bluuebunny/crossref_metadata_2025 huggingface dataset:
In primary human breast carcinomas mutations in exons 5 and 6 of the p53 gene are associated with a high s‐phase index
Authors: Merlo Giorgio R. , Bernardi Amelia , Diella Francesca , Venesio Tiziana , Cappa Alberto P. M. , Callahan Robert , Liscia Daniel S.
Published: February 2007

A series of 121 human breast tumors was screened for point mutations in exons 5 through 8 of the p53 gene, by SSCP analysis. On the same tumor samples, the S‐phase index (SPI) was determined by the incorporation of BUdR in fresh tissue. p53 mutations were observed in 29% of the cases. The frequency of point mutations for the individual exons was: exon 5, 10.0%; exon 6, 9.9%; exon 7, 7.1% and exon 8, 5.5%. Two mutations detected by SSCP were confirmed by sequencing the p53 cDNA. The presence of a p53 mutation, irrespective of its location, correlates (p = 0.003) with a high SPI. This association appears to primarily reflect mutations in exon 5 (p = 0.0002) and exon 6 (p = 0.05), since mutations in exons 7 and 8 failed to show any association. These results indicate that mutations in the p53 gene identify highly proliferating tumors, and that the position of the p53 mutation may have different effects upon the proliferative activity of tumor cells in vivo.
trk and ret proto‐oncogene expression in human neuroblastoma specimens: High frequency of trk expression in non‐advanced stages
Authors: Borrello M. G. , Bongarzone I. , Plerotti M. A. , Luksch R. , Gasparini M. , Collini P. , Pllotti S. , Rlzzetti M. G. , Mondellini P. , De Bernardi B. , Di Martino D. , Garaventa A. , Brisigotti M. , Tonini G. P.
Published: February 2007

Forty‐three fresh tumor specimens of human neuroblastoma belonging to different clinical stages were analyzed for the expression of 2 proto‐oncogenes: trk, which encodes a tyrosine‐kinase receptor for nerve growth factor (NGF) and ret, another receptor‐type tyrosine kinase whose ligand is unknown. The mRNA expression of the trk gene was detected in 67.4% of cases, with increased frequency in I, II and IVs Evans' stages and in patients with favorable prognosis according to the Shimada classification. Moreover, trk expression inversely correlated with Nmyc‐gene amplification, ret mRNA was found in 36.8% of cases and equally distributed in the different stages. In addition, ngfR (low‐affinity NGF receptor)‐gene expression was present in 9 out of 25 cases. The simultaneous presence of mRNA related to both forms of the NGF receptor, while not proving the presence of a functional receptor, indicates the existence of a sub‐set of neuroblastoma cells potentially responsive to NGF.
Sulfated proteoglycans in the extracellular matrix of human breast tissues with infiltrating carcinoma
Authors: Losa Gabriele A. , Alini Mauro
Published: February 2007

The size, content and distribution of sulfated proteoglycans, constituents of the extracellular matrix, were investigated in non‐neoplastic human breast tissues and in tissues with infiltrating carcinoma. Sulfated proteoglycans were identified as cupro‐linic‐blue‐positive elements on electron microscopy preparations by the method of the critical electrolyte concentration. Morphometric data indicated that the numerical density of PG per surface area (Na) in normal tissues was about 2 to 7 times higher respectively in dense or loose connective zone then that found in the corresponding zones of malignant tissues. By referring to the unit volume of tissue, the overall PG content (Nv) was found to be increased about 5 fold in nonneoplastic tissues. However, in tissues with carcinoma the average length of sulfated proteoglycans was about twice as long in dense and loose connective layers than in the corresponding connective zones of non‐neoplastic breast tissues. Our findings provide evidence of profound structural alterations of non‐collagenous constituents in the extracellular matrix of human mammary tissues concerned with infiltrating carcinoma.
Effect of organized screening on the risk of cervical cancer. Evaluation of screening activity in iceland, 1964–1991
Authors: Sigurdsson Kristján
Published: February 2007

The Icelandic Cancer Society launched a screening programme for cervical cancer in June 1964. The aim was to lower the incidence and mortality rates by screening the age group 25—69 at 2‐ to 3‐year intervals. This report analyses the trends in invasive and pre‐invasive disease and the distribution of stage and histology, and also evaluates the attendance, the target age group and the screening interval. Before screening, the inci dence and mortality rates were on the increase but both have since fallen significantly. Screening greatly affected the rate of microinvasive and stage ≧11 squamous‐cell carcinomas but not the rate of adeno‐ and adenosquamous carcinoma. The mean age at detection of invasive cancer has decreased significantly and cancer has become practically non‐existent among correctly screened subjects over the age of 69. Among younger women the rates of moderate and severe pre‐invasive lesions at first visit increased significantly after 1980. The rate of these lesions was fairly consistently high only I year after the first normal visit. It is concluded that organized screening, coordinated with spontaneous activity, is effective in reducing the risk of cervical cancer. Regular high attendance and strict follow‐up of abnormal cases is a prerequisite for good screening results. Screening should preferably start at about the age of 20 and extend to 60–69 years of age, depending on the number of negative smears by that age. Screening can safely start with a screening interval of 2 to 3 years, but this interval can probably be extended to 4 or 5 years at older ages.
Expression of the target antigen for cytotoxic T lymphocytes on adult T‐cell‐leukemia cells
Authors: Kannagi Mari , Matsushita Shuzo , Harada Shinji
Published: February 2007

Adult T‐cell‐leukemia (ATL) cells were examined for suscep tibility to human T‐cell‐leukemia virus type I (HTLV‐I) tax‐specific cytotoxic T lymphocytes (CTL) derived from a patient with HTLV‐l‐associated myelopathy/tropical spastic parapare sis (HAM/TSP). These CTL efficiently killed HLA‐matched leukemia cells of an ATL patient after overnight incubation. However, ATL cells immediately after isolation from the periph eral blood were only marginally susceptible to the CTL. This is not due to inappropriate expression of major‐histocompatibility‐complex(MHC)‐class‐l antigen on the leukemia cells. Addition of synthetic peptide, corresponding to the CTL epitope, to the assay enabled the CTL to kill the fresh ATL cells. Scarcity of HTLV‐I antigens in the fresh ATL cells and induction of these antigens by in vitro incubation were demonstrated both on the cell surface and in the cytoplasm. Lectin stimulation augmented synthesis of HTLV‐I antigens, but was not essential for the induction. The presence in the culture of human plasma contain ing a high titer of antibodies to HTLV‐I did not affect the induction of HTLV‐I expression in the ATL cells. Furthermore, significantly lower levels of HTLV‐I tax mRNA were present in the fresh ATL cells than in the cultured ATL cells, whereas the levels of HTLV‐I proviral tax gene did not differ among these cells. This suppression of HTLV‐I transcription in fresh ATL cells accounts for resistance to the CTL, and could be a reason for the persistence of HTLV‐I infection in vivo.
A fucose residue can mask the muc‐1 epitopes in normal and cancerous gastric mucosae
Authors: Bara J. , Imberty A. , Pérez S. , Imai K. , Yachi A. , Oriol R.
Published: February 2007

MUSE II, DF3 and SM3 MAbs react with a synthetic peptide of 20 amino‐acids: VTSAPDTRPAPGSTAPPAHG. This se quence is a tandem repeat domain of the mucin‐type glycopro tein coded by the muc‐1 gene. MUSE II and DF3 MAbs immuno react strongly with mucus cells of the normal surface gastric epithelium of Le(a+b‐) non‐secretors, but in spite of the peptidic nature of the recognized epitope, the same tissue of Le(a‐b+) secretors reacts only after treatment with α‐fucosi dase. These reactions are inhibited by the PNA lectin, which recognizes the T disaccharide antigen (βGall‐3αGalNAc), sug gesting that the peptide epitope may be close to the T‐saccha ride structure. The SM3 MAb reacted on the surface gastric epithelium of all individuals after a more drastic deglycosylation using 20 mM periodate. Computer modeling of the MUC‐I immunoreactive glycopeptide containing the H type‐3 trisaccha ride αFucl‐2βGall‐3αGalNAc‐ bound to the threonine of the PDTRP‐pentapeptide shows that the peptide epitope might be masked when the fucose is positioned over the arginine. Thus, a single fucose linked to the T structure could mask the MUC‐I epitopes. In gastric adenocarcinomas, MUSEII and SM3 epi topes are expressed in 75% (25/33) and 9% (3/33) respectively, while, after partial deglycosylation by periodate treatment, they are positive in 100% (33/33) and 70% (23/33) of cases, respectively.
In vivo cytokeratin‐expression pattern of stratified squamous epithelium from human papillomavirus‐type‐16–immortalized ectocervical and foreskin keratinocytes
Authors: Sun Qi , Tsutsumi Kouichiro , Yokoyama Masatoshi , Pater Mary M. , Pater Alan
Published: February 2007

The association between human papillomavirus (HPV) type 16 and cervical squamous‐cell carcinoma has been well documented, and HPV 16 DNA has been shown to immortalize human genital keratinocytes in vitro. Using a panel of cytokera‐tin(CK)‐specific antibodies, we examined the CK expression pattern, an important characteristic of epithelia, of the stratified squamous epithelium reconstructed in vivo from monolayer cultures of 2 human ectocervical and 3 human foreskin keratino‐cyte cell lines immortalized by HPV 16 DNA. Whereas the abnormal epithelium formed from these grafts presented certain aspects of mature terminal differentiation, such as morphology and expression of CKIO/II, the expression patterns for CK19, and especially CK13, were more obviously abnormal. CK18 expression was not detectable in any of the epithelia formed from the 5 cell lines. In contrast, for an HPV‐16–immortalized endocervical cell line and the CaSki cervicalcarcinoma cell line there was expression of CK18. Our results indicate that HPV‐16–induced immortalization of keratinocytes is associated with disruption of the normal CK expression pattern in stratified squamous epithelium and that expression of particular CKs can be differentially disrupted.
Characterization and chemosensitivity of a human epithelioid sarcoma cell line (SARCCR 2)
Authors: Roché H. , Julia A. M. , Jozan S. , Muller C. , Dastugue N. , Arquier M. A. , Marques B. , Laurent G. , Canal P.
Published: February 2007

A new cell line was derived from the epithelioid sarcoma of a Caucasian woman who had previously received chemotherapy. The cells grew as an adherent monolayer, with a doubling time of 28 hr and had mainly epithelial morphology, but with areas of mesenchymal‐like cytoplasmic extensions. The cells were tumorigenic in nude mice, with a short growth time, and a doubling time of 8 days. The cell line showed over‐expression of P‐glycoprotein by Western blot analysis, and its sensitivity to doxorubicin and vincristine was low. This sensitivity could be enhanced by reversants of multidrug resistance (MDR), such as cyclosporin or verapamil. This cell line constitutes an excellent model for studying compounds able to reverse MDR.
Eradication of spontaneous and experimental adenocarcinoma metastases with chronic indomethacin and intermittent IL‐2 therapy
Authors: Lala Peeyush K. , Parhar Ranjit S.
Published: February 2007

We had earlier shown that tumor‐bearing results in an inactivation of IL‐2–dependent effector cells by host macrophagederived PGE2, and that chronic indomethacin therapy (CIT) aimed at blocking prostaglandin synthesis, combined with multiple rounds of IL‐2, can cure experimental metastases of a variety of tumors in mice. We have now tested the efficacy of this therapy on spontaneous as well as experimental metastasis of C3–L5 mammary adenocarcinoma in C3H/HeJ mice. Mice transplanted s.c. with C3–L5 cells (and showing visible spontaneous lung metastases between days 7 and 10) were given CIT starting on day 15, plus 2 5–day rounds of IL‐2 or IL‐2 alone. Mice injected i.v. with 104 C3–L5 cells (and showing lung micrometas‐tases on day 5) were placed on CIT on day 5 and given 3 5–day rounds of IL‐2 or treated with IL‐2 alone. Control mice received vehicles alone. Results revealed that combined CIT + IL‐2 therapy in the spontaneous metastasis model caused a regression of primary tumors, a marked reduction in lung metastases scored on days 25–35 and a marked prolongation of host survival (79% cured). Survivors rechallenged with 104 tumor cells i.v. on day 210 resisted tumor growth. In the experimental metastasis model, this therapy also markedly reduced lung metastases and prolonged animal survival (50% cured). In both models, the combination therapy led to the presence of highly active tumoricidal (for C3–L5 and YAC‐I lymphoma targets) lymphocytes with AGM‐I+, Lyt‐2‐ and Thy‐l± phenotype and macrophages in the spleen and the lungs, and ADCC‐promoting activity in the serum. CIT + IL‐2 therapy can thus effectively eradicate spontaneous and experimental mammary adenocarcinoma metastasis in mice. It activates natural effector cells in situ, generates ADCC‐promoting activity in the serum and results in resistance to umor take in this moderately immunogenic tumor model.
Consistent chromosomal aberration in cell lines transformed with mareks disease herpesvirus: Evidence of genomic dna amplification
Authors: Moore F. R. , Moore F. R. , Schat K. A. , Hutchison N. , Bloom S. E.
Published: February 2007

A specific chromosomal aberration was observed in 14 of 15 avian lymphoblastoid cell lines transformed with Marek's disease herpesvirus. This aberration, designated dup(lp)(p22–p23), appeared as an extra G‐positive band and interband on the short arm of one chromosome I homolog. Using fluorescent in situ hybridization, we identified amplified genomic DNA sequences in this region. This amplification involves sequences linked to an endogenous retrovirus locus and genes in the histone multigene family. This aberration was not observed in cells transformed by reticuloendotheliosis virus or by avian leukosis virus, nor has it been observed in untransformed chicken cells. The induction of the I p+ chromosomal aberration may be an essential event in the transformation of lymphocytes by Marek's disease virus.
Geographic association between urinary excretion of N‐nitroso compounds and oesophageal cancer mortality in china
Authors: Wu Y. , Chen J. , Ohshima H. , Pignatelli B. , Boreham J. , Li J. , Campbell T. C. , Peto R. , Bartsch H.
Published: February 2007

Overnight urine samples were collected from approximately 60 male adults in each of 69 counties of China in 1989. Two specimens were collected from each subject—one after a loading dose of proline and ascorbic acid and another after a loading dose of proline only. Levels of N‐nitrosamino acids and nitrate were measured in urine samples and correlated with cumulative mortality rates for subjects aged between 0 and 64 years in the 1970s. Oesophageal cancer mortality rates were positively and significantly associated with (i) urinary levels of excreted N‐nitrosoproline (NPRO) (after proline and ascorbic acid loading or proline loading only), (ii) N‐nitrososarcosine levels, and (iii) nitrosation potential (the decrease in the amount of urinary NPRO after adding ascorbic acid to the proline load). There were also positive correlations between the urinary level of NPRO or other N‐nitrosamino acids and that of nitrate. The urinary excretion of nitrate was associated with consumption of various nitrate‐rich vegetables. The results suggest that N‐nitroso compounds (NOC) or other nitrite‐derived carcinogens are implicated in the aetiology of oesophageal cancer in China.
Intermediate filaments as differentiation markers of exocrine pancreas. II. Expression of cytokeratins of complex and stratified epithelia in normal pancreas and in pancreas cancer
Authors: Real Francisco X. , Vilá Maya R. , Skoudy Anouchka , Ramaekers Frans C. S. , Corominas Josep M.
Published: February 2007

Cytokeratin (CK) expression in tumors generally reflects the CK pattern of the corresponding normal epithelium. Pancreas cancers express CK of simple epithelia 7,8, 18 and 19, as normal ductal cells. To analyze whether CK of complex or stratified epithelia are abnormally expressed in pancreas cancers, we have used polypeptide‐specific mouse monoclonal antibodies (MAbs) detecting CK 5, CK 10, CK 13, CK 14 and CK 17, and an antibody detecting CK 13, CK 15 and CK 16. The streptavidin‐peroxidase technique was applied on sections of fresh‐frozen specimens of normal pancreas and of pancreas cancer. None of these polypeptides were expressed by normal acinar and centro‐acinar cells. CK 5, CK 14 and CK 17 were expressed by less than 5% of cells in normal ducts, whereas CK 10, CK 13, CK 15 and CK 16 were not expressed at all. In tumors, CK 14, CK 15/16 and CK 17 were detected in the majority of cases studied; CK 5, CK 10 and CK 13 were present in a sub‐population of pancreas cancers. CK of complex/stratified epithelia were detected in areas of glandular differentiation, but expression was more intense in areas of squamous differentiation. In pancreatitis adjacent to cancer, CK of complex/stratified epithelia were weakly detected or undetectable. These results suggest that up‐regulation of these CK takes place in pancreas cancer. The CK phenotype may be of help in the differential diagnosis of this tumor.
Alkylation and oxidative‐DNA damage repair activity in blood leukocytes of smokers and non‐smokers
Authors: Hall Janet , Brésil Henriette , Wild Christopher P. , Loktionova Natalya A. , Kazanova Olga I. , Komyakov Igor P. , Lemekhov Vladimir G. , Likhachev Alexei J. , Montesano Ruggero
Published: February 2007

The levels of 3 DNA repair enzymes involved in alkylation and oxidative DNA damage repair in human peripheral blood leukocytes were measured in 20 smokers and 17 non‐smokers. No differences in O6‐alkylguanine‐DNA‐alkyltransferase (AGT) activity were found between the 2 groups and the AGT distribution within the population appeared to be unimodal. In contrast, the mean activities of both the methylpurine (MeP)‐ and the 2‐6‐diamino‐4‐hydroxy‐5N formamidopyrimidine (FaPy)‐DNA glycosylases were higher in the smokers, although only the difference between the MeP‐DNA glycosylase means was statistically significant. The standard deviations of these 2 enzymes were also higher in the smokers. The MeP‐DNA glycosylase activity showed a bimodal distribution when all subjects were considered. This may in part be due to the smoking habit; 83% of the subjects with enzyme activities higher than 500fmoles/mg protein were current smokers, whilst 85% of the non‐smokers had lower enzyme activities. However, if the smokers were considered separately, a bimodal distribution of this enzyme activity could still be observed. No strong correlation was observed between enzyme activity and age, although the slopes of the regression lines of enzyme activity on age were all negative. The relationship between enzyme activities was studied by bivariate distribution and a strong correlation was only found between the MeP‐DNA glycosylase and the FaPy‐glycosylase, with the highest values of both enzyme activities being observed in the smokers and the lowest in the non‐smokers. Our results suggest that the activity of certain DNA repair enzymes can be modulated by environmental exposure.
Reverse smoking as a risk factor for palatal cancer: A cross‐sectional study in rural andhra pradesh, india
Authors: Van Der Eb M. M. , Leyten E. M. S. , Gavarasana Satyanarayana , Vandenbroucke J. P. , Meera Kahn P. , Cleton F. J.
Published: February 2007

A cross‐sectional study of reverse smoking and its association with pre‐malignant and malignant lesions of the palate was conducted in the north coastal areas of Andhra Pradesh, India. A total of 480 randomly selected persons were interviewed. Information about smoking status, diet and access to mass media was obtained in each case and an examination of the oral cavity was performed. Reverse smoking of chutta was practised by 33% of the total rural population. The prevalence rate of all palatal lesions was 55%. The prevalence rates of the separate lesions: leukoplakia palatii, palatal keratosis and palatal cancer, were 9.8%, 18.1% and 1.9%, respectively. The presence of these (pre‐)malignant lesions was strongly associated with reverse smoking and also associated with conventional chutta smoking. Reverse smoking induced significantly more lesions than conventional chutta smoking, and was a major determinant of subsequent palatal cancer: all 9 newly diagnosed palatal cancers were observed within the group of reverse smokers. There was an inverse relationship between the incidence of palatal lesions and vitamin A intake. The study of access to mass media indicated that the most favourable medium for promoting a prevention campaign would be the cinema.
Establishment and characterization of human ocular melanoma cell lines
Authors: Aubert Christian , Rouge Françoise , Reillaudou Monique , Metge Paul
Published: February 2007

Five continuous cell lines have been established from 29 ocular melanomas and maintained for periods ranging from 3 to 9 years in medium identical to that in which 3 concomitantly studied lines of cutaneous melanoma cells were cultured as controls. The long‐term problems to be overcome in establishing uveal cell lines are related to cell‐doubling times which ranged from 72 to 432 hr, and plating efficiency, which ranged from 0.5%–6.5%. Tumors and cell lines were found to contain melanosomes. The morphology of uveal cells during the early subcultures exhibited multiple changes. Two different established cell lines were obtained from one ciliary‐body tumor. Biochemical studies revealed markers of melanogenesis and neuroendocrine compounds. Cytogenetic studies revealed chromosomal abnormalities that differed between uveal and conjunctival melanomas.
Thrombin increases the metastatic potential of tumor cells
Authors: Wojtukiewicz Marek Z. , Tang Dean G. , Ciarelli James J. , Nelson Kevin K. , Walz Daniel A. , Diglio Clement A. , Mammen Eberhard F. , Honn Kenneth V.
Published: February 2007

Initial arrest of tumor cells in the microvasculature and their attachment to the endothelium and subendothelial matrix (SEM) are essential prerequisites for metastasis to occur. Factors mediating these interactions are viewed as important determinants of the tumor‐cell metastatic phenotype. In this work we have studied the effects of thrombin, its analogs and its precursors on the adhesive properties and metastatic potential of tumor cells. We show that α‐thrombin, the native form of the key coagulation enzyme, is capable of enhancing tumor‐cell adhesion to both the endothelium and SEM components represented by fibronectin. Subclotting, physiological concentrations of α‐thrombin produced a 2‐ to 5‐fold increase in tumor‐cell adhesion. A bell‐shaped dose‐response curve was observed, with maximal effect at 0.1 U/ml. Maximum effect occurred when cells were exposed to the agonist for 15 min and exposure for up to 4 hr resulted in enhanced tumor‐cell adhesion. Prolonged incubation with thrombin resulted in a decline in the thrombin‐enhanced adhesion which reached unstimulated control levels by 24 hr. Thrombin precursors and active‐site‐inhibited thrombin analogs only had minimal adhesion‐enhancing activity; nitro‐ and exosite‐α‐thrombin, which retain a functional active site, mimicked, although to a lesser degree, the action of α‐thrombin. Tumor‐cell incubation with thrombin resulted in an upregulated cell‐surface expression of the αllbβ3 integrin, a receptor mediating interactions between tumor cells and endothelial cells, and between tumor cells and SEM. Antibodies against αllbβ3 integrin effectively inhibited thrombin‐enhanced tumor‐cell adhesion. Thrombin effects on tumor cells involved the PKC signal transduction pathway as thrombin‐enhanced adhesion was inhibited by pre‐incubation with PKC inhibitors and a transient PKC translocation from cytosol to membrane was observed following thrombin challenge. In vivo, thrombin‐treated tumor cells demonstrated a 2‐fold increase in their lung‐colonizing ability. In contrast to the adhesion results, the metastasis‐enhancing effects of α‐thrombin were mimicked by a thrombin precursor (prothrombin) and thrombin analogs.
Autocrine growth mechanism by transforming growth factor (TGF)‐β1 and TGF‐β1‐receptor regulation by epidermal growth factor in a human endometrial cancer cell line IK‐90
Authors: Sakata Masahiro , Kurachi Hirohisa , Ikegami Hiromasa , Jikihara Hiroaki , Morishige Ken‐Ichiro , Miyake Akira , Terakawa Naoki , Tanizawa Osamu
Published: February 2007

Transforming growth factor‐β1 (TGF‐β1) enhanced cell proliferation in a concentration‐dependent manner in a human endometrial cancer cell line, IK‐90. Scatchard analysis of TGF‐β1 receptor in IK‐90 cells, using 125I‐TGF‐β1 as a ligand, revealed the presence of a class of high‐affinity TGF‐β1 receptors (2,000 sites per cell, KD = 74pM). Moreover, IK‐90 cells produced and secreted TGF‐β1: TGF‐β1 messenger RNA was detected at 2.5 and 4.0 kb by Northern‐blot analysis using 32P‐labeled TGF‐β1 cDNA as a probe, and TGF‐β1 activity in conditioned medium by the inhibition of 3H‐thymidine uptake into CCI 64 mink lung epithelial cells. We investigated the regulation of TGF‐β1 receptor by 4 kinds of growth factor: epidermal growth factor (EGF) but not TGF‐β1 insulin or insulin‐like growth factor‐I increased the level of TGF‐β1 binding sites in a concentration‐ and time‐dependent manner. These findings suggest that TGF‐β1 may be a potential autocrine growth factor in a human endometrial cancer cell line IK‐90 and that this autocrine mechanism may be affected by EGF.
Subtypes of epstein‐barr virus in HIV‐1‐associated and HIV‐1‐unrelated hodgkin's disease cases
Authors: De Re Valli , Boiocchi Mauro , De Vita Salvatore , Dolcetti Riccardo , Gloghini Annunziata , Uccini Stefania , Baroni Carlo , Scarpa Aldo , Cattoretti Giorgio , Carbone Antonino
Published: February 2007

Epstein‐Barr virus (EBV) type 2 is considered to be a much less potent transformer of lymphocytes than type‐1. However, type‐2 EBV may be involved in the pathogenesis of non‐Hodgkin's lymphomas (NHLs) arising in immunocompromised patients, i.e., subjects with malaria or HIV‐1 infection. To determine whether type‐2 EBV may also play a role in Hodgkin's disease (HD) developing in immunocompromised patients, we characterized EBV subtypes in EBV‐positive HD samples from 10 HIV‐1‐positive patients as well as from a control population of 24 HIV‐1 ‐negative patients. Type‐2 EBV was detected in 5/10 HD samples from the HIV‐1‐positive group (I case showed concomitant type‐1 EBV positivity), but only in 1/20 HD samples from the HIV‐1 ‐negative group, indicating that, during HIV‐1 ‐induced immunodepression, type‐2 EBV may be pathoge‐netically involved also in HD, as previously reported for HIV‐associated NHLs.
Reproductive factors and survival from ovarian cancer
Authors: Jacobsen Bjarne K. , Vollset Stein Emil , Kvåle Gunnar
Published: February 2007

During a 29‐year screening follow‐up of 63,090 Norwegian women, 644 women were found to have an ovarian cancer with known metastatic status as their first malignancy. Of these women, 419 subsequently died of ovarian cancer. As reproductive factors, particularly parity, are risk factors for ovarian cancer, we investigated possible relationships between reproductive history and survival from ovarian cancer. Except for an improved survival in women with more than one abortion, no significant relationships were found.
Allogeneic bone‐marrow transfusion suppresses development of lung metastases in osteogenic sarcoma patients after radical surgery
Authors: Esartia P. T. , Deichman G. I. , Kluchareva T. E. , Matveeva V. A. , Uvarova E. N. , Trapesnikov N. N.
Published: February 2007

On the basis of experimental data obtained in Syrian hamsters, demonstrating the highly efficient suppression of experimental and spontaneous metastases of highly‐metastatic sarcoma cells by the use of allogeneic normal bone‐marrow cells (BMC), a clinical protocol for the suppression of lung metastases of osteogenic sarcoma was started in 1984 in the Cancer Research Center, Moscow. From this time onwards, 24 osteogenic sarcoma patients, at stages 2A and 2B were treated with a combination of radical surgery and a single transfusion of normal (non‐activated) allogeneic BMC (blood‐group and Rhesus compatible). The first results of this ongoing study are now presented. Metastases appeared in 11 out of the 24 patients, generally very early during the first 3–9 months after treatment and in no case after 2 years. More than 50% of the BMC‐treated patients were free of lung metastases after 2 or more years of observation; 8 out of 15 are still metastasis‐free after 3–4 or more years of observation following treatment. The differences in the frequency of metastasis and duration of survival without metastasis of treated patients compared with a group of 41 osteogenic sarcoma patients at stages 2A and B, treated with radical surgery only (controls) reached significant levels 12 months after treatment and thereafter. Rapid recovery of NK cytotoxic activity has been observed in nearly all successfully BMC‐treated patients.
Intra‐uterine contraception and the risk of endometrial cancer
Authors: Castellsagué Xavier , Thompson W. Douglas , Dubrow Robert
Published: February 2007

Despite the increasing world‐wide popularity of contraceptive intra‐uterine devices (IUDs), their potential long‐term effects on the risk of developing endometrial carcinoma have been poorly studied. This paper reports on the relationship between intra‐uterine contraception and endometrial cancer by analyzing epidemiological data from a large, multicenter, population‐based, case‐control study of epithelial endometrial cancer. Cases were 437 women, 20 to 54 years of age, with histologically confirmed epithelial endometrial cancer ascertained through 6 population‐based cancer registries in the United States. Controls were 3200 women selected at random from the populations of these areas. The age‐ and parity‐adjusted odds ratio (OR) for the association between ever having used intra‐uterine contraception and endometrial cancer was 0.51 (95% confidence interval (Cl) 0.3–0.8). Although the protective effect increased with duration of use, a dose‐response relationship among users was not statistically demonstrable. The association did not vary significantly with age at first or last IUD use or with time elapsed since first or last IUD use. Years of education significantly modified the effect of intra‐uterine contraception. Thus, intra‐uterine contraception appeared to be strongly protective for women with at least 13 years of education (OR = 0.29, 95% Cl, 0.15–0.6). It is proposed that intra‐uterine contraception exerts its protective effect through local structural and biochemical changes in the endome‐trium that may alter endometrial sensitivity and response to circulating estrogen and progesterone.
Urinary aflatoxin levels, hepatitis‐b virus infection and hepatocellular carcinoma in taiwan
Authors: Hatch Maureen C. , Chen Chien‐Jen , Levin Bruce , Ji Bu‐Tian , Yang Guang‐Yang , Hsu Shang‐Wei , Wang Lian‐Wen , Hsieh Ling‐Ling , Santella Regina M.
Published: February 2007

Using a urinary immunoassay to measure aflatoxin metabolites, we examined the associations between exposure to aflatoxin, chronic infection with the hepatitis‐B virus (HBV) and background rates of hepatocellular carcinoma (HCC) mortality in a cross‐sectional survey of 250 residents from 8 areas of Taiwan with a 4‐fold variation in age‐adjusted HCC mortality. Specimens of fasting blood and overnight urines were used to determine HBV carrier status and excretion of aflatoxin in the subjects surveyed. While the prevalence of hepatitis‐B virus carriers showed moderate variability, there was a 500‐fold range in urinary aflatoxin levels. Mean log‐transformed levels of aflatoxin metabolites were similar in males and females and in HBV carriers and non‐carriers. In the 8 townships, HCC mortality correlated positively with both area HBV carrier prevalence and mean aflatoxin levels. The primary analyses, however, were conducted at the individual level. Each subject's aflatoxin level was treated as the response variable in a multiple regression model, and the corresponding sex‐specific area HCC rate was included as a predictor along with the individual's carrier status, age and sex; alcohol consumption and cigarette smoking were also considered. In these analyses, a significant association was again observed between the marker of aflatoxin exposure and the background rate of HCC mortality. In females, the slope of the regression line was somewhat steeper in HBV carriers, but this pattern was not seen in males and formal testing yielded no statistically significant evidence of an interaction. Our findings are consistent with the hypothesis that aflatoxin plays an independent role in hepatocellular carcinoma in Taiwan.
Importance of E‐selectin (ELAM‐1) and sialyl lewisa in the adhesion of pancreatic carcinoma cells to acttvated endothelium
Authors: Iwai Kazuhiro , Ishikura Hiroshi , Kaji Mitsuhito , Sugiura Hiroshi , Ishizu Akihiro , Takahashi Chisa , Kato Hiroyuki , Tanabe Tatsuzo , Yoshtki Takashi
Published: February 2007

Adhesion molecules involved in attachment between human pancreatic carcinoma and activated endothelial cells in vitro were investigated. Basal adhesion occurred between 6 pancreatic carcinoma cell lines and unstimulated human umbilical vein endothelial cells (HUVEC), and augmented basal adhesion to activated HUVEC was only seen when pancreatic cancer cells expressed sialyl Lewisa (SLea) and sialyl Lewisx (SLex). Activation of HUVEC with interleukin l‐β (IL‐Iβ) or tumor necrosis factor‐α (TNF‐α), but not with interferon‐γ (IFN‐γ), generated the augmentative basal adhesion. Dose dependence and additive effect were observed in augmentation of the basal adhesion induced by IL‐I β and/or TNF‐α. Increase in adhesion correlated with up‐regulation of the surface E‐selectin (or ELAM‐I) on HUVEC, and was evident at both 25°C and 4°C. Anti‐E‐selectin and anti‐SLea blocked the augmented attachment, whereas anti‐SLex, an antibody against another known ligand for E‐selectin, did not. The collective evidence indicates that attachment between pancreas carcinoma cells and activated endothelial cells is regulated by cytokines such as IL‐1 β and TNF‐α, and is mediated by SLea on pancreas carcinoma and E‐selectin on endothelial cells. These molecules may be of significant importance in blood‐borne metastasis of pancreatic carcinoma cells to inflamed sites.
Activation of the human mdr1 gene promoter in differentiated neuroblasts
Authors: Ferrandis Eric , Bénard Jean
Published: February 2007

When treated in vitro with retinoic acid, many neuroblastoma cell lines undergo neuronal differentiation and show a significant increase in human multi‐drug resistance gene (MDRI) transcript levels. To determine whether over‐expression of the gene may result from activation of its promoter by differentiating agents, the activity of the human MORI proximal promoter (MDRI pp) transfected to 2 neuroblastoma lines treated with retinoic acid and forskolin was first measured using transient expression assays. The MDRI gene transcript levels of these 2 lines were then measured by Northern blots. The results indicate that retinoic acid and forskolin were able to activate the human MDRI pp in a dose‐dependent manner after transfec‐tion of the MDRI pp‐CAT constructs in the 2 cell models tested i.e., SK‐N‐SH and IGR‐N‐91, a new human neuroblastoma cell line. A significant increase in MDRI gene transcript levels was observed upon treatment with differentiation inducers in SK‐N‐SH but not in IGR‐N‐91 neuroblasts. These results suggest that the induction of the MDRI gene promoter is necessary but not sufficient to lead to an increase in MDRI gene transcript levels, according to the neuroblast cell line considered.
Identification of H‐2Kb‐, Db‐ and Dd‐binding peptides derived from amino acid sequences of polyoma virus T antigens
Authors: Reinholdsson‐Ljunggren Git , Franksson Lars , Dalianis Tina , Ljunggren Hans‐Gustaf
Published: February 2007

Viral and tumor antigens are presented to cytotoxic T cells (CTL) in the form of short peptides. The peptide antigen is transported to the cell surface in conjunction with molecules encoded by the major histocompatibility complex (MHC). Different methods have recently been described for the analysis of the MHC‐class‐1 binding ability of synthetic peptides. Here, we describe a protocol, based on intact RMA‐S cells cultured at 26 C in the presence of synthetic peptides, which gives an allele‐specific peptide binding pattern with high resolution. This allowed an analysis of the H‐2Kb‐, Db‐ and Dd‐binding capacity of a panel of synthetic peptides with amino acid (aa) sequences derived from polyoma (py) virus large‐, middle‐ and small‐T (LT, MT and ST) antigens, previously used in immunization experiments against py‐virus‐induced tumors. Eight single aa mutants and a deletion mutant of one peptide with an ability to bind both to H‐2Kb and to Db were also analyzed. We foresee that the present protocol, or variants thereof, may serve as a simple and rapid assay for the systematic screening of the class‐l binding ability of large sets of synthetic peptides in vitro. Such analysis may facilitate the search for viral or tumor peptide epitopes that are recognized by CTL.
Adhesion of human lymphoid cell lines to immobilized carbohydrates and to bone‐marrow stromal cell layers by surface sugar receptors
Authors: Gabius Sigrun , Wawotzny Ralf , Wilholm Sabine , Martin Ulrikc , Wörmann Bernhard , Gabius Hans‐Joachim
Published: February 2007

Cell‐surface sugar receptors may participate in interactions of lymphoid cells that influence their adhesive properties and proliferation. Their expression on cells of the pre‐B line BLIN‐1, the B‐lymphoblastoid line Croco II, the myeloma line RPMI 8226 and the T‐lymphoblastoid line CCRF‐CEM was monitored with a panel of 14 types of chemically glycosylated E. coli β‐galactosi‐dase at a non‐saturating ligand concentration. Quantitative differences were determined for the capacity of the different cell types to bind constituents of the carbohydrate part of glycoconjugates. They were corroborated by analyses of binding for lactose‐, β‐N‐acetylgalactosamine‐, β‐N‐acetylglucosamine‐and fucose‐exposing neoglycoenzymes up to saturation levels. Values of dissociation constants of the tetrameric enzyme were in the range of 3–300 nM. Several types of sugar receptor led to carbohydrate‐inhibitable adhesion of cells to 6 types of nitrocellulose‐immobilized neoglycoprotein, their effectiveness being most obvious for the myeloma cells. Analyses of the carbohy‐drate‐ligand‐mediated adhesion of the other cell types revealed a comparatively decreased response. Only a few carbohydrates among the 7 types tested were effective in reducing cell adhesion to a far more complex ligand‐bearing matrix than immobilized neoglycoproteins, namely bone‐marrow stromal cell layers: sialic acid and N‐acetylgalactosamine for B‐lymphoblastoid cells and rhamnose for pre‐B cells. These cellular interactions may encompass sugar receptors on the stromal cells and other types of molecular recognition in addition to the detected activities on the lymphoid cells.
Anti‐tumor activity of a blocked ricin immunotoxin with specificity against the cluster‐5A antigen associated with human small‐cell lung cancer
Authors: Zangemeister‐Wittke Uwe , Collinson Albert R. , Fisch Igor , Jones Robert M. L. , Waibel Robert , Lehman Hans‐Peter , Stahel Rolf A.
Published: February 2007

The monoclonal antibody (MAb) SEN3I, a mouse IgG1 which recognizes the cluster‐5a antigen on small‐cell lung cancer (SCLC) cells, was used to prepare a selective and potent blocked ricin immunotoxin. In a series of experiments in vitro and in a SCLC xenograft model in nude mice, the tumor localization potential of the radiolabeled antibody SEN31 and the anti‐tumor activity of the immunotoxin SEN31‐bR, the non‐specific binding activity of which had been greatly reduced by blocking of the galactose binding domains of the B‐chain, was determined. Radiolabeling of SEN31 was performed by linking a 67Ga‐labeled desferrioxamine moiety to the oligosaccharide side chains of the antibody in order to preserve the specific cell‐binding activity. 67Ga‐SEN31 bound to the antigenic sites on cells of the SW2 SCLC cell line, with a dissociation constant of 3.5 nM and, when injected i.v., selectively localized at the site of s.c.‐growing SW2 tumor xenografts in nude mice, with a tumor‐to‐blood ratio of 3.5. The immunotoxin SEN31 ‐bR was potently and selectively active against SCLC cell lines both of classic and of variant morphologies. At a concentration of 300 pM the immunotoxin selectively eliminated 4.5 logs of clono‐genic tumor cells. In nude mice, SEN31 ‐bR was cleared from the blood with biphasic kinetics following i.v. injection and maintained a stable serum level during continuous i.p. infusion. The growth of s.c. SW2 solid‐tumor xenografts was delayed following a single i.v. injection or a continuous i.p. infusion, each at a non‐toxic dose.
Protein phosphatases limit tumor motility
Authors: Young M. Rita I. , Lozano Yvonne , Djorjevic Andelca , Maier George D.
Published: February 2007

Elevators of cAMP, such as prostaglandin E2 (PGE2), activate protein kinase A (PKA) and induce PKA‐stimulated motility and metastasis by metastatic Lewis lung carcinoma cells (LLC‐LN7). Non‐metastatic LLC (LLC‐C8) are unresponsive to cAMP elevation even though they are not deficient in the PKA enzymes. To determine whether this PKA unresponsiveness might be due to increased dephosphorylation by serine/threonine protein phosphatases (PP‐1/2A) within non‐metastatic LLC‐C8, the effects of the PP‐1/2A inhibitor okadaic acid on the migration and invasion by non‐metastatic LLC‐C8 cells was measured. Okadaic acid stimulated motility of non‐metastatic LLC‐C8 cells to a level that was comparable to that of metastatic LLC‐LN7 cells. PGE2 further increased the motility of the non‐metastatic LLC‐C8 cells when okadaic acid was present, although not in the absence of okadaic acid. The stimulation of motility by okadaic acid was diminished when PKA activity was inhibited. Dose‐response studies with concentrations of okadaic acid that selectively inhibited PP‐2A or both PP‐2A and PP‐1 showed a progressive increase in migration of non‐metastatic LLC‐C8 cells, suggesting that both PP‐1 and PP‐2A limit their motility. By contrast, metastatic LLC‐LN7 cells were more motile than were non‐metastatic LLC‐C8 cells, but this motility was only marginally affected by okadaic acid. Comparisons of the levels of PP‐1/2A enzyme activities in the LLC variants showed more activity in non‐metastatic LLC‐C8 than in metastatic LLC‐LN7 cells. The identity of the PP whose activity was increased in the non‐metastatic LLC‐C8 was assessed by using okadaic acid, which selectively inhibits PP‐2A activity at low concentrations and PP‐1 and PP‐2A at high concentrations, and calyculin A, which inhibits PP‐2A at a similar concentration to that affected by okadaic acid but is more potent at inhibiting PP‐1. The inhibition of PP activities by okadaic acid and by calyculin A showed a pattern which suggested the presence both of PP‐1 and of PP‐2A in non‐metastatic LLC‐C8 cells, but the presence of PP‐1 and a reduction in PP‐2A in metastatic LLC‐LN7 cells. The sum of these data suggests that PKA‐stimulated motility is restricted both by PP‐1 and by PP‐2A in non‐metastatic LLC, and that a deficiency in this restriction results in increased migration and invasion.
Enhanced expression of a tumor‐cell‐derived collagenase‐stimulatory factor in urothelial carcinoma: Its usefulness as a tumor marker for bladder cancers
Authors: Muraoka Keisuke , Nabeshima Kazuki , Murayama Toshihiko , Biswas Chitra , Koono Masashi
Published: February 2007

A mouse monoclonal antibody (MAb) E11F4, previously raised against the tumor‐cell‐derived collagenase‐stimulatory factor (TCSF) from LX‐1 human lung‐carcinoma cells, has been used to define the expression and distribution of TCSF in human non‐neoplastic urothelium and tumors of the urinary bladder. Immunohistochemically, TCSF was detected in 27/28 transitional‐cell carcinomas (TCC) of the bladder, of which 23 were judged to be positive for TCSF according to objective criteria. Twenty‐four of 28 non‐neoplastic urothelium from 22 individuals were judged to be negative for TCSF by this criteria. However, TCSF immunostaining that was confined to the superficial umbrella cells was frequently observed in nonneoplastic urothelium. In bladder carcinomas, TCSF was in most cases demonstrated in the majority of cells, including at the invasion front. Its localization to the cell membrane was demonstrated by immunoelectron microscopy. The high level of expression of TCSF in bladder tumors, but not in non‐neoplastic urothelium, was also demonstrated by immunoblotting of tissue extracts. Furthermore, E11F4 immunostaining identified tumor cells obtained from bladder washings or voided urine and detected more TCC cases than conventional cytology. Since TCSF immunostaining was positive even in low‐grade TCC (immunohistochemically and immunocytochemically in 4/5 TCC grade I), the application of TCSF immunostaining to urine cytology appears promising as a valuable adjunct to conventional methods in the clinical evaluation of patients with TCC. © 1993 Wiley‐Liss, Inc.
Risk factors for renal‐cell carcinoma in a French case‐control study
Authors: Benhamou Simone , Lenfant Marie‐Hélène , Ory‐Paoletti Catherine , Flamant Robert
Published: February 2007

A hospital‐based case‐control study of renal‐cell carcinoma was conducted in France from 1987 to 1991. A total of 196 histologically confirmed cases (138 males and 58 females) and 347 controls (235 males and 112 females), matched for sex, age at interview, hospital and interviewer, were included. The risk of renal‐cell carcinoma was not apparently increased with number of cigarettes per day, duration of smoking or early age at first cigarette smoking in males. No significant trend was found in the risks with increasing Quetelet index (Ql) at the age of 20 in males. On the contrary, the risks increased significantly with an increasing Ql prior to diagnosis. In females, the trends in risks were significant both for the relative weight at the age of 20 and prior to diagnosis. The consumption of regular or decaffeinated coffee, tea or alcoholic beverages was not associated with renal‐cell carcinoma, in males or in females. © 1993 Wiley‐Liss, Inc.
C‐erbB‐2 oncoprotein in screen‐detected breast carcinoma: An immunohistological study
Authors: Soomro Salma , Taylor P. , Shepard H. M. , Feldmann M. , Sinnett H. D. , Shousha S.
Published: February 2007

This study was aimed at comparing screen‐detected and symptomatic breast carcinomas with regard to the prevalence of positive immunostaining for c‐erb‐B‐2 oncoprotein. Paraffin sections of 81 breast carcinomas detected through the National Screening Programme were examined for the over‐expression of c‐erbB‐2 oncoprotein using the avidin‐biotin immunoperoxidase technique and 2 different specific antibodies: 21N and 4D5. Twenty‐one other carcinomas detected in symptomatic patients were similarly examined for comparison. The screen‐detected lesions were of 2 types: palpable and impalpable which required needle localization prior to surgical removal. Of the 81 screen‐detected tumours, only 8 were c‐erbB‐2 positive, compared with 5 out of 21 non‐screen‐detected tumours. When only invasive carcinomas were considered, 5 out of 63 screen‐detected cases were positive, compared with 5 out of 15 symptomatic cases. Four out of the 5 screen‐detected positive invasive carcinomas were clinically palpable. Our results show an obvious trend towards a lower prevalence of c‐erbB‐2 oncoprotein over‐expression in screen‐detected carcinomas. As this over‐expression is thought to be associated with increased tumour aggressiveness, the findings suggest a low prevalence of aggressive tumours in screen‐detected lesions, particularly impalpable invasive carcinomas, identified so far. © 1993 Wiley‐Liss, Inc.