bluuebunny/crossref_metadata_2025 huggingface dataset:
Carcinogenic risk of dark VS. light liquor
Authors: Day Gina L. , Blot William J. , McLaughlin Joseph K. , Fraumeni Joseph F.
Published: February 2007

A previous report suggested that the cancer risk associated with hard liquor is greater among users of dark liquors, which may contain more potentially carcinogenic compounds than light liquors. To test this hypothesis, we examined alcohol consumption data obtained by interview with 921 cases and 900 controls who participated in 1984–1985 in a population‐based case‐controls study of oral and pharyngeal cancer conducted in 4 areas of the United States. Among heavy liquor drinkers (30+ drinks/week), odds ratios were 13.2 (95% Cl = 5.2–33.5) for those who usually drank light liquors vs. 4.6 (95% Cl = 2.7–7.9) for those who usually drank dark liquors, with higher risks for light vs., dark liquors at each anatomical subsite. This analysis provides no support for the notion that dark liquors are more carcinogenic than light liquors or that non‐ethanolic ingredients of alcoholic beverages are major contributors to the excess risk of oral and pharyngeal cancer. © 1994 Wiley‐Liss, Inc.
Expression of the FGFR1 gene in human breast‐carcinoma cells
Authors: Jacquemier Jocelyne , Adelaide José , Parc Patricia , Penault‐Llorca Frédérique , Planche Jacqueline , Delapeyriere Odile , Birnbaum Daniel
Published: February 2007

Fibroblast growth factors (FGF) constitute a family of at least 9 members which act through high‐affinity tyrosine‐kinase receptors encoded by 4 distinct genes. In humans, the FGFRI gene is located in chromosomal region 8pl2. Its amplification and expression were examined in a panel of 110 breast carcinoma samples by Southern‐ and Northern‐blot analyses. FGFRI was amplified in 9% and overexpressed in about 15% of the tumors studied. In situ hybridization experiments were performed on tissue sections of normal breast and tumors with a high level of FGFRI expression. In both normal and tumoral tissues, FGFRI RNA was detected in the epithelial cells. Overexpression of FGFRI seems to be associated with small, well‐differentiated diploid tumors. © 1994 Wiley‐Liss, Inc.
Growth advantage of human leiomyoma cells compared to normal smooth‐muscle cells due to enhanced sensitivity toward insulin‐like growth factor I
Authors: Van Der Ven Leo T. M. , Gloudemans Ton , Roholl Paul J. M. , Van Buul‐Offers Sylvia C. , Bladergroen Bellinda A. , Welters Marij J. P. , Sussenbach John S. , Otter Willem Den
Published: February 2007

Human uterine leiomyomas exhibit increased IGF‐I binding compared to myometrium, while both tissues show IGF‐I gene expression. In this study we have examined the functional importance of these findings by testing the presence of IGF‐I in 15 leiomyoma biopsies and in 18 myometrium biopsies and the capacity of smooth‐muscle cells cultured from these tissues to react to IGF‐I. The mean IGF‐I peptide concentration in leiomyomas was 3 times higher than in myometrium. This resulted from increased IGF‐I uptake in leiomyomas rather than from increased synthesis, as these tissues contain higher concentrations of type‐IIGF receptors, as detected by immunohistochemistry, and equal levels of IGF‐I mRNA. Blocking IGF‐I transport with cytochalasin‐B and with the type‐I IGF receptor blocking antibody αIR3 in cultured cells induced decreased immunostaining intensity for IGF‐I in most myometrium and leiomyoma cultures, indicating that the detected IGF‐I is internalized. Depending on the culture conditions, IGF‐I administration yielded increased survival or a higher proliferation rate in leiomyoma cultures than in myometrium cultures, indicating the increased importance of exogenous IGF‐I for the growth of transformed smooth‐muscle cells. We conclude that the increased concentrations of type‐I IGF receptors in leiomyoma compared to myometrial smooth‐muscle cells are functional with respect to the enhanced internalization of IGF‐I and that they provide these tumor cells with a growth advantage compared to their normal counterparts. © 1994 Wiley‐Liss, Inc.
Growth inhibition of human colorectal‐carcinoma cells by interleukin‐4 and expression of functional interleukin‐4 receptors
Authors: Lahm Harald , Schnyder Bruno , Wyniger Josiane , Borbenyi Zita , Yilmaz Aysim , Car Bruce D. , Fischer Jürgen R. , Givel Jean‐Claude , Ryffel Bernhard
Published: February 2007

The growth‐inhibitory effect of interleukin‐4 (IL‐4) was investigated in a panel of 7 human colorectal‐carcinoma cell lines. In 5 cell lines (HT29, WiDr, LS41 IN, LS513, LS1034) a dosedependent reduction of proliferation was documented. At 100 U/ml, IL‐4 inhibited thymidine incorporation between 45 and 75% and MTT conversion (26 to 41%). The ability of LS513 and WiDr cells to form colonies after IL‐4 treatment was reduced by 85 and 62% respectively. LS513 was the most sensitive cell line, with IL‐4 inducing half‐maximal inhibition at 5 to 6 U/ml. The inhibitory effect of IL‐4 was completely neutralized by anti‐IL‐4 antibodies. Northern‐blot analysis revealed the presence of IL‐4‐receptor (IL‐4R) mRNA in all cell lines. The membrane expression of the 130‐kDa IL‐4R was assessed by FACS, utilizing an anti‐IL‐4R monoclonal antibody and was confirmed by biotinylated IL‐4 binding. Our results attribute an important role for IL‐4 as a negative regulator of colorectal‐carcinoma cell growth, thus indicating a possible avenue for intervention in this disease. © 1994 Wiley‐Liss, Inc.
Use of analgesics and risk of renal cell cancer
Authors: Chow Wong‐Ho , McLaughlin Joseph K. , Linet Martha S. , Niwa Shelley , Mandel Jack S.
Published: February 2007

Although heavy or long‐term use of analgesics has been related to risk of renal cell cancer in several studies, evidence for such an association remains inconclusive. In a populationbased case‐control study including 440 renal cell cancer cases, spouses of an additional 151 cases, and 691 controls, we assessed renal cell cancer risk associated with lifetime consumption among those who reported during in‐person interviews regular (at least 2 or more times per week for I month or longer) use of analgesics. Odds ratios (OR) were computed using logistic regression analyses. No excess risk was associated with regular use of aspirin, acetaminophen, phenacetin or combinations of these agents, nor did risks rise with increasing cumulative intake of these analgesics. A non‐significant increased risk (OR = 2.1, 95% CI = 0.6–6.9) was observed among women who used only acetaminophen‐containing analgesics, but little excess was seen in men. Earlier studies reported a link to phenacetin‐containing analgesics, but no one reported exclusive use of phenacetin‐containing drugs in our study. The findings suggest that use of analgesics is not likely to play a major role in renal cell cancer development and that for cases diagnosed in the late 1980s or later, after the earlier withdrawal of phenacetin‐containing drugs from the market, a hazard from this analgesic no longer exists. © 1994 Wiley‐Liss, Inc.
Vascular endothelial growth factor and glioma angiogenesis: Coordinate induction of VEGF receptors, distribution of VEGF protein and possible In vivo regulatory mechanisms
Authors: Plate Karl H. , Breier Georg , Weich Herbert A. , Mennel Hans D. , Risau Werner
Published: February 2007

We have previously suggested that tumor angiogenesis in human gliomas is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and flt‐I (VEGF‐receptor I). VEGF, an endothelial‐cell‐specific mitogen, is abundantly expressed in glioma cells which reside along necrotic areas, whereas fit‐I, a tyrosine‐kinase receptor for VEGF, is expressed in tumor endothelial cells, but not in endothelial cells in normal adult brain. Recently, a second tyrosine‐kinase receptor which binds VEGF with high affinity, designated KDR or flk‐I, has been described. We performed in situ hybridization for VEGF mRNA, flt‐I mRNA and KDR mRNA on serial sections of normal brain, low‐grade and high‐grade glioma specimens. We show that KDR mRNA is co‐expressed with flt‐I in vascular cells in glioblastoma but not in low‐grade glioma. Since flt‐I and KDR are not expressed in endothelial cells in the normal adult brain, the coordinate up‐regulation of 2 receptors for VEGF appears to be a critical event which controls tumor angiogenesis. Immunocytochemistry with a monoclonal anti‐VEGF antibody revealed significant amounts of VEGF protein in the same glioma cells that expressed VEGF mRNA. The largest amount of VEGF immunoreactivity, however, was detected on the vasculature of glioblastomas, the site where VEGF exerts its biological functions. These findings suggest that VEGF is produced and secreted by glioma cells and acts on tumor endothelial cells which express VEGF receptors. To further characterize VEGF‐producer cells in vivo, we investigated cellular proliferation, immunoreactivity to the p53 tumor‐suppressor gene product and epidermal‐growth‐factor‐receptor(EGFR) expression on serial sections by immunocytochemistry. VEGF‐producer cells did not show increased cellular proliferation, p53 immunoreactivity or EGFR immunoreactivity as compared with glioma cells which did not express VEGF. Our studies therefore do not demonstrate evidence for a growth advantage of VEGF‐producer cells in vivo or VEGF induction by p53 mutation or EGFR over‐expression. © 1994 Wiley‐Liss, Inc.
Accumulation in “normal” lungs of live tumorigenic cells during sub‐cutaneous growth of weakly and highly metastasizing tumors and their In vitro sensitivity to growth regulation by normal fibroblasts
Authors: Deichman Galina I. , Gurova Katherina V. , Dyakova Natalia A.
Published: February 2007

The main purposes of the study were: (I) in vivo comparison of accumulation of live tumorigenic cells (LTC) in macroscopcally normal lungs of animals bearing 6 s.c. Syrian hamster sarcomas differing in spontaneous metastasizing activity (SMA); (2) in vitro examination of the sensitivity of these cell strains to the growth‐regulating signals of normal fibroblasts. Cell strains used differed in SMA from very weak (WM) to extremely high (HM). The numbers of LTC doses in “normal” lung tissue of tumorbearing animals were determined in s.c. transplantation tests by titrating single‐cell suspensions prepared from the lung tissues of 5 tumor‐bearing animals, for each cell strain, every 5 days during 30 days of s.c. tumor growth, until the appearance of the first spontaneous lung metastases. The sensitivity of WM and HM cells to growth‐regulating signals of normal hamster embryo fibroblasts (HEFs) was examined by in vitro co‐culturing during 6 days with daily determination of 3H‐TdR incorporation in the WM and HM cells grown with or without contact with HEFs. The data presented demonstrate (I) the surprisingly similar efficiency in the occupation of macroscopically normal lung tissues by live tumorigenic cells of WM and HM strains, disseminating spontaneously from the s.c. tumors; (2) the significantly lower sensitivity of HM cells, in contrast to WM, to growth inhibition by contact with HEFs and especially their marked ability to usurp the growth‐stimulating signals of normal HEFs. © 1994 Wiley‐Liss, Inc.
Initiated stem cells in murine intestinal carcinogenesis: Prolonged survival, control by nk cells, and progression
Authors: Altmann G. G. , Lala P. K.
Published: February 2007

Weekly injections of dimethylhydrazine (DMH) (25 mg/kg), or azoxymethane (AOM) (8 mg/kg) to young adult male CDI mice for 1–2 months produced generalized intestinal crypt hyperplasia, which we measured in duodenum in terms of number of interphase and mitotic cells present in crypts. As shown earlier, the crypts expanded because of the presence of a hyperproliferative “initiated” crypt subpopulation which was also sensitive to natural killer (NK) cells. Hyperplasia was thus present as long as NK activity was suppressed by the carcinogen treatment. After interruption of the treatment for periods of 1, 2, 3, 6 and 10 months in the various groups, hyperplasia soon regressed as a result of elimination of the subpopulation by the recovering NK cells. When NK activity was once again eliminated during the terminal days of these “interruption periods” (by injections of anti‐asialo GM‐l antibody, αAGM‐l), the original hyperplasia was fully reconstituted, apparently from stem cells of the subpopulation which survived up to 10 months in their crypt base location. These “initiated stem cells” represented, then, the original carcinogenic insult during the pre‐cancerous period. They also appeared to be the source of the eventual neoplasia, as treating the animals with mutagens during the interruption periods produced specific changes in crypt base histology: new “crypt base basophilic” (CBB) cells appeared which produced large accumulations as well as microscopic tumors when NK activity was suppressed (by αAGM‐l). Some of the initiated stem cells were apparently transformed into neoplastic ones which remained under NK control, the NK cells preventing the establishment of their progeny. Further experiments indicated that, although the initiated stem cells are not eliminated by normal NK activity, activated NK cells can kill them, thereby eliminating the potential source of neoplasia. © 1994 Wiley‐Liss, Inc.
Pathogenetic significance of p53 and c‐Ki‐ras gene mutations and human papillomavirus dna integration in adenocarcinoma of the uterine cervix and uterine isthmus
Authors: Jiko Kumiko , Tsuda Hitoshi , Sato Shinji , Hirohashi Setsuo
Published: February 2007

The pathogenetic significance of p53 and c‐Ki‐ras gene mutations and genomic integration of human papillomavirus (HPV) DNA was examined in surgically resected specimens of adenocarcinomas of the uterine cervix and isthmus using polymerase chain reaction (PCR), single‐strand‐conformation polymorphism and Southern blotting analysis. Among 25 cervical adeno‐carcinomas, p53 gene mutations between exons 5 and 8 were detected in 32%, and the incidence of these mutations was higher in cases at advanced clinical stages and with high grades of nuclear and structural atypia both in endocervical and in endometrioid types. HPV DNA type 16 or 18 in cervical adenocarcinomas was detected in 35% of cases by PCR and in 29% by Southern blotting, and, in contrast to the p53 mutations, the majority of cases with the HPV DNA were at a relatively early clinical stage with low‐grade histological atypia. c‐Ki‐ras gene mutation was detected in only 4% of cervical adenocarcinomas. Among 8 isthmus adenocarcinomas, the incidence of p53 and c‐Ki‐ras gene mutations, and the presence and integration of HPV DNA type 16 or 18 were 38%, 50%, 57% and 25% respectively. The pattern of p53 mutations differed between isthmus and cervical adenocarcinomas: all of the mutations in the former were one‐base substitutions of the transition type, whereas in the latter nearly half of the mutations were of the transversion type. Among cervical adenocarcinomas, p53 mutations between exons 5 and 8 were indicated as being mostly involved in the pathogenesis and development of biologically aggressive tumors, whereas HPV type 16 or 18 infection appeared to be involved in less aggressive cases. In isthmus adenocarcinoma, c‐Ki‐ras gene mutation, apart from p53 mutation and HPV‐type‐16 or −18 infection, appeared to be involved frequently in cancer development.
Oncogene amplifications in early‐stage human prostate carcinomas
Authors: Latil Alain , Baron Jean‐Christophe , Cussenot Olivier , Fournier Georges , Boccon‐Gibod Laurent , Le Duc Alain , Lidereau Rosette
Published: February 2007

Oncogene amplifications are frequently found in solid tumours and are often associated with more aggressively growing forms of human cancer. The proto‐oncogenes c‐myc, c‐erbB2/neu and the IIq13 band are the most frequently amplified regions in adenocarcinomas of various origins. The present study was undertaken to define whether c‐myc, int2/FGF3 (11q13 region) and c‐erbB2/neu genes are involved in prostate tumorigenesis. Tumours and peripheral lymphocyte DNA from 21 localized early‐stage prostatic carcinomas were analysed by Southern‐blot electrophoresis for amplification of the c‐myc and c‐erbB2/neu genes and the 11q13 region (int2/FGF3). We detected no amplification of these 3 oncogenes in our panel.
A HLA class I cis‐regulatory element whose activity can be modulated by hormones
Authors: Sim Bee C. , Hui Kam M.
Published: February 2007

To elucidate the basis of the down‐regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA‐binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis‐regulatory element (NRE) has been identified using band‐shift assays employing DNA sequences derived from the 5′‐flanking region of HLA class I genes. This 9‐bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expressior of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti‐sense orientation. More interstingly, NRE can suppress dexamethasone‐mediated gene activation in the context of the reported glucocorticoidresponsive element (GRE) in MCF‐7 cells but has no influence on the estrogen‐mediated transcriptional activation of MCF‐7 cells in the context of the reported estrogen‐responsice element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down‐regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans‐activators are novel and suggest a versatile form of transcriptional control.
Intrinsic MDR‐1 gene and P‐glycoprotein expression in human melanoma cell lines
Authors: Berger Walter , Elbling Leonilla , Minai‐Pour Michael , Vetterlein Monika , Pirker Robert , Kokoschka Eva‐Maria , Micksche Michael
Published: February 2007

Metastatic malignant melanoma is considered a chemotherapy‐refractory malignancy. A few previous studies have delivered contradictory results regarding the presence and functionality of P‐glycoprotein (P‐gp), a transmembranous protein associated with the classical multidrug resistance (cMDR), in malignant melanoma. Therefore we have investigated this issue on 33 cell lines established from primary and metastatic lesions of human malignant melanoma, comparing different cMDR detection methods. Immunocytochemically 33% of the cell lines stained positive for P‐gp. The data correlated with those of a P‐gp‐radioimmunometric (antibody‐binding) assay. When RT‐PCR was used for MDR‐I mRNA determination, 76% of the melanoma cell lines scored positive. Slot‐blot analysis was seen to be less sensitive than RT‐PCR. Results from the functional P‐gp assays, using daunomycin (DM) as MDR‐substrate, showed no influence of P‐gp expression on drug accumulation and cytotoxicity. However, the cMDR‐modifier verapamil (VP) significantly increased both parameters in those melanoma cells with the highest P‐gp levels. We conclude that cMDR is apparently not the decisive but probably a complementary protective mechanism against toxic agents in malignant melanoma.
Genotypic analysis of epstein‐barr virus isolates associated with nasopharyngeal carcinoma in chinese immigrants to the united states
Authors: Li Lung Maria , Chang Garrick C. , Miller Theodore R. , Wara William M. , Phillips Theodore L.
Published: February 2007

EBV genotypes of first‐ and second‐generation Chinese diagnosed with nasopharyngeal carcinoma in the United States were analyzed by PCR techniques. Previous studies showed a geographical distribution of genotypically distinct sub‐types of EBV. Viruses detected at a higher frequency among Chinese NPC patients (Cf) were distinguished from those found in the majority of Caucasian NPC patients (DF) in the United States by polymorphisms in the BamHI F and I regions. Exploiting this distinction, we analyzed the biopsies of Chinese immigrants in the United States for their C/D and F/f genotypes to evaluate the importance of retention of the Cf virus among Chinese NPC patients in a geographical area where the DF virus prevails. This study shows that approximately 45.5 to 50% of first‐ and second‐generation Chinese NPC patients in California harbor the Cf virus, which is present in only 8% of Caucasian NPC patients in California. It is interesting that, while only 48% of the viral isolates from immigrant Chinese to California harbor the “f” variant, 96% harbor the type‐C viruses.
The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short‐term prognostic indicators of survival
Authors: Dix Brett R. , Robbins Peter , Soong Richie , Jenner Deborah , House Anthony K. , Iacopetta Barry J.
Published: February 2007

Our study was undertaken to determine the prognostic significance of several common genetic alterations observed in colorectal carcinomas. We have previously analysed loss of heterozygosity of the MCC, APC, p53 and DCC tumour suppressor gene loci as well as p53 gene mutations and protein over‐expression in a series of 100 Dukes' stage B and C colorectal tumours obtained at surgery. To extend our observations of alterations that may occur in these tumours, mutations to the c‐Ki‐ras oncogene and APC tumour suppressor gene were detected by PCR single‐strand conformation polymorphism analysis. Short‐term follow‐up revealed no significant association between overall patient survival and any single, or combination of, genetic alteration(s). Surprisingly, patients whose tumours showed evidence of p53 protein over‐expression/ accumulation by immunocytochemistry (ICC) had a significantly better prognosis (p = 0.039) than those whose tumours had no p53 ICC reactivity.
Intake of fried meat and risk of cancer: A follow‐up study in finland
Authors: Knekt Paul , Steineck Gunnar , Järvinen Ritva , Hakulinen Timo , Aromaa Arpo
Published: February 2007

It has been suggested that mutagens in fried meat may be involved in the cancer process. Therefore the relationships between intake of fried meat and subsequent risk of cancers at different sites were studied among 9,990 Finnish men and women, 15–99 years of age and initially free of cancer. The baseline study was carried out in 1966–1972, and cases of cancer were identified through data linkage with the Finnish Cancer Registry. During a 24‐year follow‐up, 853 cancer cases were diagnosed. The intake of fried meat was estimated from a dietary history interview covering the total diet of the participants during the previous year. There was a positive association between fried meat intake and the risk of female‐hormone‐related cancers, i.e., cancer of the breast, endometrium and ovary combined. The relative risk of these cancers combined between persons in the highest and lowest tertiles of daily intake of fried meat adjusted for age, personal characteristics and intake of other main food groups was 1.77 (95% confidence interval = 1.11–2.84). Pancreatic and nervous system cancers also presented non‐significant suggestive associations. No associations were observed with respect to other single cancer sites studied or to all sites of cancer combined. Further epidemiological efforts are needed to ascertain the potential link between fried‐food mutagens and cancer risk.
Incidence and risk factors for childhood brain tumors in the ILE DE France
Authors: Cordier Sylvaine , Iglesias Maria‐José , Le Goaster Corinne , Guyot Marie‐Madeleine , Mandereau Laurence , Hemon Denis
Published: February 2007

A case‐control study investigating risk factors for childhood brain tumors was conducted in the lle de France (Paris region). During a 2‐year period (1985–1987) 109 newly diagnosed cases were identified and, of these, 75 could be interviewed. In the same region, 113 population controls, frequency‐matched for year of birth, were interviewed. Odds ratios adjusted for child's age and sex and for maternal age were estimated for each risk factor present in utero or during childhood by conditional logistic regression. Statistically significant associations were found for the following risk factors: farm residence, cat scratches, home treated with pesticides, passive smoking, family history of cancer, antihistamine intake. Intake of vitamin supplements during childhood was associated with a decrease in risk. This study is part of a multicentric case‐control study coordinated by the International Agency for Research on Cancer and its results will be compared for consistency, and pooled with those of other centers using the same protocol.
Effective anti‐metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with newcastle disease virus (NDV)
Authors: Plaksin Daniel , Porgador Angel , Vadai Ezra , Feldman Michael , Schirrmacher Volker , Eisenbach Lea
Published: February 2007

The therapeutic efficacy of active immunization with B16‐F10.9 melanoma cells transfected with syngeneic major histocompatibility complex (MHC) class‐l genes, modified by infection with Newcastle Disease virus (NDV) or modified by both treatments, was compared. B16‐F10.9 tumor‐bearing mice were treated at various stages of tumor growth and metastasis with irradiated, modified tumor‐cell vaccines. Irradiated tumor cells and H‐2Db transfectants did not stimulate anti‐tumor immunity while H‐2Kb transfectants and NDV‐modified F10.9 cells showing low and high expression of MHC class‐l genes efficiently prevented metastasis of small established tumors. NDV‐modified parental‐cell vaccines functioned optimally and improved overall survival by about 60%, also at early stages of metastasis establishment. A synergistic effect of H‐2Kb expression and virus modification on rejection of micrometastases was observed in mice bearing advanced tumors. Postoperative vaccination of mice carrying multiple metastases with NDV‐modified vaccines caused significant, but incomplete, reduction of metastatic tumor load. The therapeutic effect of NDV‐modified tumor vaccines was dependent on multiple immune mechanisms. Depletion of CD8, CD4 or NK cells by in vivo treatment with monoclonal antibodies reversed the immunotherapeutic effects of the vaccine. Thus, tumor xenogenization and gene modification may act synergistically to vaccinate against advanced tumors, while single modalities can effectively vaccinate against metastasis at early stages of tumor growth.
Lysosomes as photochemical targets
Authors: Berg Kristian , Moan Johan
Published: February 2007

Sulfonated tetraphenyl porphines (TPPSn) are photosensitizing dyes that localize in lysosomes of NHIK 3025 cells. In order to elucidate the mechanisms of cell inactivation by photochemical treatment with TPPSn, lysosomal enzyme inactivation and release of lysosomal contents were examined after treatment. In cells treated with TPPS4, and light, the lysosomal enzymes β‐N‐acetyl‐D‐glucosaminidase (β‐AGA) and cathepsin(L + B) were almost completely inactivated and no enzyme activities were released from the lysosomes. In contrast, a maximum of 30 and 50% of the initial β‐AGA activity was released from lysosomes after treatment with TPPS1and TPPS2a, respectively. Forty per cent of the initial β‐AGA activity was released after treatment with TPPS2aand a non‐cytotoxic dose of light. After such a treatment only approximately 10% of the initial cathepsin activity was found in the cytosol fraction and in all other cases no cathepsin activity was recovered in the cytosol fraction after photochemical treatment. It was found that the constituents of the cytosol partly inhibited cathepsin activity. This inhibitory effect was not influenced by the photochemical treatment, neither was the colony‐forming ability of photochemically treated cells influenced by pre‐treatment with the cathepsin inhibitor E64. The present results indicate that NHIK 3025 cells are not killed by lysosomal disruption after photochemical treatment. This is partly due to photochemical inactivation of the lysosomal enzymes and to the action of cytosolic cysteine cathepsin inhibitors. The present results also indicate that cells can survive a partial lysosomal disruption.
The evaluation of screening for gastric cancer in miyagi prefecture, Japan: A population‐based case‐control study
Authors: Fukao Akira , Tsubono Yoshitaka , Tsuji Ichiro , Hisamichi Shigeru , Sugahara Nobuyuki , Takano Akira
Published: February 2007

Although a screening program for gastric cancer, using barium X‐ray examination, has been carried out widely in Japan for the past 3 decades, there is insufficient evidence to confirm its effectiveness in terms of reducing mortality. To evaluate the effectiveness of the screening, a population‐based case‐control study was carried out in Miyagi Prefecture, japan. Case subjects, who had died from gastric cancer (198) and control subjects matched in age, sex and residence (577) were selected from among members of the National Health Insurance. Their screening histories during 5 years before the cases were diagnosed were surveyed on the basis of records of the regional cancer registry and the cancer‐detection center. The odds ratio (OR) of death from gastric cancer for the persons who participated in the screening at least once during 5 years was 0.41. For those who participated only once during 5 years the OR was 0.43, and for those whose last participation was 5 years earlier it was 0.30. Our data suggest that screening for gastric cancer at 5‐year intervals might reduce mortality by 60%, and that the effect might remain for at least 5 years. © 1995 Wiley‐Liss, Inc.
Altered intracellular processing and enhanced secretion of procathepsin D in a highly deviated rat hepatoma
Authors: Isidoro Ciro , Demoz Marina , De Stefanis Daniela , Mainferme Francis , Wattiaux Robert , Baccino Francesco M.
Published: February 2007

Both freshly‐isolated rat hepatocytes and Morris hepatoma 7777 cells synthesized cathepsin D as a precursor that was either processed intracellulary to smaller mature forms or secreted into the medium. The pattern of mature enzyme forms was different in the 2 cell types. In addition, the relative amount of precursor secreted was much higher for hepatoma cells. Monensin strongly enhanced the secretion and also impaired the intracellular transport‐linked maturation of procathepsin D in hepatocytes, while it markedly inhibited intracellular maturation and only slightly increased secretion of the pro‐enzyme in hepatoma cells. Ammonium chloride influenced the intralyso‐somal segregation and maturation of procathepsin D in hepatocytes but not in hepatoma cells. Our observations indicate that (i) the lysosomal segregation of cathepsin D was less efficient and its fractional secretion higher in hepatoma cells than in hepatocytes; (ii) in the 2 cell types, delivery to lysosomes and processing of procathepsin D were differently sensitive to increases in the vacuolar pH. © 1995 Wiley‐Liss, Inc.
Burkitt's lymphoma cells are resistant to programmed cell death in the presence of the epstein‐barr virus latent antigen EBNA‐4
Authors: Silins Sharon L. , Sculley Tom B.
Published: February 2007

Group I Epstein‐Barr virus (EBV)‐positive Burkitt's lymphoma (BL) cells display a surface phenotype characteristic of germinal centre B cells and readily undergo apoptosis in response to a variety of stimuli, including serum deprivation. Activation of EBV latent gene expression has been shown to increase the survival of these tumour cells by blocking programmed cell death. To investigate the nature of this protection, we assessed the function of the EBV latent EBNA‐4 gene in a group 1 lymphoma line, dG75. Group I BL cells induced to undergo apoptosis in response to serum starvation were protected in the presence of EBNA‐4 protein. A possible factor underlying this EBNA‐4‐associated survival was increased expression of the oncoprotein bcl‐2, a known repressor of cell death. Together these data suggest that EBNA‐4 plays an important role in the regulation of programmed cell death in BL tumour cells. © 1995 Wiley‐Liss, Inc.
New short‐chain analogs of a substance‐P antagonist inhibit proliferation of human small‐cell lung‐cancer cells in vitro and in vivo
Authors: Orosz Antal , Schrett János , Nagy Józscf , Bartha László , Schön István , Nyéki Olga
Published: February 2007

Human small‐cell lung‐cancer cells (SCLC) produce and secrete gastrin‐releasing peptide (GRP), the mammalian equivalent of bombesin (BN). There is some evidence to suggest that GRP is an autocrine regulator of SCLC cell growth. In the search for potent BN antagonists, several substance‐P (SP) analogs were found to inhibit the growth of SCLC cells. We found that a known short‐chain SP antagonist, pHOPA‐DTrp‐Phe‐DTrp‐Leu‐Leu‐NH2 (NY3238), inhibits the binding of 125l‐Tyr4‐BN on Swiss 3T3 cell line expressing BN receptors, as well as the proliferation of NCI‐H69 SCLC cells. In this study we tested several analogs of NY3238 and we found that NY3521 and NY3460 are more effective in inhibition of proliferation of SCLC cells but less potent in inhibition of binding of 125l‐Tyr4‐BN on Swiss 3T3 cells than NY3238. Furthermore, we detected specific binding of radiotabelled NY3238 even below I nM on NCI‐H69 cells that could have been inhibited by SP and NY3460 rather than by BN. In addition to these in vitro studies, NY3460 proved to be effective in inhibiting the growth of NCI‐H69 SCLC xenografts in nude mice in vivo. These analogs of NY3238 could be promising therapeutic agents in the treatment of SCLC. © 1995 Wiley‐Liss, Inc.
Transformation of human keratinocytes is characterized by quantitative and qualitative alterations of the T‐16 antigen (Trop‐2, MOv‐16)
Authors: Schön Michael P. , Orfanos Constantin E.
Published: February 2007

The regulation of synthesis and post‐translational processing of the T‐16 antigen, a human cell‐surface glycoprotein of 50 to 60 kDa, was investigated in normal and transformed human keratinocytes in vitro. Normal keratinocytes of interfollicular and follicular origin were compared with squamous‐cell‐carcinoma lines, spontaneously immortalized keratinocytes, and SV‐40 transformed keratinocytes. FACS analysis and radio‐immunoprecipitation showed that the synthesis and expression of T‐16 was 3‐ to 4‐fold higher in transformed keratinocytes than in their normal counterparts. In normal keratinocytes, no quantitative differences were observed among freshly prepared cells, primary cultures and sub‐cultures. In SDS‐PAGE, a single broad band at 50 to 60 kDa was observed in normal keratinocytes, whereas 2 bands at 42 and 45 to 55 kDa were detected after transformation. Tunicamycin treatment of living cells and glycosidase digestion of immunopurified T‐16 antigen revealed this molecular heterogeneity to be due to different N‐glycosylation in normal and transformed keratinocytes. In pulse‐chase experiments, 2 distinct precursor proteins at 38 and 42 kDa were detected in transformed keratinocytes, whereas in normal cells the 38‐kDa signal was dramatically decreased. These findings indicate that quantitative and qualitative changes of T‐16 mark the transformation process of human keratinocytes, showing similar post‐translational alterations in all transformed populations investigated. © 1995 Wiley‐Liss, Inc.
Characterisation of four merkel cell carcinoma adherent cell lines
Authors: Leonard J. Helen , Dash Peter , Holland Peter , Kearsley John H. , Bell John R.
Published: February 2007

We have previously described the establishment of a number of cell lines from Merkel cell carcinoma (MCC), also known as small cell cancer of the skin or neuroendocrine carcinoma of the skin. These cells, all of which grew as suspension cultures, were found to resemble small cell lung cancer (SCLC) lines types 1, 2 and 3 by their morphology and growth characteristics. We now report 4 more MCC cell lines which resemble the SCLC type 4 cell lines in that they grow as adherent monolayers. These MCC lines would belong to the variant subgroup as they no longer express most neuroendocrine markers, grow at low cell density and have population doubling times of 1–5 days in contrast to the MCC suspension lines which have doubling times of 6–12 days. MCC 14/1 and MCC 14/2 were established from the same metastatic node and would appear to represent 2 clones of the tumour which differ in morphology, histochemical markers and DNA content. We present details of the morphology, DNA content and immunohistochemistry of these 4 lines and com‐pare their growth patterns with those of SCLC and MCC lines which grow in suspension. © 1995 Wiley‐Liss, Inc.
THE role of indoleamine 2,3‐dioxygenase in the anti‐tumour activity of human interferon‐γ in vivo
Authors: Burke Frances , Knowles Richard G. , East Nick , Balkwill Frances R.
Published: February 2007

We have studied the relationship between L‐tryptophan metabolism and the response to human IFN‐γ in 3 human ovarian cancer xenografts growing in nude mice. During IFN‐γ therapy all 3 tumours showed a profound depletion in L‐tryptophan and a corresponding rise in L‐kynurenine. The microenvironment surrounding the tumours was also depleted of L‐tryptophan. The IFN‐γ‐inducible enzyme indoleamine dioxygenase, IDO, was induced in treated tumours. While there was a variability in IDO mRNA expression in the different xenografts tested, in situ hybridization showed that the gene was induced at all levels of the tumour, and not just the periphery. These results show that induction of IDO by IFN‐γ in vivo can metabolize L‐tryptophan rapidly enough for it to become depleted, despite a continued supply of L‐tryptophan from the host. The IDO mRNA and protein remained induced after the L‐tryptophan levels had returned to normal, suggesting that the gene may be post‐transcriptionally regulated and/or the IDO co‐factor supply may be limited. Another IFN‐γ‐inducible gene, tryptophanyl tRNA synthetase, was also induced in the tumour. It is possible that this enzyme, which is responsible for synthesizing tryptophanyl tRNA, acts in a compensatory manner by allowing protein synthesis to continue despite low free Ltryptophan concentrations. There was no correlation of the above parameters with the anti‐tumour response to IFN‐γ, suggesting that other mechanisms must play a role. Ltryptophan depletion may be a contributor to a multifactorial growth inhibition of tumour cells following IFN‐γ treatment, but cannot on its own explain their growth inhibition. © 1995 Wiley‐Liss, Inc.
Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis
Authors: Easty David J. , Herlyn Meenhard , Bennett Dorothy C.
Published: February 2007

Protein tyrosine kinases have been implicated in tumor initiation and progression. Here we used Northern blotting to study expression of their genes in cultured normal melanocytes and 19 melanoma cell lines from different stages of tumor progression. We detected transcripts for 2 cytoplasmic (ABL and FES) and 6 receptor (ECK, ERB‐B2, FGF‐R4, IGFI‐R, KDR and TIE) kinases but not for receptors RET or TRK‐A. Genes for ECK, FGF‐R4 and TIE were expressed ectopically in melanomas (not in normal melanocytes). Similarly, ECK protein was detected by immunoblotting in metastatic melanomas but not in normal melanocytes. ECK mRNA levels tended to increase again during late melanoma progression. ECK and TIE mRNAs were also detected in highly metastatic variant cells but not in the corresponding poorly metastatic parental lines. Conversely, FES and KDR gene expression was lost in most advanced primary and metastatic melanomas. These findings suggest positive and negative roles for specific tyrosine kinases during progression. © 1995 Wiley‐Liss, Inc.
A dose‐response curve for sun exposure and basal cell carcinoma
Authors: Kricker Anne , Armstrong Bruce K. , English Dallas R. , Heenan Peter J.
Published: February 2007

A population‐based case‐control study of sun exposure and basal cell carcinoma (BCC) was conducted in Western Australia in 1988. Its aim was to examine the relationship between risk of BCC and the amount and pattern of sun exposure. This report deals with amount of exposure. The odds ratios (ORs) for BCC on the head and neck and limbs decreased with increasing total exposure, whereas the opposite was observed for BCC on the less heavily exposed trunk, with the highest OR in those with the greatest exposure. In an analysis of all body sites together in which the total hours of exposure to the specific site was treated as a continuous variable, an initial rise in risk of BCC was seen with a peak OR of 1.4 at about 35,000 hr of exposure, followed by a fall. In contrast to these site‐specific patterns, lifetime accumulated sun exposure of the whole body showed no appreciable association with BCC either in total or for working days only. Risk of BCC was positively associated with lifetime exposure on non‐working days, however, with an OR for higher than baseline categories of around 1.7. There was a significant interaction between ability to tan and total and occupational sun exposure. Risk increased with increasing exposure in those who tanned well but not in those who tanned poorly. This pattern is consistent with other observations which indicate that beyond a certain level of sun exposure risk of BCC does not increase further.
Does intermittent sun exposure cause basal cell carcinoma? a case‐control study in Western Australia
Authors: Kricker Anne , Armstrong Bruce K. , English Dallas R. , Heenan Peter J.
Published: February 2007

Our report deals with the relationship of pattern and timing of sun exposure to basal cell carcinoma (BCC) in a population‐based case‐control study conducted in Western Australia in 1988. The main measure of intermittent exposure was based on the amount of exposure on non‐working days relative to that over the whole week. Outdoor recreational activities, holidays and sunburn were also considered to be markers of intermittent exposure. We observed a statistically significant increase in risk of BCC with increasing proportion of weekly sun exposure obtained at the weekend, especially in late teenage (OR = 3.9, 95% CI 1.9‐7.8 for maximum intermittency of exposure), exposure of the site of skin cancer during holidays (OR = 1.9, 95% CI 1.1‐3.1 for the highest exposure quarter) and sunburn to the site (ORs of 1.8 for 3‐10 and 1.5 for 11+ sunburns in a lifetime). Risk of BCC increased substantially with increasing intermittency in poor tanners but not at all in good tanners. Our data suggest that a particular amount of sun exposure delivered in infrequent, probably intense increments will increase risk of BCC more than a similar dose delivered more continuously over the same total period of time.
Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells
Authors: Sidell Neil , Wada Randal , Han Guangyang , Chang Bieshia , Shack Sonsoles , Moore Theodore , Samid Divorit
Published: February 2007

Phenylacetate, a natural metabolite of phenylalanine which was originally described as a plant growth hormone, has recently gained attention as a possible differentiation inducer for a variety of human tumor cell types. This interest prompted us to assess the ability of sodium phenylacetate (NaPA) to promote the differentiation of human neuroblastoma cells, both alone and in combination with retinoic acid (RA), a known inducer of neuroblastoma differentiation and maturation. Using the LA‐N‐5 cell line, we have determined that NaPA can stimulate the differentiation of neuroblastoma cells, as evidenced by dose‐dependent inhibition of cell proliferation, neu‐rite outgrowth, increased acetylcholinesterase activity and reduction of N‐myc expression. Furthermore, NaPA and RA synergized in inducing differentiation, in that combination treatment resulted in cessation of cell growth along with morphologic and biochemical changes indicative of the loss of malignant properties. We have determined that NaPA can markedly enhance mRNA levels of the nuclear RA receptor‐β (RARβ) in LA‐N‐5 cells prior to morphologic or other pheno‐typic changes induced by this compound. This effect appeared to be distinct from the ability of NaPA to alter tumor cell lipid metabolism via inhibition of protein isoprenylation. Thus among its varied effects on LA‐N‐5 cells, NaPA appears to interact with the RA pathway at the nuclear level by up‐regulating RARβ expression.
Survival in breast cancer: A population‐based study in Bangalore, India
Authors: Nandakumar Ambakumar , Anantha Narayanappa , Venugopal T. C. , Sankaranarayanan Rengaswamy , Thimmasetty K. , Dhar Murali
Published: February 2007

Survival from cancer reflects the aggressiveness of the disease, the effectiveness of treatment and host factors such as age. While hospital‐based survival rates are typically used to evaluate the care provided in a particular hospital, population‐based survival reflects the effectiveness of the overall cancer control strategy in the region. Here, we report the survival experience of 1514 breast cancer patients registered by the Bangalore population‐based registry during 1982‐1989. There have been very few reports on survival from cancer in India, mainly because of poor patient follow‐up and inadequate system of registration of death. This has been largely overcome in this study by means of active follow‐up through visits of homes of patients. Scrutiny of medical records and matching with death certificates, was also carried out in a small proportion (12%) of cases. Thus, information on vital status (whether dead or alive) as on January 1, 1993 was available for 1334 (88%) subjects and partial follow up data were available for a further 34 (2%). The observed 5 year survival was 42.3% and the corresponding relative survival was 46.8%. The observed survival was 57.4% for localized disease, 45.8% for direct extension, 37% for those with regional node involvement, 14.2% for distant metastasis and 38.3% for those with unstaged disease. The clinical extent of disease and the educational status were independent predictors of survival.
Immunohistochemical localization of the plasminogen activator inhibitor‐1 in breast cancer
Authors: Bianchi Elisabetta , Cohen Robert L. , Dai Aihua , Thor Ann T. , Shuman Marc A. , Smith Helene S.
Published: February 2007

We used an immunohistochemical assay with an antigen‐retrieval technique to study plasminogen activator inhibitor type‐1 (PAI‐I) expression in paraffin‐embedded breast tissue samples at different stages of malignant transformation. We detected PAI‐I in 15/20 invasive tumors. In several cases staining was localized to the stromal component. PAI‐I‐positive fibroblasts could be seen surrounding tumor nodules or at tumor margins. In addition, tumor‐infiltrating macrophages (13 cases) and endothelial cells (5 cases) were positive. In 11 specimens PAI‐I‐positive cancer cells were also detected. In 2 strongly positive cases secreted PAI‐I was visible in the extracellular matrix surrounding the cells. Six of 9 samples of carcinoma in situ (DCIS) were weakly positive. No staining of endothelial cells was visible in DCIS. Only a few positive adenomatous epithelial cells could be seen in 3 of 7 papillomas. All biopsies of normal breast tissue were negative, with the exception of one sample, obtained from a patient with a previous segmental mastectomy for DCIS. PAI‐I production by invasive breast cancers could reflect a general upregulation of the plasminogen activation system in proliferating cancer cells, as suggested by the finding that normal mammary epithelium cultures expressed PAI‐I in all cases examined. In addition, production of PAI‐1 by the tumor stroma could protect the tumor itself from excessive proteolysis.