bluuebunny/crossref_metadata_2025_split huggingface dataset:
High simian T‐cell leukemia virus type 1 proviral loads combined with genetic stability as a result of cell‐associated provirus replication in naturally infected, asymptomatic monkeys
Authors: Gabet Anne‐Sophie , Gessain Antoine , Wattel Eric 
Published: August 2003

AbstractSimian T‐cell leukemia virus type 1 (STLV‐1) is a primate T cell leukemia virus of the group of oncogenic delta retroviruses. Sharing a high level of genetic homology with human T cell leukemia virus type 1 (HTLV‐1), it is etiologically linked to the development of simian T cell malignancies that closely resemble HTLV‐1 associated leukemias and lymphomas and might thus constitute an interesting model of study. The precise nature of STLV‐1 replication in vivo remains unknown. The STLV‐1 circulating proviral load of 14 naturally infected Celebes macaques (Macaca tonkeana) was measured by real‐time quantitative PCR. The mean proportion of infected peripheral mononuclear cells was 7.9%, ranging from <0.4% to 38.9%. Values and distributions were closely reminiscent of those observed in symptomatic and asymptomatic HTLV‐1 infected humans. Sequencing more than 32 kb of LTRs deriving from 2 animals with high proviral load showed an extremely low STLV‐1 genetic variability (0.113%). This paradoxical combination of elevated proviral load and remarkable genetic stability was finally explained by the demonstration of a cell‐associated dissemination of the virus in vivo. Inverse PCR (IPCR) amplification of STLV‐1 integration sites evidenced clones of infected cells in all infected animals. The pattern of STLV‐1 replication in these asymptomatic monkeys was indistinguishable from that of HTLV‐1 in asymptomatic carriers or in patients with inflammatory diseases. We conclude that, as HTLV‐1, STLV‐1 mainly replicates by the clonal expansion of infected cells; accordingly, STLV‐1 natural monkey infection constitutes an appropriate and promising model for the study of HTLV‐1 associated leukemogenesis in vivo. © 2003 Wiley‐Liss, Inc.
Role of the stromal microenvironment in carcinogenesis of the prostate
Authors: Cunha Gerald R. , Hayward Simon W. , Wang Y.Z. , Ricke William A. 
Published: August 2003

AbstractThe topic of this review is the role of stromal‐epithelial interactions in normal and malignant prostatic growth. Because cell‐cell interactions and androgens play such key roles in the prostate, the goal of this review will be to apply endocrinologic and developmental concepts to the understanding of normal and malignant prostatic growth. Prostatic development is induced by androgens, which act via androgen receptors. Androgens elicit prostatic epithelial growth during fetal and prepubertal periods, and in adulthood androgens act via reciprocal homeostatic stromal‐epithelial interactions to maintain functional differentiation and growth quiescence. During carcinogenesis, these reciprocal homeostatic stromal‐epithelial interactions are disrupted. In this review, 2 models of prostatic carcinogenesis will be reviewed, both of which emphasize the role of the stromal microenvironment in the carcinogenic process. Hormonal carcinogenesis of the prostate can be elicited by treatment of rats and mice with testosterone plus estradiol (T+E2). Using an immortalized but nontumorigenic human prostatic epithelial cell line (BPH‐1), tissue recombinant studies were employed to explore the cellular mechanisms of prostatic carcinogenesis. Accordingly, human BPH‐1 prostatic epithelial cells were combined with rat UGM, and the resultant UGM+BPH–1 recombinants were grown in adult male nude mouse hosts. In untreated mouse hosts, UGM+BPH–1 recombinants produced solid branched epithelial cords and ductal structures exhibiting benign growth. In T+E2‐treated hosts, UGM+BPH–1 recombinants formed invasive carcinomas. Since BPH‐1 cells lack androgen and estrogen receptors, whereas rat UGM expresses both of these receptors, it is proposed that hormonal carcinogenesis is elicited by T+E2 via paracrine mechanisms mediated by the stromal microenvironment. During prostatic carcinogenesis in rats and humans, the periepithelial stroma undergoes progressive loss in smooth muscle with the appearance of carcinoma‐associated fibroblasts (CAFs). This abnormal stroma was shown to promote carcinogenesis in genetically abnormal but nontumorigenic epithelial cells. CAF+BPH‐1 tissue recombinants grown in male hosts formed carcinomas, whereas benign growth and orderly tissue architecture developed in recombinants composed of normal prostatic stroma+BPH‐1. Malignant transformation triggered by CAF was associated with additional genetic alterations and changes in gene expression in the BPH‐1 cells. Thus, the stromal microenvironment is a critical determinant of benign versus malignant growth. © 2003 Wiley‐Liss, Inc.
Sensitization of ara‐C‐resistant lymphoma cells by a pronucleotide analogue
Authors: Galmarini Carlos María , Clarke Marilyn L. , Santos Cheryl L. , Jordheim Lars , Perigaud Christian , Gosselin Gilles , Cros Emeline , Mackey John R. , Dumontet Charles 
Published: August 2003

AbstractAdequate intracellular concentrations of ara‐CMP, the monophosphorylated derivative of ara‐C, are essential for its cytotoxicity. The critical step for ara‐CMP formation is intracellular phosphorylation of ara‐C by deoxycytidine kinase (dCK). A common nucleoside resistance mechanism is mutation affecting the expression or the specificity of dCK. We describe the ability of a tert‐butyl S‐acyl‐thioethyl (SATE) derivative of ara‐CMP (UA911) to circumvent ara‐C resistance in a dCK‐deficient human follicular lymphoma cell line (RL‐G). The RL‐G cell line was produced by continuous exposure to gemcitabine and displayed low dCK mRNA and protein expression that conferred resistance both to ara‐C (2,250‐fold) and to gemcitabine (2,092‐fold). RL‐G cells were able to take up the UA911 pronucleotide by diffusion and metabolize it to the corresponding ara‐CMP and ara‐CTP nucleotides, exhibiting a 199‐fold reduction in resistance ratios, and a similar cell cycle arrest to the parental RL‐7 cells. Exposures to 10, 50 or 100 μM concentrations of UA911 produced 160 ± 7, 269 ± 8 and 318 ± 62 pmol ara‐CTP/mg protein in RL‐7 cells, and 100 ± 12, 168 ± 10 and 217 ± 39 pmol ara‐CTP/mg protein in RL‐G cells, respectively. Exposure of RL‐G cells to underivatized, radiolabeled ara‐C produced no detectable amounts of the active triphosphate metabolites. We conclude that the UA911 pronucleotide is capable of overcoming dCK‐mediated resistance. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the intracellular delivery of ara‐CMP to dCK‐deficient cells. © 2003 Wiley‐Liss, Inc.
Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer
Authors: Samoszuk Michael , Corwin Mark A. 
Published: August 2003

AbstractHuman breast cancer is extensively infiltrated by mast cells that contain powerful anticoagulants such as heparin, tryptase and chymase. To determine if human breast cancer is associated with mast cell activation, we measured the levels of mast cell tryptase (an indicator of mast cell activation) in the blood of 20 women with varying stages of breast cancer. The mean level of tryptase in women with breast cancer (10.3 ± 4.2 μg/L) was significantly higher than in 50 normal healthy women without breast cancer (3.0 ± 2.5 μg/L, p < 0.05 by two‐tailed t‐test). To explore the role of mast cells in breast cancer in more detail, we then carried out experiments that were aimed at determining if an inhibitor of mast cell function, sodium cromolyn, could increase blood clotting and hypoxia within subcutaneous implants of the 4T1 mammary adenocarcinoma cell line in mice. We treated tumor‐bearing mice with 5 consecutive daily doses of sodium cromolyn (10 mg/kg, i.p.). An average of 30% of the periphery of the tumors from the 5 drug‐treated mice contained large lakes of clotted blood that were not evident in any of the tumors from the control (untreated) mice. By computerized image analysis of tumors immunostained for a hypoxia marker (pimonidazole), the tumors from the treated mice had significantly more hypoxia (35 ±12 % hypoxic regions, n = 5) than the tumors from untreated (control) mice (16 ± 7%, n = 5). We conclude that sodium cromolyn enhanced peri‐tumoral blood clotting and intratumoral hypoxia. These results suggest that mast cells may play an important role in regulating blood clotting and hypoxia within breast cancer. © 2003 Wiley‐Liss, Inc.
Spindle assembly checkpoint defects and chromosomal instability in head and neck squamous cell carcinoma
Authors: Minhas Khalid M. , Singh Bhuvanesh , Jiang Wei‐wen , Sidransky David , Califano Joseph A. 
Published: August 2003

AbstractAlterations in chromosomal number and structure are found in most solid malignancies including head and neck squamous cell carcinoma (HNSC), however, the presence of ongoing, chromosomal instability in HNSC and its relation to spindle assembly checkpoint defects has not been formally demonstrated. We investigated the status of chromosomal instability (CIN) in HNSC primary tumors and cell lines as well as spindle assembly checkpoint integrity in HNSC cell lines. Centromeric fluorescence in situ hybridization (FISH) was carried out on expanded single cell‐derived colonies from HNSC cell lines and primary HNSC touch preparations. The deviation of chromosomes from the modal number in single cell derived colonies was 18.4–27% in 6 HNSC cell lines, and 2–3% in a control cell line, HCT116. Twelve primary tumors and 4 normal controls were also studied; all primary tumors demonstrated significant deviation from the modal chromosomal number (average 33.7%, range = 29.9–43.9%), compared to normal controls (average 4.6%, range = 3.6–5.6%). Additional characterization of the rate of chromosomal breakage was carried out by dual color FISH simultaneously using centromeric and telomeric probes for individual chromosomes on expanded singe cell‐derived colonies and primary HNSC. Control HCT 116 colonies demonstrated a mean discordance between number of centromeric and telomeric hybridization signals in 21% (range = 19–23%) of cells, whereas HNSC cell line colonies demonstrated a mean discordance of 50% (range = 38–55%), with the majority of instances of discordant signal indicating telomeric loss. Similarly, touch preparations from primary HNSC demonstrated discordance in hybridization signal of centromeric vs. telomeric signal of 26.3% (range = 18.5–42%), with normal controls showing a rate of discordance of 6.4% (range = 4–8%). Finally, all 6 HNSC cell lines demonstrated partial impairment of mitotic arrest in response to nocodazole, indicating that impairment of the spindle assembly checkpoint may contribute to chromosomal instability in HNSC. Ongoing instability in chromosomal number and structure are consistent features of primary HNSC and cell lines. Spindle assembly checkpoint impairment occurs in HNSC cell lines and may contribute to chromosomal instability in HNSC. © 2003 Wiley‐Liss, Inc.
Smoking and liver cancer in China: Case‐control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths
Authors: Chen Zheng‐ming , Liu Bo‐qi , Boreham Jillian , Wu Ya‐ping , Chen Jun‐shi , Peto Richard 
Published: August 2003

AbstractLiver cancer and liver cirrhosis are common causes of death in China, where chronic lifelong hepatitis B infection is a major cause of both diseases. To help determine whether smoking is a cofactor for the development of liver cancer, we ascertained retrospectively the smoking habits of 36,000 adults who had died from liver cancer (cases) and 17,000 who had died from cirrhosis (controls) in 24 Chinese cities and 74 rural counties. Calculations of the smoker vs. nonsmoker risk ratios (RR) for liver cancer mortality were standardised for age and locality. Among adult men (aged 35+) there was a 36% excess risk of death from liver cancer among smokers (smoker vs. nonsmoker standardised risk ratio [RR] =1.36, with 95% confidence interval [CI] 1.29–1.43, 2p<0.00001; attributable fraction 18%). In the general male population this indicates absolute risks of death from liver cancer before age 70 of about 4% in smokers and 3% in nonsmokers (in the absence of other causes). Most liver cancer, however, occurs among the 10–12% of men with haematological evidence of chronic hepatitis B infection, so among them the corresponding risks would be about 33% in smokers and 25% in nonsmokers. The RR was approximately independent of age, was similar in urban and rural areas, was not significantly related to the age when smoking started but was significantly (p<0.001) greater for cigarette smokers than for smokers of other forms of tobacco. Among men who smoked only cigarettes, the RR was significantly (p<0.001 for trend) related to daily consumption, with a greater hazard among those who smoked 20/day (RR 1.50, 95% CI 1.39–1.62) than among those who smoked fewer (mean 10/day: RR=1.32, 95% CI 1.23–1.41). Smoking was also associated with a significant excess of liver cancer death in women (RR 1.17, 95% CI 1.06–1.29, 2p=0.003; attributable fraction 3%), but fewer women (17%) than men (62%) were smokers, and their cigarette consumption per smoker was lower. Among women who smoked only cigarettes, there was a significantly greater hazard among those who smoked at least 20/day (mean 22/day: RR=1.45, 95% CI 1.18–1.79) than among those who smoked fewer (mean 8/day: RR=1.09, 95% CI 0.94–1.25). These associations indicate that tobacco is currently responsible for about 50,000 liver cancer deaths each year in China, chiefly among men with chronic HBV infection. © 2003 Wiley‐Liss, Inc.
Mutational analysis of the LMO4 gene, encoding a BRCA1‐interacting protein, in breast carcinomas
Authors: Sutherland Kate D. , Visvader Jane E. , Choong David Y.H. , Sum Eleanor Y.M. , Lindeman Geoffrey J. , Campbell Ian G. 
Published: August 2003

AbstractThe LIM domain‐only genes LMO1 and LMO2 are translocated in acute T cell leukemia (T‐ALL) and have been shown to be oncogenes in T lymphoid cells. LMO4, the fourth member of this family, is overexpressed in more than 50% of sporadic breast cancers, suggesting a role in breast oncogenesis. We recently found that LMO4 interacts with the breast/ovarian tumor suppressor BRCA1 and that LMO4 can repress its transcriptional activity. Since proto‐oncogene deregulation can result from activating mutations in their coding or regulatory sequences, we explored whether the LMO4 gene undergoes somatic mutagenesis in breast cancer. Mutation analysis of the coding and 3′ untranslated regions of the LMO4 gene was performed on 82 primary breast and 22 tumor cell lines. A somatic mutation was detected in one primary breast cancer, at the 3′ end of exon 2, but was not present in normal DNA derived from the same patient. This mutation causes a frame‐shift and potentially results in a truncated LMO4 polypeptide, LIM1mut, lacking the second LIM domain. This mutant protein could still bind Ldb1 but no longer associated with CtIP or BRCA1. Our results show that somatic mutations within the LMO4 gene do occur in breast cancer but at a very low frequency. Thus, the primary mechanism by which LMO4 is deregulated in breast cancers appears to reflect overexpression of the gene rather than the acquisition of activating genetic mutations. © 2003 Wiley‐Liss, Inc.
Negative regulatory role of PI3‐Kinase in TNF‐induced tumor necrosis
Authors: Matschurat Susanne , Blum Sabine , Mitnacht‐Kraus Rita , Dijkman Henry B.P.M. , Kanal Levent , de Waal Robert M.W. , Clauss Matthias 
Published: August 2003

AbstractTissue factor is the prime initiator of blood coagulation. Expression of tissue factor in tumor endothelial cells leads to thrombus formation, occlusion of vessels and development of hemorrhagic infarctions in the tumor tissue, often followed by regression of the tumor. Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor α (TNF α) and synergistically enhances the TNF‐induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44/42 and p38 mitogen‐activated protein (MAP) kinases, and stress‐activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)‐kinase, led to strongly enhanced expression of tissue factor in TNF‐ and VEGF‐treated cells, implicating a negative regulatory role for PI3‐kinase. In vivo, the application of wortmannin promoted the formation of TNF‐induced hemorrhages and intratumoral necroses in murine meth A tumors. The co‐injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF‐sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF‐treatment in combination with specific inhibition of PI3‐kinase is a novel concept in anti‐cancer therapy. © 2003 Wiley‐Liss, Inc.
Smoking, DNA repair capacity and risk of nonsmall cell lung cancer
Authors: Shen Hongbing , Spitz Margaret R. , Qiao Yawei , Guo Zhaozheng , Wang Li‐E , Bosken Carol H. , Amos Christopher I. , Wei Qingyi 
Published: August 2003

AbstractTobacco‐related carcinogens cause a variety of DNA damage that is repaired by different enzymatic pathways, suggesting that DNA repair plays an important role in tobacco‐induced carcinogenesis. In a large hospital‐based case‐control study, we investigated DNA repair capacity (DRC) as a biomarker for susceptibility to nonsmall cell lung cancer (NSCLC) and evaluated the possible interaction between DRC and tobacco smoke in 467 newly diagnosed NSCLC patients and 488 cancer‐free controls. We measured DRC in cultured peripheral lymphocytes using the host‐cell reactivation assay with a reporter gene damaged by an activated tobacco carcinogen, benzo[a]pyrene diol epoxide. The results showed that current smokers exhibited the highest DRCs as compared to former and nonsmokers both among patients and control subjects. There were no differences of DRC among 3 different histopathologic types of NSCLC. Logistic regression analysis revealed that suboptimal DRC and pack‐years smoked were independent predictors of NSCLC risk. The overall 15.5% reduction in DRC observed in the cases (7.84%) compared to the controls (9.28%) (p<0.001) was associated with an approximately 2‐fold increased risk of NSCLC (adjusted odds ratio (OR) = 1.85, 95% confidence interval (CI) 1.42–2.42). There was a significant dose‐response association between decreased DRC and increased risk of lung cancer. Furthermore, we observed a nonstatistically significant additive but not multiplicative interaction between DRC and pack‐years smoked on lung cancer risk, particularly in the histopathologic types of NSCLC other than adenocarcinoma. The results suggest that suboptimal DRC is associated with increased risk of NSCLC and DRC may modulate the risk of lung cancer associated with smoking but the latter needs to be verified in larger studies. © 2003 Wiley‐Liss, Inc.
Promoter methylation of the TSLC1 gene in advanced lung tumors and various cancer cell lines
Authors: Fukami Takeshi , Fukuhara Hiroshi , Kuramochi Masami , Maruyama Tomoko , Isogai Kana , Sakamoto Michiie , Takamoto Shinichi , Murakami Yoshinori 
Published: August 2003

AbstractWe previously identified TSLC1, a tumor suppressor gene in human nonsmall cell lung cancer (NSCLC). TSLC1 belongs to immunoglobulin superfamily molecules and is involved in cell adhesion. Loss of TSLC1 expression was strongly correlated with the promoter hypermethylation in several NSCLC cell lines. Here, we examined the methylation status of the TSLC1 gene promoter in 48 primary NSCLC tumors by bisulfite SSCP in combination with bisulfite sequencing. Six CpG sites around the promoter regions were significantly methylated in 21 of 48 primary NSCLC tumors (44%). Promoter methylation was more likely to be observed in relatively advanced tumors with TNM classification of pT2, pT3 or pT4 (19 of 33, 58%) than in those with pT1 (2 of 15, 13%), suggesting that alteration of TSLC1 would be involved in the progression of human NSCLC. Loss of TSLC1 expression was also observed in 20 of 46 (43%) human cancer cell lines, including those from esophageal (3 of 3), gastric (8 of 9), ovarian (2 of 5), endometrial (2 of 2), breast (1 of 3), colorectal (2 of 8) and small cell lung cancers (2 of 10). Combined analysis of promoter methylation and the allelic state in these cell lines indicated that the TSLC1 gene was often silenced not only by mono‐allelic methylation associated with loss of the other allele but also through bi‐allelic methylation. These results suggest that alteration of TSLC1 would be involved in advanced NSCLC as well as in many other human cancers. © 2003 Wiley‐Liss, Inc.
Human papillomavirus and risk factors for cervical cancer in Chennai, India: A case‐control study
Authors: Franceschi Silvia , Rajkumar Thangarajan , Vaccarella Salvatore , Gajalakshmi Vendhan , Sharmila Ajit , Snijders Peter J.F. , Muñoz Nubia , Meijer Chris J.L.M. , Herrero Rolando 
Published: August 2003

AbstractTo evaluate the role of human papillomavirus (HPV) and other risk factors in the aetiology of invasive cervical carcinoma (ICC), we conducted a hospital‐based case‐control study in Chennai, Southern India. A total of 205 ICC cases (including 12 adenocarcinomas) and 213 frequency age‐matched control women were included. HPV DNA in cervical cells was evaluated by means of a polymerase chain‐reaction assay. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were computed by means of unconditional multiple logistic regression models. HPV infection was detected in all but one ICC cases and in 27.7% of control women (OR = 498). Twenty‐three different HPV types were found. HPV 16 was the most common type in either cases or controls, followed by HPV 18 and 33. The association of ICC with HPV 18 and HPV 16‐associated types was somewhat stronger than the one with HPV 16. Multiple HPV infections did not show a higher OR for ICC than single infections. Other than HPV infection, high parity (OR for >4 vs. ≤2 births = 7.3), a woman's report of her husband's extramarital sexual relationships (OR = 10.0) and early menopause (OR for <45 vs. ≥45 years = 4.2) were significantly associated with ICC, also after restricting the analysis to HPV‐positive cases and controls. Poor hygienic conditions were associated with an increased risk of HPV infection among control women but not with ICC risk among HPV‐positive women. A vaccine against HPV 16 and 18 may be effective in more than three‐quarters of ICC in the study area. © 2003 Wiley‐Liss, Inc.