negative. All the patients were genotyped for glutathione‐S‐transferase (GST) μ, an enzyme possibly involved in the detoxification of AFB1, and 12 out of 15 had the null genotype. In general, the level of aflatoxin‐albumin adducts in sera and the prevalence of p53 mutation at codon 249 in HCC were lower than in other areas at high risk of HCC, including southern China and parts of Africa.
A sub‐site‐specific analysis of the relationship between colorectal cancer and parity in complete male and female norwegian birth cohorts
Authors: Kravdal Øystein , Glattre Eystein , Kvåle Gunnar , Tretli Steinar
Published: February 2007

Register and census data for complete cohorts of Norwegian men and women born between 1935 and 1969 have been used to examine the relationship between reproductive factors and the incidence of colorectal cancer. Among 1.1 million men and 1.1 million women under observation, 491 male and 859 female cases of colorectal cancer were diagnosed during the period of follow‐up. Our hazard model estimates clearly show that in these young cohorts, women with 2 or more children run a lower risk of having a malignant tumor in the cecum or ascending colon than do other women of the same age and in the same birth cohort. No association with parity is found with respect to cancer in the transverse or descending colon, whereas a downward trend in the effect estimates, followed by an upturn, appears for the rectum, sigmoid colon and rectosigmoid junction. Such correlations, which also hold when we control for education and place of residence, are not found for men. The observed relationship between parity and cancer incidence is not likely to be exclusively explained by life‐style differentials. Presumably, there is a biological effect of the number of pregnancies and deliveries, net of age at first birth and other reproductive factors, on the development of colorectal cancer.
Interferon‐γ modulates retinoblastoma gene mrna in monocytoid cells
Authors: Mistchenko Alicia S. , Diez Roberto A. , Romquin Nicole , Sancéau Josiane , Wietzerbin Juana
Published: February 2007

To study the effect of interferon gamma (IFN‐γ) on the expression of the retinoblastoma (RB) susceptibility gene, we performed Northern‐blot analysis on RNA extracted from Wish, HEL and monocytoid cell lines U‐937 and THP‐I treated with 1,000 IU/ml of recombinant IFN‐γ. In U‐937 and THP‐I cells, IFN‐γ increased the abundance of RB mRNA. In Wish and HEL cells, co‐treatment with cycloheximide was required for IFN‐γ to increase the level of RB mRNA. Pre‐treatment THP‐I cells with cycloheximide prior to IFN‐y treatment augmented the effects of IFN‐γ on RB gene expression. The effect of IFN‐γ in THP‐I cells was observed after 3 hr treatment, being more pronounced after 6 hr and persisting until at least 18 hr, although at a lower level. These results suggest that IFN‐γ regulates the level of RB mRNA by different mechanisms in the different cell types. This cytokine increases the abundance of RB mRNA in monocytoid cell lines, reinforced by prior treatment with cycloheximide. Inhibition of protein synthesis is required in Wish and HEL cell lines before IFN‐γ has an effect on RB gene expression.
Induction of apoptosis in human leukemic cells by the ether lipid 1‐octadecyl‐2‐methyl‐RAC‐glycero‐3‐ phosphocholine. A possible basis for its selective action
Authors: Diomede Luisa , Colotta Francesco , Piovani Bianca , Re Fabio , Modest Edward J. , Salmona Mario
Published: February 2007

Ether‐linked glycerophospholipids (ether lipids, EL) are membrane‐interactive drugs selectively cytotoxic toward neoplastic cells compared with normal cells. No conclusive explanation has yet been provided for this selectivity. We now present data indicating that the drug 1‐octadecyl‐2‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OMe) induces apoptosis, or programmed cell death, in human leukemic cells. Apoptotic death is induced selectively by ET‐18‐OMe in HL60 cells, which are sensitive to the drug's cytotoxic action, but not in the resistant K562 cell line. Enrichment of HL60 cells with cholesterol (HWO‐CHOL cells) significantly protects the cells from the cytotoxic effect and from the induction of apoptosis by ET‐18‐OMe; the percentage of fragmented DNA is only 17% for HL60‐CHOL, compared with 50% in native HL60 cells after exposure to 20 μ ET‐18‐OMe for 24 hr. Our study provides a possible explanation for differences in sensitivity to EL among different cell types and illustrates an indirect interaction of EL with cellular DNA.
Production and characterization of a mouse/human chimeric antibody directed against human neuroblastoma
Authors: Amstutz H. , Rytz Ch. , Novak‐Hofer I. , Spycher M. , Schubiger P. A. , Blaser K. , Morgenthaler J.‐J.
Published: February 2007

Hybridoma CE7 produces a murine antibody (yl/k) which binds to a 190‐kDa cell‐surface glycoprotein of human neuroblas‐toma. Because of its tumor specificity, it has been used routinely in clinical pathology to confirm diagnosis of neuroblastoma. We have Isolated the gene segments coding for the variable regions of the immunoglobulin Hand L chain of this hybridoma. These V genes were used to construct mouse/human chimeric H and L chain genes (yl/K) which were then expressed in SP2/0 cells. A cell‐blnding inhibition assay showed that the specificity of the chimeric CE7 antibody (chCE7) is identical to that of the original CE7. Radioiodinated chCE7 binds to approximately 43,000 sites per neuroblastoma cell with an affinity of IOIO M‐I. In neuroblastoma‐bearing nude mice, biodistribution studies with [I25I]ch‐CE7 were performed and tumor accumulations of up to 32% of injected dose/g tissue together with low blood and organ uptake were found.
Effects of EGF, BFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain‐tumour biopsies In Vitro
Authors: Engebraaten Olav , Bjerkvig Rolf , Pedersen Paal‐Henning , Laerum Ole Didrik
Published: February 2007

Spheroids initiated directly from human primary gliomas were used to investigate the effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferation, migration and invasion into foetal rat brain tissue. EGF increased tumour spheroid volume in 10 of 13 glioblastomas studied, whereas 5 of 11 tumours responded to bFGF. NGF increased the spheroid volume in 2 of 5 tumours. In 8 tumours, PDGF(bb) had no effect on tumour spheroid volume. An increase in BUdR‐labelling indices confirmed that cell proliferation was responsible for the volume increase observed in stimulated spheroids. EGF stimulated cell migration in 5 and bFGF in 3 of 8 tumours studied. NGF stimulated cell migration in 1 of 5 glioblastomas, whereas 1 of 3 glioblastomas responded to PDGF(bb). The effects of growth factors on the invasion of spheroids prepared from the glioblastoma biopsy specimens were also studied in vitro using foetal rat brain aggregates as target tissue. EGF stimulated invasion in 7 of 8 glioblastomas studied, whereas bFGF stimulated invasion in 2 of these tumours. NGF or PDGF(bb) did not increase the invasiveness of the glioblastoma tissue. Our results represent the net effect of the growth factors on a complex tumour‐cell population. We conclude that exogenously administered growth factors, EGF in particular, increase the cell proliferation as well as migratory and invasive capacities of cultured primary brain tumour biopsies in vitro.
Long‐term impact of reproductive factors on cancer risk
Authors: La Vecchia Carlo , Negri Eva , Franceschi Silvia , Parazzini Fabio
Published: February 2007

The relationship between reproductive variables (parity, age at first birth, number of induced and spontaneous abortions) and cancer risk has been analysed using data from an integrated series of case‐control studies conducted in northern Italy between 1983 and 1992. The overall data‐set included women below age 75 with histologically confirmed cancers of the following sites: oesophagus, 58; stomach, 280; colon, 405; rectum, 210; liver, 82; gall‐bladder, 29; pancreas, 129; breast, 3,415; cervix, 742; endometrium, 725; ovary, 953; bladder, 68; kidney, 56; thyroid, 180; lymphomas, 80; myelomas, 57; and a total of 5,619 controls admitted to hospital for acute non‐neoplastic, non‐gynaecological, non‐hormone‐related conditions. Multivariate odds ratios, as estimators of relative risks (RR), were obtained after allowance for age, education, use of oral contraceptives and oestrogen replacement treatments, plus various reproductive factors. Direct significant trends with parity were observed for cancer of the liver (RR for women with ≥4 births vs. nulliparae = 3.3) and cervix uteri (RR = 4.1). The risk of gall‐bladder cancer was also elevated for multiparae (RR = 1.9). No significant inverse trend in risk emerged. However, the RRs in multiparae were significantly below unity for breast (RR = 0.8), endometrium (RR = 0.7), and ovary (RR = 0.8). With reference to age at first birth, a significant trend in risk was observed for breast cancer (RR = 1.4 for 25 to 29 and 1.5 for ≥30 vs. ≤ 25 years). In contrast, the risk of cervical cancer was inversely related to age at first birth. For spontaneous abortions, the only significant inverse trend was for ovarian cancer (RR = 0.7 for ≥2 vs. 0 abortions), but also the point estimate for endometrial cancer in women with ≥2 abortions was below unity. For induced abortions, there was a strong inverse trend in risk for endometrial cancer (RR = 0.5), and the RRs were below unity also for colon and breast cancer. In contrast, cervical cancer was directly associated with the number of spontaneous abortions. Although the underlying aetiological interpretations are different for various cancer sites, this study provides, in a large and uniform data‐set, quantitative information on the long‐term impact of reproductive factors on cancer risk.
Sinonasal cancer and occupational exposure to formaldehyde and other substances
Authors: Luce Danièle , Gérin Michel , Leclerc Annette , Morcet Jean‐François , Brugère Jacques , Goldberg Marcel
Published: February 2007

A case‐control study of cancer of the nose and paranasal sinuses was conducted in France to determine whether occupational exposure to formaldehyde was associated with an Increased risk of sinonasal cancer. Exposures to 14 other substances or groups of substances were also studied (wood dust, leather dust, textile dust, flour dust, sugar dust, coal/coke dust, nickel compounds, chromium compounds, chromium VI, welding fumes, soldering fumes, cutting oils, paints and lacquers, glues and adhesives). Cases (n = 207) and controls (n = 409) were interviewed to obtain detailed information on job history and other potential risk factors for sinonasal cancer. In addition, a questionnaire specially designed for this study was used to help assess exposures to formaldehyde and other substances of interest. The questionnaires were translated into history of occupational exposure by an expert in industrial hygiene, without knowledge of case‐control status. Several exposure variables (lifetime average level, duration, cumulative level) were used to describe the risks related to exposure to formaldehyde. Potential confounding factors (occupational and non occupational) were examined and adjusted for when necessary.

No significant association was found between exposure to formaldehyde and squamous‐cell carcinomas of the sinonasal cavities.

Because of the strong association between exposure to wood dust and nasal adenocarcinoma, it was not possible to assess an independent effect of formaldehyde on this type of cancer. However, among males exposed to medium or high levels of wood dust, the risk of adenocarcinoma associated with formaldehyde was significantly elevated for the highest exposure categories for average level (OR = 5.3, 95% confidence interval = 1.3‐22.2), cumulative level (OR = 6.9, 95% CI = 1.7‐ 28.2) and duration of exposure (OR = 6.9,95% CI = 1.7‐27.8).

Although a residual confounding effect of wood dust could not be excluded, this study suggests that exposure to both formaldehyde and wood dust may increase the risk of nasal adenocarcinoma, by comparison with the risk due to wood dust alone.

This study also indicated an increased risk among males who had been exposed to glues and adhesives, for all histologic types, which was not explained by a confounding effect of paints and lacquers, wood dust or formaldehyde. No other significant association was observed.
Characteristic patterns of hox gene expression in different types of human leukemia
Authors: Celetti Angela , Barba Pasquale , Cillo Clemente , Rotoli Bruno , Boncinelli Edoardo , Magli Maria Cristina
Published: February 2007

Homeobox‐containing genes are a network of genes encoding DNA‐binding proteins highly conserved throughout evolution. They are involved in the control of normal development as well as in the regulation of gene expression in adult differentiating systems, including hematopoiesis. Aberrant expression of homeobox‐containing genes has recently been related to leukemic phenotype. Human homeobox‐containing genes of the HOX family are organized into 4 large clusters. We have analyzed the expression of HOX genes in different types of human leukemia to investigate whether the physical organization of HOX loci reflects a regulatory hierarchy involved in the differentiation of hematopoietic cells or whether HOX gene expression might contribute to the leukemic phenotype. Our results show that HOX genes are coordinately regulated in blocks in myeloid cells whereas they appear to function as isolated genes in lymphoid cells. Six contiguous genes of the HOX2 locus, highly expressed in acute non‐lymphocytic leukemia, are switched off in chronic myelogenous leukemia, suggesting that down‐regulation of HOX2 genes might be required for cell maturation of the myeloid lineages. In contrast, a few scattered genes are active in lymphoid populations. These observations suggest that hematopoietic cells express a repertoire of HOX genes characteristic of a particular cell lineage at a specific stage of differentiation. The characteristic patterns of HOX gene expression may reflect the potentially important role that these genes play in cell lineage determination during both normal and leukemic hematopoiesis.
Cancer‐cell traffic in the liver. II. Arrest, transit and death of B16F10 and M5076 cells in the sinusoids
Authors: Barbera‐Guillem Emilio , Smith Isabel , Weiss Leonard
Published: February 2007

Fluorescent probes were used to detect BUdR‐labelled B16F10 and M5076 cancer cells delivered to the livers of mice via intrasplenic injection. In liver sections stained for succinic dehydrogenase, which permits the periportal, acinar zone I to be distinguished from the pericentral zone 3, counts were made the zonal distribution of fluorescent, intact cancer cells and, by default, the numbers of “lost” cells. Very few intact cancer cells leave the liver from the single bolus of the intrasplenic injection, and even fewer of these generate pulmonary lesions; therefore, within the time limits of these experiments, the liver virtually a closed system. A dynamic view of intrahepatic cancer‐cell traffic with respect to zones I (periportal) and 3 (pericentral) was obtained from static measurements of cell densities at different times after intrasplenic injection, by means of Markov chain probability analysis. This indicated that, during the first hour after arrival in zone I of the liver sinusoids, there is 10% probability of a B16F10 cell remaining intact in zone 1, an 89% probability of cell death in zone 1 and only a 1% probability of the cell passing into zone 3. During the same period, there is a 77% probability of an M5076 cell remaining intact in zone 1, 21% probability of death, and a 2% probability of relocation to zone 3. In both cell types, very few cells were lost from zone 3. Further proportional death in zone 1 diminished over the next 23 hr, concomitant with an increased proportion of cell death in zone 3. Our results indicate that, although there is considerable variation between the 2 cell types studied here, most (B16) or many (M5076) of these cancer cells entering the liver via the portal vein die within 1 hr in zone 1 of liver lobules. In addition, very few of the cells delivered to zone 1 travel along the sinusoids to zone 3, and few of these reach the lungs in a viable state.
Carcinogen‐induced accumulation of adeno‐associated parvovirus dna is transient as a result of two antagonistic activities that both require De Novo protein synthesis
Authors: Bantel‐Schaal Ursula
Published: February 2007

Helper‐independent synthesis of adeno‐associated parvovirus type 5 (AAV‐5) DNA in SV40‐transformed Syrian hamster cells is induced by chemical carcinogens, UV light and other stress treatments and has previously been shown to be transient. To gain some insight into the underlying mechanism, the influence of inhibitors of protein synthesis on AAV DNA accumulation was investigated. It is shown that transience is the result of 2 antagonistic activities‐synthesis and decomposition. Both depend on de novo protein synthesis and are in part overlapping. The 2 activities are influenced by the amount of AAV uptake and/or by cell density. In less dense cultures, calculated initial amount of AAV DNA and relative accumulation per cell are higher. The effect may be due to the activity of transiently synthesized AAV‐encoded regulatory proteins that increase replication and have inhibitory effects on DNA decomposition, or to the influence on cellular adhesion.
Loss of heterozygosity at the short arm of chromosome 3 in renal‐cell cancer correlates with the cytological tumour type
Authors: Van Hout A. H. Der , Van Berg E. Den , Van Vlies P. Der , Dijkhuizen T. , Störkel S. , Oosterhuis J. W. , De Jong B. , Buys C. H. C. M.
Published: February 2007

A majority of renal‐cell tumours retain heterozygosity at the short arm of chromosome 3. To investigate possible histopathological differences between tumours with and without such losses, we compared loss of heterozygosity data from 51 tumours with 1 histological and 2 different cytological classifications of renal‐cell tumour. Using the cytological classification of Thoenes et al., we only found tumours with loss of heterozygosity in these authors' clear‐cell category. Possibly, only these tumours arise by a mechanism of double loss of a tumour‐suppressor gene on 3p, non‐clear‐cell renal tumours having a different genetic background. Alternatively, deletions may occur in all subtypes, in which case those subtypes in which no LOH is found may also contain deletions too small to be detected with the set of 3p probes we used. A cytogenetic analysis was carried out on 30 of the tumours. Results of molecular and microscopic cytogenetic analyses did not seem to be in agreement in 12 cases. In 6 of these we found allelic losses in tumours showing morphologically normal copies of chromosome 3. Mitotic recombination or loss of one chromosome 3 homologue followed by duplication of the remaining homologue is a likely explanation. The other 6 cases showed microscopic abnormalities of chromosome 3 which were not reflected, or only partly reflected, as allelic losses. These discrepancies are caused either by the limitations of microscopic analysis in exactly determining a breakpoint or tracing a translocated part of a chromosome, or by the failure of molecular analysis to demonstrate LOH if this occurs in only a minority of cells.
Comparative cytogenetic and dna flow cytometric analysis of 150 bone and soft‐tissue tumors
Authors: Mandahl Nils , Baldetorp Bo , Fernö Mårten , Åkerman Måns , Rydholm Anders , Heim Sverre , Willén Helena , Killander Dick , Mitelman Felix
Published: February 2007

Samples from 48 benign and 102 malignant bone and soft‐tissue tumors were analyzed cytogenetically and by DNA flow cytometry. Clonal chromosome abnormalities were found in 82 tumors and normal karyotypes in 68; 61 tumors were DNA‐non‐diploid and 89 were diploid. The cytogenetically abnormal tumors were used for comparison between the 2 types of investigation; 45 of these tumors were DNA‐diploid and 37 were DNA‐non‐diploid. There was, with few exceptions, good correspondence between the quantitative estimates of genomic changes by the 2 methods, indicating that the cells cytogenetically analyzed from short‐term cultures are representative of the in vivo cell populations. Discrepancies were primarily found in cases with indexes above 1.5, in which the DNA index was higher than the chromosome index. The chromosome analysis suggested that skewed stemline (G0/G1) peaks in the diploid region in DNA histograms indicate the presence of cell populations with small net quantitative genomic changes, although not all such populations were detected by DNA flow cytometric analysis. The view that one of the peaks in bimodal stemline DNA histograms with narrow peaks represents a non‐diploid cell population was also corroborated. On average, the cell populations giving rise to double stemlines in DNA histograms showed quantitatively larger genomic changes than those that gave rise to broad or skewed diploid G0/G1 peaks. The findings indicate that these histogram profiles are not artifactual but reflect chromosomal changes in the tumor parenchyma.
Over‐expression of p53 nuclear oncoprotein in transitional‐cell bladder cancer and its prognostic value
Authors: Lipponen Pertti K.
Published: February 2007

Two hundred and twelve archival bladder‐cancer biopsy specimens were analyzed immunohistochemically to detect over‐expression of p53 protein. The results of immunohistochemical analysis were correlated to established histological and quantitative prognostic factors and survival of patients during a mean follow‐up period of more than 10 years. Twentynine percent of tumours were positive for p53 protein, and over‐expression was associated with high histological grade, non‐papillary growth architecture, dense inflammatory cell reaction, DNA aneuploidy, high S‐phase fraction, high mitotic frequency and high SD of nuclear area. Progression in T, N and M categories was significantly related to over‐expression of p53 protein. In univariate survival analysis, over‐expression of p53 predicted poor outcome in the entire cohort, in papillary tumours and in muscle‐invasive tumours but not in superficial tumours. In a multivariate survival analysis, over‐expression of p53 oncoprotein had no independent prognostic value over clinical stage and mitotic index. The results confirm that p53 is involved in the growth regulation of bladder cancer and is certainly a subject for detailed analysis of specific mutations.
Differential regulation of gelatinase b and tissue‐type plasminogen activator expression in human bowes melanoma cells
Authors: Houde Michel , De Bruyne Georges , Bracke Marc , Ingelman‐sundberg Magnus , Skoglund GÓRan , Masure Stefan , Van Damme Jo , Opdenakker Ghislain
Published: February 2007

A comparison of the production of tissue‐type plasminogen activator (t‐PA) and gelatinases A and B was made at the mRNA and protein levels in human Bowes melanoma cells treated with phorbol myristate acetate (PMA). Immunocytochemical analysis confirmed previous quantitative data on PMA‐mediated induction of t‐PA. It also showed that t‐PA immunoreactivity can be restrained to the local environment of the producing cell, most probably by interaction with extracellular matrix components. Zymographical analysis showed that gelatinase B protein was induced by PMA, whereas gelatinase A remained at the constitutive level. Protein kinase C (PKC) appeared to be involved in this regulation since, after PMA treatment (I) the PKC activity was found to be translocated from the cytosol to the particulate fraction of the cells and (2) addition of staurosporine and H‐7 blocked the gelatinase B increase. Northern‐blot hybridization showed a transient rise in t‐PA and gelatinase B mRNA levels whereas gelatinase A mRNA levels remained unchanged. When c‐fos and c‐jun mRNAs were investigated, only that of c‐fos was affected by PMA. Activation by PMA can be kinetically ordered as follows: translocation of PKC to the membrane fraction, transcription of the c‐fos gene and eclipsing of gelatinase B mRNA, increase in steady‐state mRNA levels of t‐PA and gelatinase B and, finally, secretion of t‐PA and gelatinase B glycoproteins. Our data also suggest that various proteases that are known to cooperate in the remodeling of the extracellular matrix can be differently regulated in one tumor‐cell type.
Antibody‐induced growth inhibition is mediated through immunochemically and functionally distinct epitopes on the extracellular domain of the c‐erbb‐2 (her‐2/neu) gene product p185
Authors: Xu Fengji , Lupu Ruth , Rodriguez Gustavo C. , Whitaker Regina S. , Boente Matthew P. , Berchuck Andrew , Yu Yinhua , Desombre Karen A. , Boyer Cinda M. , Bast Robert C.
Published: February 2007

Over‐expression of the c‐erbB‐2 (HER‐2/neu) gene product p185 occurs in 30% of breast and ovarian cancers. The p185 protein might serve as a target for serotherapy in that antibodies against different epitopes on the extracellular domain of p185 can inhibit growth of tumor cells in the absence of cellular or humoral effector mechanisms. To define epitopes of functional relevance, II monoclonal antibodies (MAbs) were evaluated for their ability to bind to the extracellular domain of p185. Results of competition studies with 1251‐labeled and non‐labeled antibodies indicated that 10 of 11 epitopes were grouped in a linear array. Antibodies against 7 epitopes inhibited anchorageindependent growth and antibodies against 2 of these epitopes also inhibited anchorage‐dependent growth of SKBr3 breast‐cancer cells that over‐expressed p185. Treatment with antibodies exerted cytotoxic rather than cytostatic effects. When antibodies were used in combination, additive or supra‐additive inhibition of anchorage‐independent and anchorage‐dependent growth was observed between pairs of antibodies. Growth inhibition did not relate to the affinity of the antibody or its isotype. Two antibodies that inhibited both anchorage‐dependent and anchorage‐independent growth also blocked binding of the HER‐2/neu ligand, whereas 5 antibodies that inhibited only anchorage‐independent growth had no effect on ligand binding. Inhibition of cell growth did not correlate with internalization of p185 or down‐regulation of p185 on the cell surface. Fab fragments of active antibodies could also inhibit anchorage‐independent growth of SKBr3. Thus, murine MAbs and their fragments recognized both immunochemically distinct and functionally distinct epitopes on the p185 molecule. Whereas inhibition of anchorage‐dependent growth correlated with the ability of antibodies to block ligand binding, inhibition of anchorage‐independent growth did not correlate with effects on ligand binding, internalization, cell‐surface expression or cross‐linking of pl85.