bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constitutive activation of the androgen receptor by a point mutation in the hinge region: A new mechanism for androgen‐independent growth in prostate cancer
Authors: Céraline Jocelyn , Cruchant Marion D. , Erdmann Eva , Erbs Philippe , Kurtz Jean‐Emmanuel , Duclos Brigitte , Jacqmin Didier , Chopin Dominique , Bergerat Jean‐Pierre 
Published: November 2003

AbstractAndrogen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen‐dependent to androgen‐independent growth. We use a yeast‐based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c‐terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation‐induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation. © 2004 Wiley‐Liss, Inc.
Geographic variation in Epstein‐Barr virus–associated Burkitt's lymphoma in children from Brazil
Authors: Klumb Claudete Esteves , Hassan Rocio , De Oliveira Deilson Elgui , De Resende Lídia Maria Magalhães , Carriço Maria Kadma , De Almeida Dobbin Jane , Pombo‐De‐Oliveira Maria S. , Bacchi Carlos E. , Maia Raquel Ciuvalschi 
Published: November 2003

AbstractIn developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV‐associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin‐embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA‐2 common region while the nested reaction amplified the region discriminating between EBV types 1 and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type 1 virus infected the majority of EBV‐positive BLs (18/21). There was a trend for younger age in children with EBV‐positive BL compared to EBV‐negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV‐associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil. © 2003 Wiley‐Liss, Inc.
Familial risk of cancer: Data for clinical counseling and cancer genetics
Authors: Hemminki Kari , Li Xinjun , Czene Kamila 
Published: November 2003

AbstractFamilial risks for cancer are important for clinical counseling and understanding cancer etiology. Medically verified data on familial risks have not been available for all types of cancer. The nationwide Swedish Family‐Cancer Database includes all Swedes born in 1932 and later (0–to 68‐year‐old offspring) with their parents, totaling over 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age‐specific familial risk in offspring by an exact proband status. The familial risks for offspring cancer were increased at 24/25 sites from concordant cancer in only the parent, at 20/21 sites from a sibling proband and at 12/12 sites from a parent and sibling proband. The highest SIRs by parent were for Hodgkin's disease (4.88) and testicular (4.26), non‐medullary thyroid (3.26), ovarian (3.15) and esophageal (3.14) cancer and for multiple myeloma (3.33). When a sibling was affected, even prostate, renal, squamous cell skin, endocrine, gastric and lung cancer and leukemia showed SIRs in excess of 3.00. The highest cumulative risks were found for familial breast (5.5%) and prostate (4.2%) cancers. We identified reliable familial risks for 24 common neoplasms, most of which lack guidelines for clinical counseling or action level. If, for example, a familial SIR of 2.2 would be use as an action level, counseling would be needed for most cancers at some diagnostic age groups. The present data provide the basis for clinical counseling. © 2003 Wiley‐Liss, Inc.
Inhibition of prostate cancer metastatic colonization by ∼4.2 Mb of human chromosome 12
Authors: Jaeger Erich B. , Chekmareva Marina A. , Tennant Thelma R. , Luu Hue H. , Hickson Jonathan A. , Chen Stephen L. , Samant Rajeev S. , Sokoloff Mitchell H. , Rinker‐Schaeffer Carrie W. 
Published: November 2003

AbstractOur previous studies demonstrate that introduction of a ∼70 cM region (now estimated at 63.75 Mb by the Human Genome Project) of human chromosome 12 into the highly metastatic Dunning rat prostate cancer cell line AT6.1 results in >30‐fold (≥90%) reduction in the number of overt metastases in spontaneous metastasis assays. We report the further localization and biological characterization of the metastasis‐suppressor activity encoded by a reduced region of chromosome 12. To localize this metastasis‐suppressor activity, a panel of AT6.1 microcell hybrids that retain varying portions of human chromosome 12 was constructed and subjected to sequence‐tagged site (STS)‐based PCR analysis and assessment of in vivo metastatic ability. Data from these complementary approaches localized the metastasis‐suppressor activity to a ∼4.2 Mb portion of human chromosome 12q24.3 comprised of 3 separate regions. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) and immunoblotting were used for differential expression analyses to identify which characterized genes, predicted gene sequences and expressed sequence tags (ESTs) within this region could be responsible for the observed metastasis suppression. Comprehensive in vivo studies showed that suppressed AT6.1‐12 hybrids that retain the metastasis‐suppressor region on 12q24.3 are capable of arriving at the secondary site, but are not able to persist there. Thus, unlike other metastasis‐suppressor genes characterized to date, the metastasis‐suppressor gene encoded by this region appears to utilize a different biologic mechanism to suppress the growth of overt metastases at the secondary site. © 2003 Wiley‐Liss, Inc.
Clusterin (SGP‐2, ApoJ) expression is downregulated in low‐ and high‐grade human prostate cancer
Authors: Scaltriti Maurizio , Brausi Maurizio , Amorosi Andrea , Caporali Andrea , D'Arca Domenico , Astancolle Serenella , Corti Arnaldo , Bettuzzi Saverio 
Published: November 2003

AbstractClusterin is overexpressed during tissue and cell involution and downregulated in proliferating cells. Its role in cell survival, cell death and neoplastic transformation remains debated. We studied the expression and distribution of clusterin mRNA and protein in human prostate carcinoma (CaP) specimens of different degrees of malignancy. Fresh CaP specimens were obtained from 25 patients subjected to long‐term androgen ablation before surgery. Clusterin expression was studied by Northern and Western analysis, in situ hybridization and immunohistochemistry, in comparison with Gas1 and histone H3 mRNA (markers of cell quiescence and S phase of the cell cycle, respectively). Clusterin is downregulated in CaP in comparison with matched benign controls. In low‐grade CaP, clusterin colocalized with Gas1 to the stromal compartment, and in some glands, the basal lamina was heavily stained. In high‐grade CaP clusterin stained the remnants of stromal matrix while histone H3 localized to cancer cells, which were very rarely clusterin positive. High clusterin expression was found in the branches of a nerve infiltrated by tumor. The periglandular clusterin expression found in low‐grade CaP could result from induction of quiescence and/or apoptosis of prostatic fibroblasts lining those glands in which tumor invasion is at an initial stage, involving basal lamina. In advanced CaP, the staining of the remnants of the extracellular matrix suggests a role for clusterin in the process of dismantling the stromal organization caused by cancer progression. © 2003 Wiley‐Liss, Inc.
Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines
Authors: Choudhury Aniruddha , Charo Jehad , Parapuram Sunil K. , Hunt Richard C. , Hunt D. Margaret , Seliger Barbara , Kiessling Rolf 
Published: November 2003

AbstractSilencing of a specific mRNA using double stranded RNA oligonucleotides represents one of the newest technologies for suppressing a specific gene product. Small interfering RNA (siRNA) are 21 nucleotides long, double stranded RNA fragments that are identical in sequence to the target mRNA. We designed 3 such siRNA against the Her2/neu (HER2) gene. The HER2 gene is known to play an important role in the oncogenesis of several types of cancers, such as breast, ovarian, colon and gastric cancers. Introduction of the siRNA into HER2 positive tumor lines in vitro greatly reduced the cell surface expression of the HER2 protein. Concurrently, a range of effects on cell physiology, such as growth inhibition or apoptosis, was observed. The expression of HLA class I was observed to be upregulated when HER2 was silenced with siRNA. Treatment of SKBr3 and MCF7/HER2 tumor cell lines with the HER2 siRNA resulted in growth arrest of cells in the late G1/S‐phase. Our results suggest that siRNA may be an effective method of abrogating the effect of HER2 in tumorigenesis. © 2003 Wiley‐Liss, Inc.
Tenascin‐C regulates angiogenesis in tumor through the regulation of vascular endothelial growth factor expression
Authors: Tanaka Keiichiro , Hiraiwa Noriko , Hashimoto Hisashi , Yamazaki Yoji , Kusakabe Moriaki 
Published: November 2003

AbstractIn order to verify whether tenascin‐C (TN‐C) is involved in angiogenesis as an extracellular signal molecule during tumorigenesis, cancerous cell transplantation experiments and coculture experiments were carried out, focusing on the regulation of vascular endothelial growth factor (VEGF). The A375 human melanoma cells introduced the GFP gene (A375‐GFP), implanted subcutaneously into BALB/cA nude (WT) and TN‐C knockout BALB/cA nude (TNKO) congenic mice. Furthermore, coculture experiments between A375‐GFP and embryonic mesenchyme, which was prepared from both genotypes, were carried out to investigate the molecular mechanism in the cell‐cell interactions. Both the content of TN‐C and that of VEGF in the tumor and the conditioned medium were analyzed by the sandwich ELISA method. Seven days after transplantation of the A375‐GFP, capillary nets became far more abundant in the tumors grown in WT mice than those in TNKO mice. Interestingly, VEGF and TN‐C expressions showed antithetical expression patterns between the tumors in WT mice and those in TNKO mice. This peculiar phenomenon seems to be caused by a time lag prior to the onset of the mesenchymal regulation for the TN‐C expression of A375‐GFP. The coculture experiments revealed that WT mesenchyme had a much stronger effect than TNKO mesenchyme on both TN‐C and VEGF expression. However, the defects of TNKO mesenchyme were restored in all cases by additional TN‐C. These results clearly indicated that the expressions of both TN‐C and VEGF depend on the surrounding mesenchyme, and that the function of mesenchyme is regulated by its own mesenchymal TN‐C. In conclusion, the present data suggest that the matrix microenvironment organized by the host mesenchyme is very important for angiogenesis in tumor development. © 2003 Wiley‐Liss, Inc.
Detecting lung cancer in plasma with the use of multiple genetic markers
Authors: Andriani Francesca , Conte Davide , Mastrangelo Tiziana , Leon MariaElena , Ratcliffe Cathy , Roz Luca , Pelosi Giuseppe , Goldstraw Peter , Sozzi Gabriella , Pastorino Ugo 
Published: November 2003

AbstractRecent studies have demonstrated the possibility to detect genetic changes in plasma DNA of cancer patients. The goal of this study was to validate a panel of molecular markers for lung cancer detection in plasma DNA. Three markers, p53, FHIT and microsatellite alterations at loci on chromosome 3, were used to detect mutations in tumor and plasma DNA of 64 stage I–III non small cell lung cancer patients. p53 mutations were studied by direct sequencing of exons 5 through 8 in tumor DNA and by plaque hybridization assay and sequencing in plasma DNA. Allelic losses were evaluated by fluorescent PCR in tumor and plasma DNA. p53 genomic mutations were detected in 26 (40.6%) of 64 tumor DNA samples and the identical mutation was identified in plasma of 19 (73.1%) of them. Microsatellite alterations at FHIT and 3p loci were observed in 40 (62.5%) tumors and in 23 (35.9%) plasma samples. Of the 40 patients showing microsatellite alterations in tumors, 19 (47.5%) displayed the same change in plasma DNA. At least 1 of the 3 genetic markers (p53, FHIT and 3p) was altered in plasma of 51.6% of all patients and 60.7% of stage I patients. Moreover, genetic markers in plasma identified 29 of 45 (64.4%) of all stages and 15 of 22 (68.2%) of stage I patients whose tumors had an alteration. These results provide the proof of principle that plasma DNA alterations are tumor‐specific in most cases and support blood testing as a noninvasive strategy for early detection. © 2003 Wiley‐Liss, Inc.
Reversal of breast cancer resistance protein (BCRP/ABCG2)‐mediated drug resistance by novobiocin, a coumermycin antibiotic
Authors: Shiozawa Ken , Oka Mikio , Soda Hiroshi , Yoshikawa Megumi , Ikegami Yoji , Tsurutani Junji , Nakatomi Katsumi , Nakamura Yoichi , Doi Seiji , Kitazaki Takeshi , Mizuta Yohei , Murase Kunihiko , Yoshida Hisahiro , Ross Douglas D. , Kohno Shigeru 
Published: November 2003

AbstractBreast cancer resistance protein (BCRP/ABCG2) of an ATP‐binding cassette half‐transporter confers resistance against mitoxantrone and camptothecin derivatives of topotecan and irinotecan. Novobiocin, a coumermycin antibiotic, is known to enhance anticancer drug sensitivity of cancer cells in vitro and in vivo, the mechanism of which remains undetermined. Here we focused on drug efflux pump and examined whether novobiocin reversed drug resistance in multidrug‐resistant cells highly expressing BCRP. To explore the reversal mechanisms, intracellular drug accumulation was measured by flow cytometry, and a topotecan transport study using plasma membrane vesicles was performed. We used PC‐6/SN2‐5H2 small cell lung cancer and MCF‐7/MX breast cancer cells selected with SN‐38 of the active irinotecan metabolite and mitoxantrone, respectively, and the BCRP cDNA transfectant MCF‐7/clone 8 cells. These cells expressed high levels of BCRP mRNA but not other known transporters. Compared to the parental PC‐6 cells, PC‐6/SN2‐5H2 cells were 141‐, 173‐ and 57.2‐fold resistant to topotecan, SN‐38 and mitoxantrone, respectively. Novobiocin at 60 μM decreased the degree of the above resistance by approximately 26‐fold in PC‐6/SN2‐5H2 cells, and similarly reversed resistance in MCF‐7/MX, MCF‐7/clone 8 and un‐selected NCI‐H460 cells highly expressing BCRP. Furthermore, novobiocin increased the intracellular topotecan accumulation in these cells and inhibited the topotecan transport into the membrane vesicles of PC‐6/SN2‐5H2 cells. No effects of novobiocin in these assay were observed in the parental PC‐6 and MCF‐7 cells. The kinetic parameters in the transport study indicated that novobiocin was a inhibitor for BCRP, resulting in competitive inhibition of BCRP‐mediated topotecan transport. These findings suggest that novobiocin effectively overcomes BCRP‐mediated drug resistance at acceptable concentrations. © 2004 Wiley‐Liss, Inc.
Combined inhibition of estrogen‐dependent human breast carcinoma by soy and tea bioactive components in mice
Authors: Zhou Jin‐Rong , Yu Lunyin , Mai Zhiming , Blackburn George L. 
Published: November 2003

AbstractBreast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF‐7 androgen‐dependent human breast tumor in female SCID mice. MCF‐7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin‐rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose‐dependent inhibition of MCF‐7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti‐breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)‐α and serum levels of insulin‐like growth factor (IGF)‐I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen‐dependent breast cancer. © 2003 Wiley‐Liss, Inc.
Alterations of ΔTA‐p 73 splice transcripts during melanoma development and progression
Authors: Tuve Sebastian , Wagner Stephan N. , Schittek Birgit , Pützer Brigitte M. 
Published: November 2003

AbstractIn the last 2 years, it has become apparent that the p53‐family members p53 and p73 play fundamentally different roles in human malignancies. In contrast to p53, many studies on cancer patients failed to detect mutational inactivation of p73 and reported overexpression of wild‐type p73 instead. A possible explanation was provided by the recent discovery of N‐terminal truncated isoforms of p73 (ΔTA‐p73) that act as dominant‐negative inhibitors of wild‐type p53 and TA‐p73 and result in tumor growth in nude mice. We investigated the role of ΔTA‐p73 in the development and progression of human melanomas, which lack p53 mutations. We analyzed 8 benign melanocytic nevi, 8 primary melanomas and 19 melanoma metastases for alterations of TA‐p73 and ΔTA‐p73 expression using isoform‐specific real‐time RT‐PCR. Based on our results, p73Δex2 and Δex2/3 spliced transcripts derived from the first promoter were significantly up‐regulated in melanoma metastases, whereas ΔN‐p73 generated from the second promoter was the predominant isoform in benign nevi. Moreover, increased expression of p73Δex2 and p73Δex2/3 correlated with high‐levels of both TA‐p73 and E2F1. Our data suggest a potential function of ΔTA‐p73 splice isoforms in melanoma progression. © 2003 Wiley‐Liss, Inc.
Lead time associated with screening for prostate cancer
Authors: Törnblom Magnus , Eriksson Henry , Franzén Stefan , Gustafsson Ove , Lilja Hans , Norming Ulf , Hugosson Jonas 
Published: November 2003

AbstractScreening serum levels of prostate‐specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value ≥10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan‐Meier) of PC in the 946 participants (ED) during 12 years of follow‐up was compared to that of an age‐matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values ≥3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the “catch‐up” point). After 12 years of follow‐up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow‐up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow‐up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection. © 2003 Wiley‐Liss, Inc.
Altered conjugate formation and altered apoptosis of multidrug‐resistant human leukemia cell line affects susceptibility to killing by activated natural killer (NK) cells
Authors: Treichel Robin S. , Bunuan Michael , Hahn Nancy , Wee Kathleen 
Published: November 2003

AbstractMost leukemias that exhibit P‐glycoprotein (P‐gp)‐associated multidrug resistance (MDR) exhibit reduced susceptibility to immune cytotoxicity mediated by natural killer (NK) cells. To explore this phenomenon we investigated N6/ADR, a doxorubicin‐selected, P‐gp‐positive variant of the human acute lymphoblastic leukemia (ALL) cell line NALM6. Each stage of the NK cytolytic pathway, (binding, activation and killing) was evaluated to identify the alterations responsible for the reduced cytotoxicity of the variant relative to its drug‐sensitive parental line. The major cause of the decreased susceptibility to NK cytolysis was found to be reduced conjugate formation by the MDR variant. Activation of NK effectors by parental and MDR cells with concomitant release of tumor necrosis factor‐alpha (TNF‐α) correlated with conjugate formation. N6/ADR was also more resistant than NALM6 to antibody‐dependent cellular cytotoxicity and to cytotoxic factors released from NK cells as measured both by 51Cr‐release and by DNA fragmentation. This is the first report of a P‐gp‐positive leukemic line that exhibits reduced conjugate formation as well as increased resistance to NK‐mediated killing mechanisms. Our results suggest caution in the use of NK‐based immunotherapy as an alternative treatment for multidrug‐resistant leukemias. © 2003 Wiley‐Liss, Inc.