bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbonic anhydrases IV and IX: subcellular localization and functional role in mouse skeletal muscle
Authors: Scheibe Renate J. , Mundhenk Karsten , Becker Tilman , Hallerdei Janine , Waheed Abdul , Shah Gul N. , Sly William S. , Gros Gerolf , Wetzel Petra
Published: November 2007

The subcellular localization of carbonic anhydrase (CA) IV and CA IX in mouse skeletal muscle fibers has been studied immunohistochemically by confocal laser scanning microscopy. CA IV has been found to be located on the plasma membrane as well as on the sarcoplasmic reticulum (SR) membrane. CA IX is not localized in the plasma membrane but in the region of the t-tubular (TT)/terminal SR membrane. CA IV contributes 20% and CA IX 60% to the total CA activity of SR membrane vesicles isolated from mouse skeletal muscles. Our aim was to examine whether SR CA IV and TT/SR CA IX affect muscle contraction. Isolated fiber bundles of fast-twitch extensor digitorum longus and slow-twitch soleus muscle from mouse were investigated for isometric twitch and tetanic contractions and by a fatigue test. The muscle functions of CA IV knockout (KO) fibers and of CA IX KO fibers do not differ from the function of wild-type (WT) fibers. Muscle function of CA IV/XIV double KO mice unexpectedly shows a decrease in rise and relaxation time and in force of single twitches. In contrast, the CA inhibitor dorzolamide, whether applied to WT or to double KO muscle fibers, leads to a significant increase in rise time and force of twitches. It is concluded that the function of mouse skeletal muscle fibers expressing three membrane-associated CAs, IV, IX, and XIV, is not affected by the lack of one isoform but is possibly affected by the lack of all three CAs, as indicated by the inhibition studies.
Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model
Authors: Tomei Alice A. , Choe Melanie M. , Swartz Melody A.
Published: November 2007

Asthmatic patients are more susceptible to viral infection, and we asked whether dynamic strain on the airway wall (such as that associated with bronchoconstriction) would influence the rate of viral infection of the epithelial and subepithelial cells. To address this, we characterized the barrier function of a three-dimensional culture model of the bronchial airway wall mucosa, modified the culture conditions for optimization of ciliogenesis, and compared epithelial and subepithelial green fluorescent protein (GFP) transduction by a pWpts-GFP lentivirus, pseudotyped with VSV-G, under static vs. dynamic conditions. The model consisted of human lung fibroblasts, bronchial epithelial cells, and a type I collagen matrix, and after 21 days of culture at air liquid interface, it exhibited a pseudostratified epithelium comprised of basal cells, mucus-secreting cells, and ciliated columnar cells with beating cilia. Microparticle tracking revealed partial coordination of mucociliary transport among groups of cells. Slow dynamic compression of the airway wall model (15% strain at 0.1 Hz over 3 days) substantially enhanced GFP transduction of epithelial cells and underlying fibroblasts. Fibroblast-only controls showed a similar degree of transduction enhancement when undergoing dynamic strain, suggesting enhanced transport through the matrix. Tight junction loss in the epithelium after mechanical stress was observed by immunostaining. We conclude that dynamic compressive strain such as that associated with bronchoconstriction may promote transepithelial transport and enhance viral transgene delivery to epithelial and subepithelial cells. This finding has significance for asthma pathophysiology as well as for designing delivery strategies of viral gene therapies to the airways.
Variable-length poly-C tract polymorphisms of the β2-adrenergic receptor 3′-UTR alter expression and agonist regulation
Authors: Panebra Alfredo , Schwarb Mary Rose , Swift Steven M. , Weiss Scott T. , Bleecker Eugene R. , Hawkins Gregory A. , Liggett Stephen B.
Published: November 2007

β2-Adrenergic receptors (β2-AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for β-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5′-flanking or coding region of the intronless β2-AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3′-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the β2-AR (Arg16) coding sequence followed by its 3′-UTR with the various polymorphic poly-C tracts. β2Arg16-11C had 25% lower mRNA expression and 33% lower β2-AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, β2Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with β2Arg16-12C and -13C. However, β2Arg16-12C underwent 50% less downregulation of receptor expression during β-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (β2Arg16-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (β2Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to β-agonist, and genotyping to identify these 3′-UTR polymorphisms may improve predictive power within the context of β2-AR haplotypes in pharmacogenetic studies.
Targeting Vacuolar H+-ATPases as a New Strategy against Cancer
Authors: Fais Stefano , De Milito Angelo , You Haiyan , Qin Wenxin
Published: November 2007

Growing evidence suggests a key role of tumor acidic microenvironment in cancer development, progression, and metastasis. As a consequence, the need for compounds that specifically target the mechanism(s) responsible for the low pH of tumors is increasing. Among the key regulators of the tumor acidic microenvironment, vacuolar H+-ATPases (V-ATPases) play an important role. These proteins cover a number of functions in a variety of normal as well as tumor cells, in which they pump ions across the membranes. We discuss here some recent results showing that a molecular inhibition of V-ATPases by small interfering RNA in vivo as well as a pharmacologic inhibition through proton pump inhibitors led to tumor cytotoxicity and marked inhibition of human tumor growth in xenograft models. These results propose V-ATPases as a key target for new strategies in cancer treatment. [Cancer Res 2007;67(22):10627–30]
PCPH/ENTPD5 Expression Enhances the Invasiveness of Human Prostate Cancer Cells by a Protein Kinase Cδ–Dependent Mechanism
Authors: Villar Joaquín , Arenas María Isabel , MacCarthy Caitlin M. , Blánquez María José , Tirado Oscar M. , Notario Vicente
Published: November 2007

Previous reports showed that PCPH is mutated or deregulated in some human tumors, suggesting its participation in malignant progression. Immunohistochemical analyses showed that PCPH is not expressed in normal prostate, but its expression increases along cancer progression stages, being detectable in benign prostatic hyperplasia, highly expressed in prostatic intraepithelial neoplasia, and remaining at high levels in prostate carcinoma. Experiments designed to investigate the contribution of PCPH to the malignant phenotype of prostate cancer cells showed that PCPH overexpression in PC-3 cells, which express nearly undetectable PCPH levels, increased collagen I expression and enhanced invasiveness, whereas shRNA-mediated PCPH knockdown in LNCaP cells, which express high PCPH levels, down-regulated collagen I expression and decreased invasiveness. PCPH regulated invasiveness and collagen I expression by a mechanism involving protein kinase Cδ (PKCδ): (a) PCPH knockdown in LNCaP cells decreased PKCδ levels relative to control cells; (b) PKCδ knockdown in LNCaP cells recapitulated all changes caused by PCPH knockdown; and (c) forced expression of PKCδ in cells with knocked down PCPH reverted all changes provoked by PCPH down-regulation and rescued the original phenotype of LNCaP cells. These results strongly suggested that the expression level and/or mutational status of PCPH contributes to determine the invasiveness of prostate cancer cells through a mechanism involving PKCδ. Data from immunohistochemical analyses in serial sections of normal, premalignant, and malignant prostate specimens underscored the clinical significance of our findings by showing remarkably similar patterns of expression for PCPH and PKCδ, thus strongly suggesting their likely coregulation in human tumors. [Cancer Res 2007;67(22):10859–68]
Dietary Feeding of Silibinin Inhibits Prostate Tumor Growth and Progression in Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Raina Komal , Blouin Marie-José , Singh Rana P. , Majeed Noreen , Deep Gagan , Varghese Leyon , Glodé L. Michael , Greenberg Norman M. , Hwang David , Cohen Pinchas , Pollak Michael N. , Agarwal Rajesh
Published: November 2007

Herein, for the first time, we evaluated the chemopreventive efficacy of dietary silibinin against prostate cancer (PCa) growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice from two different genetic backgrounds [C57BL/6 (TRAMP) × FVB; C57BL/6 (TRAMP) × C57BL/6]. At 4 weeks of age, mice were fed control or 0.1% to 1% silibinin–supplemented diets until 23 to 24 weeks of age. Silibinin-fed groups had a lower tumor grade and higher incidence of prostatic intraepithelial neoplasia (PIN) at the expense of a strong decrease in adenocarcinoma incidence. Prostate tissue showed a 47% (P < 0.001) decrease in proliferating cell nuclear antigen (PCNA)–positive cells and an ∼7-fold (P < 0.001) increase in apoptotic cells at the highest silibinin dose. As potential mechanisms of silibinin efficacy, an ∼50% (P < 0.05) decrease in insulin-like growth factor (IGF) receptor type Iβ and an ∼13-fold (P < 0.001) increase in IGF-binding protein 3 (IGFBP-3) protein levels were also observed. These changes were specific to tumors as they were not reflected in circulating IGF-IGFBP-3 system. Additionally, silibinin decreased protein expression of cyclin-dependent kinases (Cdk) by more than 90% (P < 0.001) with a concomitant increase in Cdk inhibitors, Cip1/p21 and Kip1/p27 (P < 0.05, for both). A dose-dependent decrease was also observed in cyclin B1, cyclin E, and cyclin A protein levels by silibinin. Together, these findings suggest that oral silibinin blocks PCa growth and progression at PIN stage in TRAMP mice via modulation of tumor IGF-IGFBP-3 axis and cell cycle regulation, and therefore it has practical and translational potential in suppressing growth and neoplastic conversion of PIN to PCa in humans. [Cancer Res 2007;67(22):11083–91]
Antimetastatic Activity of a Preventive Cancer Vaccine
Authors: Nanni Patrizia , Nicoletti Giordano , Palladini Arianna , Croci Stefania , Murgo Annalisa , Antognoli Agnese , Landuzzi Lorena , Fabbi Marina , Ferrini Silvano , Musiani Piero , Iezzi Manuela , De Giovanni Carla , Lollini Pier-Luigi
Published: November 2007

The development of prophylactic cancer vaccines that protect healthy hosts from tumor development leaves open the question whether such vaccines are also effective against established tumors and metastases. We tested the therapeutic activity of a proven prophylactic anti-HER-2/neu vaccine against successive stages of mammary carcinoma progression in HER-2/neu transgenic mice. The vaccine consisted of transgenic mammary carcinoma cells expressing HER-2/neu and two adjuvants: allogeneic class I histocompatibility antigens and interleukin (IL)-12. Vaccination of mice bearing lung micrometastases resulted in a 90% inhibition of metastasis development, whereas vaccination of mice with incipient local tumors was ineffective. The antimetastatic response was hampered by immune tolerance, as the protection of transgenic mice was lower than that of wild-type congenics not tolerant to HER-2/neu. A significant gain in immunotherapeutic activity in transgenic mice was obtained through the coadministration of anti-CD25 monoclonal antibody targeting regulatory T cells, which resulted in a >99% inhibition of metastasis. The immune responses elicited in transgenic mice comprised the activation of lung granulocytes and macrophages and of systemic adaptive responses based on helper T cells and their cytokines (IFN-γ and IL-4) and anti-HER-2/neu antibodies. Dissection of relevant antimetastatic mechanisms by means of knockout mice and of depleting antibodies revealed a major difference between tumor prevention, which was completely dependent on anti-HER-2/neu antibodies, and metastasis therapy, which was antibody independent. In conclusion, a vaccine successfully developed for cancer immunoprevention showed a strong therapeutic activity against lung metastases mediated by protective immune mechanisms distinct from those preventing the onset of primary mammary carcinoma. [Cancer Res 2007;67(22):11037–44]
Nitric Oxide–Donating Aspirin Derivatives Suppress Microsatellite Instability in Mismatch Repair–Deficient and Hereditary Nonpolyposis Colorectal Cancer Cells
Authors: McIlhatton Michael A. , Tyler Jessica , Burkholder Susan , Ruschoff Josef , Rigas Basil , Kopelovich Levy , Fishel Richard
Published: November 2007

Nitric oxide–donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as cancer chemopreventive agents. Aspirin and sulindac have been shown to be effective in selecting for cells with reduced microsatellite instability (MSI) that is inherent in mismatch repair (MMR)–deficient hereditary nonpolyposis colorectal cancer (HNPCC) cells. The effect of NO-NSAIDs on MSI in MMR-deficient HNPCC cells is unknown. Here, we have examined genetically defined MMR-deficient murine embryo fibroblasts, murine colonocytes, and isogenic human HNPCC tumor cell lines treated with acetylsalicylic acid (aspirin; ASA) and three isomeric derivatives of NO-aspirin (NO-ASA). The MSI profiles were determined and compared with the Bethesda Criteria. We found that the ASA- and NO-ASA–treated MMR-deficient cell lines displayed a dose-dependent suppression of MSI that appeared as early as 8 weeks and gradually increased to include up to 67% of the microsatellite sequences examined after 19 to 20 weeks of continuous treatment. Residual resistance to microsatellite stabilization was largely confined to mononucleotide repeat sequences. Control (MMR-proficient) cells showed no changes in microsatellite status with or without treatment. The relative dose-dependent stabilization selection was: ortho-NO-ASA ≈ para-NO-ASA > meta-NO-ASA ≫ ASA. Moreover, the doses required for stabilization by the ortho- and para-NO-ASA were 300- to 3,000-fold lower than ASA. These results suggest that NO-ASA derivatives may be more effective at suppressing MSI in MMR-deficient cell lines than ASA and should be considered for chemopreventive trials with HNPCC carriers. [Cancer Res 2007;67(22):10966–75]
Haplotype ofN-Acetyltransferase 1 and 2 and Risk of Pancreatic Cancer
Authors: Jiao Li , Doll Mark A. , Hein David W. , Bondy Melissa L. , Hassan Manal M. , Hixson James E. , Abbruzzese James L. , Li Donghui
Published: November 2007

We examined the association between N-acetyltransferase 1 and 2 (NAT1 and NAT2) haplotype and risk of pancreatic cancer by genotyping eight NAT1 and seven NAT2 single nucleotide polymorphisms in 532 patients and in 581 healthy controls (all non-Hispanic white) who were recruited at M. D. Anderson Cancer Center from January 2000 to December 2006. Haplotypes were reconstructed by using an expectation-maximization algorithm. Odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression models. Covariates included age (continuous variable), sex, pack-year of smoking (categorical), and history of diabetes when appropriate. NAT1 and NAT2 genotype was mutually adjusted. The prevalence of haplotype NAT1*10-NAT2*6A was 4.3% versus 2.7% (P = 0.06) and NAT1*11-NAT2*6A was 1.2% versus 0.4% (P = 0.05) in patients and controls, respectively. The diplotype NAT1*10/*10 or NAT1*10/*11 and NAT2*6A/any slow allele was associated with a higher risk of pancreatic cancer compared with other diplotypes (multivariate odds ratio, 4.15; 95% confidence interval, 1.15-15.00; P = 0.03). NAT2 slow genotype were associated with increased risk of pancreatic cancer among heavy smokers and among individuals with a history of diabetes. We for the first time found that rare NAT1*10 or NAT1*11-NAT2*6A diplotype may be an “at-risk” genetic variant for pancreatic cancer. The NAT2*6A/any slow acetylation genotype may be a predisposing factor for pancreatic cancer among diabetics with smoking exposure. Our observations must be confirmed in larger independent studies. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2379–86)
Sex- and Kindred-Specific Familial Risk of Non–Hodgkin's Lymphoma
Authors: Czene Kamila , Adami Hans-Olov , Chang Ellen T.
Published: November 2007

A family history of non–Hodgkin's lymphoma (NHL) confers increased risk of NHL, but it is unknown whether the excess risk in males and females varies by the sex or kinship of the affected relative. We linked nationwide Swedish registries to identify parents and siblings of NHL patients who developed NHL between January 1, 1961 and December 31, 2002. In males, parental risks were approximately the same from fathers and mothers, whereas sibling risks were higher from brothers [standardized incidence ratio (SIR), 1.8; 95% confidence interval (95% CI), 1.0-2.9] than sisters (SIR, 0.9; 95% CI, 0.2-1.9). In females, parental and sibling risks were higher from same-sex relatives (SIR from mothers, 1.9; 95% CI, 1.2-2.7; SIR from sisters, 6.3; 95% CI, 4.0-9.3) than from opposite-sex relatives (SIR from fathers, 1.2; 95% CI, 0.7-1.9; SIR from brothers, 0.7; 95% CI, 0.2-1.6). These findings did not vary substantially by the age of diagnosis of the offspring. Risk of NHL in offspring was also increased among those with a parent diagnosed with multiple myeloma or leukemia. The relative risk of NHL among those with a parent diagnosed with any hematopoietic cancer was 1.5 (95% CI, 1.4-1.7) and that for having a sibling with any hematopoietic cancer was also 1.5 (95% CI, 1.2-1.9). Our results suggest that part of the familial risk of NHL may be attributable to shared environmental exposures, particularly between same-sex siblings. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2496–9)
Autoantibody Approach for Serum-Based Detection of Head and Neck Cancer
Authors: Lin Ho-Sheng , Talwar Harvinder S. , Tarca Adi L. , Ionan Alexei , Chatterjee Madhumita , Ye Bin , Wojciechowski Jerzy , Mohapatra Saroj , Basson Marc D. , Yoo George H. , Peshek Brian , Lonardo Fulvio , Pan Chuan-Ju G. , Folbe Adam J. , Draghici Sorin , Abrams Judith , Tainsky Michael A.
Published: November 2007

Currently, no effective tool exists for screening or early diagnosis of head and neck squamous cell carcinoma (HNSCC). Here, we describe an approach for cancer detection based on analysis of patterns of serum immunoreactivity against a panel of biomarkers selected using microarray-based serologic profiling and specialized bioinformatics. We biopanned phage display libraries derived from three different HNSCC tissues to generate 5,133 selectively cloned tumor antigens. Based on their differential immunoreactivity on protein microarrays against serum immunoglobulins from 39 cancer and 41 control patients, we reduced the number of clones to 1,021. The performance of a neural network model (Multilayer Perceptron) for cancer classification on a data set of 80 HNSCC and 78 control samples was assessed using 10-fold cross-validation repeated 100 times. A panel of 130 clones was found to be adequate for building a classifier with sufficient sensitivity and specificity. Using these 130 markers on a completely new and independent set of 80 samples, an accuracy of 84.9% with sensitivity of 79.8% and specificity of 90.1% was achieved. Similar performance was achieved by reshuffling of the data set and by using other classification models. The performance of this classification approach represents a significant improvement over current diagnostic accuracy (sensitivity of 37% to 46% and specificity of 24%) in the primary care setting. The results shown here are promising and show the potential use of this approach toward eventual development of diagnostic assay with sufficient sensitivity and specificity suitable for detection of early-stage HNSCC in high-risk populations. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2396–405)
Intra-individual Variation of Plasma Adipokine Levels and Utility of Single Measurement of These Biomarkers in Population-Based Studies
Authors: Lee Sang-Ah , Kallianpur Asha , Xiang Yong-Bing , Wen Wanqing , Cai Qiuyin , Liu Dake , Fazio Sergio , Linton MacRae F. , Zheng Wei , Shu Xiao Ou
Published: November 2007

Adipokines, soluble mediators produced by adipocytes, may link adipose tissue to the inflammatory, metabolic, and immune dysregulation that characterize many obesity-related diseases. The stability of plasma adipokine levels within individuals, their seasonal variability, intercorrelations, and relationships to well-established measures of adiposity are incompletely defined. We measured levels of 12 adipokines [interleukin 1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1 (PAI-1), high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), nerve growth factor (NGF), leptin, adiponectin, hepatocyte growth factor (HGF), and resistin] in four seasonal random plasma samples of 48 male participants of a population-based cohort study. The representativeness of single measurements was assessed by correlating the adipokine levels of a single, random sample with the mean levels from the remaining three samples using a bootstrap approach and using intra-class correlation coefficients (ICC). Spearman correlations between adipokine levels, age, body mass index (BMI), and waist-to-hip ratio (WHR) were estimated. Correlations between plasma adipokine levels from one random sample and the mean of the remaining three seasonal samples ranged from 0.57 to 0.89. Over the 1-year study period, the ICCs for adipokine levels ranged from 0.44 (PAI-1) to 0.83 (HGF). IL-8, MCP-1, and resistin levels were positively associated with age; HGF and PAI-1 levels were correlated with BMI and WHR. This study suggests that adipokine levels in a single blood sample may be useful biomarkers of inflammation in population-based studies of obesity-related disease. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2464–70)
Common Genetic Variation in GATA-Binding Protein 3 and Differential Susceptibility to Breast Cancer by Estrogen Receptor α Tumor Status
Authors: Garcia-Closas Montserrat , Troester Melissa A. , Qi Ying , Langerød Anita , Yeager Meredith , Lissowska Jolanta , Brinton Louise , Welch Robert , Peplonska Beata , Gerhard Daniela S. , Gram Inger Torhild , Kristensen Vessela , Børresen-Dale Anne-Lise , Chanock Stephen , Perou Charles M.
Published: November 2007

GATA-binding protein 3 (GATA3) is a transcription factor and a putative tumor suppressor that is highly expressed in normal breast luminal epithelium and estrogen receptor α (ER)–positive breast tumors. We hypothesized that common genetic variation in GATA3 could influence breast carcinogenesis. Four tag single-nucleotide polymorphisms (SNP) in GATA3 and its 3′ flanking gene FLJ4598 were genotyped in two case control studies in Norway and Poland (2,726 cases and 3,420 controls). Analyses of pooled data suggested a reduced risk of breast cancer associated with two intronic variants in GATA3 in linkage disequilibrium (rs3802604 in intron 3 and rs570613 in intron 4). Odds ratio (95% confidence interval) for rs570613 heterozygous and rare homozygous versus common homozygous were 0.85 (0.75-1.95) and 0.82 (0.62-0.96), respectively (Ptrend = 0.004). Stronger associations were observed for subjects with ER-negative, than ER-positive, tumors (Pheterogeneity = 0.01 for rs3802604; Pheterogeneity = 0.09 for rs570613). Although no individual SNPs were associated with ER-positive tumors, two haplotypes (GGTC in 2% of controls and AATT in 7% of controls) showed significant and consistent associations with increased risk for these tumors when compared with the common haplotype (GATT in 46% of controls): 1.71 (1.27-2.32) and 1.26 (1.03-1.54), respectively. In summary, data from two independent study populations showed two intronic variants in GATA3 associated with overall decreases in breast cancer risk and suggested heterogeneity of these associations by ER status. These differential associations are consistent with markedly different levels of GATA3 protein by ER status. Additional epidemiologic studies are needed to clarify these intriguing relationships. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2269–75)
Cholesterol-Lowering Drugs and Prostate Cancer Risk: A Population-based Case-Control Study
Authors: Murtola Teemu J. , Tammela Teuvo L.J. , Lahtela Jorma , Auvinen Anssi
Published: November 2007

Background: Previous studies have shown that statin use may reduce prostate cancer risk. In the current study, we evaluated the association between serum cholesterol–lowering medication use and prostate cancer risk at the population level.

Materials and Methods: All newly diagnosed prostate cancer cases in Finland during 1995 to 2002 and matched controls (24,723 case control pairs) were identified from the Finnish Cancer Registry and the Population Register Center, respectively. Detailed information on cholesterol-lowering drug purchases during the study period was obtained from the prescription database of the Social Insurance Institution of Finland.

Results: After adjustment for potential confounders, having ever-use of any statin was associated with marginally elevated overall prostate cancer risk [odds ratio (OR), 1.07; 95% confidence interval (95% CI), 1.00-1.16]. However, none of the statins was associated with the overall prostate cancer risk when analyzed separately. On the other hand, the risk of advanced prostate cancer was decreased among users of atorvastatin, lovastatin, and simvastatin (OR 0.61, 95% CI 0.37-0.98; OR 0.61, 95% CI 0.43-0.85; and OR 0.78, 95% CI 0.61-1.01, respectively). The risk was not affected among users of other cholesterol drug groups.

Conclusions: Our large population-based study showed no evidence for reduced overall prostate cancer risk among users of cholesterol-lowering drugs, whereas the risk of advanced cancer was decreased among statin users. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2226–32)
Quality of Care Issues in Colorectal Cancer
Authors: Leonardi Michael J. , McGory Marcia L. , Ko Clifford Y.
Published: November 2007

Colorectal cancer is a common, detectable, and treatable malignancy. Given the aging of the population, the number of patients diagnosed with colorectal cancer will likely increase; thus, efforts to improve the quality and delivery of appropriate care to patients with colorectal cancer are needed. The overarching goal of this article is to summarize recent efforts to evaluate and improve the quality of colorectal cancer care through the use of selective referral, quality performance measures, and assessment of outcomes. First, we provide a framework for quality of care assessment, including a discussion of the structural, process, and outcome components of care for colorectal cancer. Second, we discuss the current level of assessment of colorectal cancer care quality, highlighting four potential targets for quality improvement: increased provider volume for colorectal cancer resection, process-based quality measures for colorectal cancer care (including measures specific to colorectal cancer surgery), data collection and feedback programs for colorectal cancer care, and evaluation of health-related quality of life in patients with colorectal cancer. Further research is needed to evaluate both the implementation and effectiveness of these quality improvement strategies for improving outcome in patients with colorectal cancer.
A Mycoplasma Peptide Elicits Heteroclitic CD4+ T Cell Responses against Tumor Antigen MAGE-A6
Authors: Vujanovic Lazar , Mandic Maja , Olson Walter C. , Kirkwood John M. , Storkus Walter J.
Published: November 2007

Purpose: Although T-helper (Th) epitopes have been previously reported for many tumor antigens, including MAGE-A6, the relevant HLA-DR alleles that present these peptides are expressed by only a minority of patients. The identification of tumor antigenic epitopes presented promiscuously by many HLA-DR alleles would extend the clinical utility of these peptides in vaccines and for the immunomonitoring of cancer patients.

Experimental Design: A neural network algorithm and in vitro sensitization assays were employed to screen candidate peptides for their immunogenicity.

Results: The MAGE-A6140-170, MAGE-A6172-187, and MAGE-A6280-302 epitopes were recognized by CD4+ T cells isolated from the majority of normal donors and melanoma patients evaluated. Peptide-specific CD4+ T cells also recognized autologous antigen-presenting cell pulsed with recombinant MAGE-A6 (rMAGE) protein, supporting the natural processing and MHC presentation of these epitopes. Given the strong primary in vitro sensitization of normal donor CD4+ T cells by the MAGEA6172-187 epitope, suggestive of potential cross-reactivity against an environmental stimulus, we identified a highly homologous peptide within the Mycoplasma penetrans HF-2 permease (MPHF2) protein. MPHF2 peptide–primed CD4+ T cells cross-reacted against autologous APC pulsed with the MAGE-A6172-187 peptide or rMAGE protein and recognized HLA-matched MAGE-A6+ melanoma cell lines. These responses seemed heteroclitic in nature because the functional avidity of MPHF2 peptide-primed CD4+ T cells for the MAGE-A6172-187 peptide was ∼1,000 times greater than that of CD4+ T cells primed with the corresponding MAGE-A6 peptide.

Conclusions: We believe that these novel “promiscuous” MAGE-A6/MPHF2 Th epitopes may prove clinically useful in the treatment and/or monitoring of a high proportion of cancer patients.
Detection of Horse Allergen around a Stable
Authors: Elfman Lena , Brännström Johan , Smedje Greta
Published: November 2007

Background: Integrating horse stables with built-up areas may lead to conflicts. Dispersion of horse allergen may become a health risk for allergic people. The aim was to measure the dispersion of horse allergen around a stable, considering wind speed and direction and vegetation. The disturbance of staff at a workplace nearby a stable was investigated. Methods: Air sampling was performed around a stable (32 horses) at distances of 50–500 m in all directions. Sampling was done with a pump and an IOM sampler. Samples were collected at 50 points during all seasons. Horse allergen levels were determined using ELISA. Disturbance by horses was studied with a questionnaire handed to the employees in an office near the stable. Results: The median horse allergen level at the stable entrance was 316 U/m3, in the horse fields 40 U/m3 and in the whole source area 16 U/m3, which declined to <2 U/m3 at about 50 m from the source area. Downwind of the prevailing winds low levels of horse allergen (2–4 U/m3) could sometimes be detected at up to 500 m. The staff, including those allergic to horses, managed to tolerate horses close to the workplace. Conclusions: At low winds horse allergen spread in ambient air about 50 m from the stable and horse fields. At higher winds low allergen levels were sometimes found in open areas up to 500 m from the source area. These levels were similar to those found in the office after moving away from the stable area. The employees did not report more symptoms of allergy or asthma while working close to the stable compared to after the move.
Modulation of the Cationic Amino Acid Transport System y+L by Surface Potential, Ouabain and Thrombin in Human Platelets: Effects of Uremia
Authors: Alves de Sá Siqueira Mariana , Martins Marcela Anjos , Rodrigues Pereira Natália , Bandeira Moss Monique , Santos Sérgio F.F. , Mann Giovanni E. , Mendes-Ribeiro Antônio C. , Brunini Tatiana M.C.
Published: November 2007

Background: Nitric oxide (NO), a key endogenous mediator involved in the maintenance of platelet function, is synthesized from the amino acid L-arginine. We have shown that L-arginine transport in platelets is rate-limiting for NO synthesis. A disturbance in the L-arginine-NO pathway in platelets was previously described in chronic renal failure (CRF) patients. Methods: Detailed kinetic studies were performed in platelets from controls (n = 60) and hemodialysis patients (n = 26). Results: The transport of L-arginine in platelets is mediated via system y+L, which is competitively inhibited by L-leucine in the presence of Na+ and by the irreversible inhibitor pCMB. In platelets, system y+L is markedly stimulated by an Na+/K+-ATPase inhibitor, ouabain, and by changes in surface potential, while it is downregulated by intraplatelet amino acid depletion (zero-trans) and by thrombin. In CRF patients, activation of L-arginine transport was limited to well-nourished patients compared to malnourished patients and controls, where it was reduced and did not differ significantly among the groups under zero-trans conditions. Conclusion: Our results provide the first evidence that system y+L in platelets is modulated by zero-trans conditions, surface potential, thrombin and intraplatelet Na+ concentration. Our findings suggest that enhanced transport in CRF involves increased L-arginine exchange with intraplatelet neutral amino acids.
Heterogeneity in 5-HT-Induced Contractile and Proliferative Responses in Rat Pulmonary Arterial Bed
Authors: Rodat-Despoix L. , Crevel H. , Marthan R. , Savineau J.-P. , Guibert C.
Published: November 2007

Aims: 5-Hydroxytryptamine (5-HT) is a potent vasoconstrictor and mitogen in the pulmonary vascular bed which exhibits phenotypical and functional heterogeneity according to size of the vessels. Methods: We thus investigated both contractile response and smooth muscle cell (SMC) proliferation in response to 5-HT in rat main extrapulmonary artery (MPA) and intrapulmonary arteries of the first and second order (IPA1 and IPA2). Results: The contractile effect of 5-HT was higher in IPA1 and IPA2 compared to MPA. 5-HT2 receptor antagonists like ketanserin and ritanserin and a 5-HT1B/D receptor antagonist, GR127935, partially inhibited the contraction. α-Methyl-5-HT, a 5-HT2 receptor agonist, induced a higher contraction in MPA than in IPA and inversely 5-carboxamidotryptamine, a 5-HT1 receptor agonist, induced a higher contraction in IPA2 than in MPA and IPA1. Nitrendipine reduced the contraction, whereas the addition of thapsigargin, an inhibitor of the sarcoplasmic reticulum Ca-ATPases, had an additive blocking effect only in IPA1. The residual contraction to 5-HT was abolished by Y-27632, a rho kinase inhibitor. Finally, SMC proliferation in response to 5-HT was higher in MPA than in IPA2. Conclusion: Our results demonstrate regional differences in SMC proliferation as well as in the functional role of 5-HT receptors and the sarcoplasmic reticulum in the contraction.
A Large Brunner’s Gland Hamartoma Causing Gastrointestinal Bleeding and Obstruction
Authors: de Nes L.C.F. , Ouwehand F. , Peters S.H.A. , Boom M.J.
Published: November 2007

Context: Clinical symptoms of Brunner’s gland (BG) hamartoma are rare. Most lesions are small and asymptomatic. Symptomatic BG hamartoma may mimic a malignancy of the duodenal-pancreatic area. Though standard mucosal biopsies are inferiorly diagnostic due to normal duodenal mucosa surrounding, a biopsy was indicated in this case. Case Report: We report the case of a 37-year-old man with a large BG hamartoma mimicking a malignancy. Preoperatively the biopsy led to an inconclusive diagnosis. Due to its large size and its presence of symptoms, a surgical excision was performed. Conclusion: BG hamartoma may be a rare indication for surgery.
Early Imatinib Mesylate-Induced Hepatotoxicity in Chronic Myelogenous Leukaemia
Authors: Kong Jee Hyun , Yoo Seung-Hyun , Lee Kyoung Eun , Nam Seung Hyun , Kwon Jung Mi , Lee Sang Min , Chang Hye Jung , Choi Moon Young , Cho Min Sun , Mun Yeung-Chul , Nam Eunmi , Lee Soon Nam , Seong Chu-Myong
Published: November 2007

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.
The Roles of Serum Leptin Concentration and Polymorphism in Leptin Receptor Gene at Codon 109 in Breast Cancer
Authors: Liu Chien-Liang , Chang Yuan-Ching , Cheng Shih-Ping , Chern Schu-Rern , Yang Tsen-Long , Lee Jie-Jen , Guo Ing-Cherng , Chen Chih-Ping
Published: November 2007

Aims: We investigated the relationship between serum leptin concentrations and polymorphism of the leptin receptor gene and breast cancer. Methods: Serum leptin concentrations were measured by enzyme-linked immunosorbent assay in 47 women with invasive breast cancer compared with 41 age-matched controls without cancer. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the leptin receptor gene at codon 109 (LEPR-109) was performed by polymerase chain reaction-restriction fragment length polymorphism. Results: Patients with breast cancer had a higher mean serum leptin concentration than women in the control group, but the difference was not statistically significant. Among those with breast cancer, the serum leptin concentration was higher in women with high-grade cancers (p = 0.020). The LEPR-109RR genotype was more frequent in premenopausal patients with tumors larger than 2 cm (p = 0.039) and in premenopausal women who were overweight (p = 0.029). Among patients with the LEPR-109RR genotype, higher mean serum leptin concentrations were present in those with triple-negative cancers (p = 0.048). Conclusions: Our study suggests an association between serum leptin concentration and tumor progression. LEPR-109 polymorphism in premenopausal women appears to be associated with obesity and tumor progression.
Commentary: Is It Safe to Limit Allogeneic Red Blood Cell Transfusions to Neonates?
Authors: Strauss Ronald G.
Published: November 2007

Two randomized clinical trials, conducted independently, have reported results of neonates transfused with red blood cells (RBCs) given per either liberal (relatively high pretransfusion blood hematocrit levels) or restrictive (relatively low pretransfusion blood hematocrit levels) transfusion programs. Both found fewer RBC transfusions given per restrictive programs and comparable outcomes for several clinical endpoints. However, the Iowa trial found significantly more problems with apnea, intraparenchymal brain hemorrhage and periventricular leukomalacia in infants transfused per the restrictive program – findings not found by the Canadian trial. A critical analysis of both trials and possible reasons for the discrepant findings are discussed. Until definitive data are reported by additional studies, it seems prudent not to severely restrict/limit allogeneic RBC transfusions to neonates – except in approved investigational settings.
Cord Blood KL-6, a Specific Lung Injury Marker, Correlates with the Subsequent Development and Severity of Atypical Bronchopulmonary Dysplasia
Authors: Kim Do-Hyun , Kim Han-Suk , Shim So-Yeon , Lee Jin-A , Choi Chang Won , Kim Ee-Kyung , Kim Beyong Il , Choi Jung-Hwan
Published: November 2007

Background: A considerable number of preterm infants may have been exposed to inflammation in utero and may be born with an inflamed lung. Objectives: To determine the impact of antenatal lung injury and inflammatory response on the pathogenesis of bronchopulmonary dysplasia (BPD) according to its clinical pattern, using KL-6 (as a lung injury marker) and C-reactive protein (CRP) (as a marker of inflammatory response). Methods: In this case-control study, a total of 74 infants (<32 weeks of gestation) including BPD with minimal early lung disease (‘atypical’; 21 infants), BPD with significant early lung disease (‘classic’; 29 infants) and the non-BPD (24 infants) groups underwent KL-6 and CRP in cord blood determinations. Results: The cord plasma KL-6 levels were significantly higher in the atypical and the total BPD groups than in the non-BPD group (median = 60.9 vs. 34.5 U/ml, p = 0.031; 43.5 vs. 34.5 U/ml, p = 0.02). However, the cord plasma CRP levels were not significantly different among the study groups. The cord plasma KL-6 levels in patients with atypical BPD were significantly higher in infants with moderate or severe BPD than in infants with mild BPD (median = 88.3 vs. 41.5 U/ml, p = 0.041) and were found to be significantly correlated with the duration of oxygen therapy (r = 0.502, p = 0.024). Conclusions: The present study shows that cord plasma KL-6, a specific lung injury marker, is increased and objectively reflects disease severity in atypical BPD.
Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma
Authors: Rikimaru Tatsuya , Taketomi Akinobu , Yamashita Yo-ichi , Shirabe Ken , Hamatsu Takayuki , Shimada Mitsuo , Maehara Yoshihiko
Published: November 2007

Objective: Histone deacetylases (HDACs) play an important role in chromatin remodeling, gene repression and regulating cell cycle progression and differentiation. This study was designed to clarify the role of HDAC1 expression in hepatocellular carcinoma (HCC). Method: The expression of HDAC1 in 47 patients with surgically resected HCC was immunohistochemically examined and analyzed in relation to their clinicopathological factors. The patients were divided into two groups according to the expression status of HDAC1: a high HDAC1 group (n = 25) with more than 20% of positively stained cells and a low HDAC1 group (n = 22) with 20% or fewer positively stained cells. Results: A high HDAC1 expression indicated a higher incidence of cancer cell invasion into the portal vein, a poorer histological differentiation, and a more advanced TNM stage. The survival rates after a surgical resection in low and high HDAC1 patients at 1, 3, 5 and 10 years were 100, 95.5, 81.8 and 60.8% and 88.0, 60.0, 40.0 and 32.0%, respectively (p = 0.008). A multivariate analysis using the Cox regression analysis showed that a high HDAC1 expression was an independent prognostic factor of HCC in patients after hepatic resection (relative risk: 10.1, p = 0.0018). Conclusions: High HDAC1 expression might have an important role in the aggressiveness and cell dedifferentiation, and its expression status may be a useful biomarker for predicting the outcome of the patients with HCC.
Microsatellite Instability Did Not Predict Individual Survival in Sporadic Stage II and III Rectal Cancer Patients
Authors: Meng Wen-Jian , Sun Xiao-Feng , Tian Chao , Wang Ling , Yu Yong-Yang , Zhou Bing , Gu Jun , Xia Qing-Jie , Li Yuan , Wang Rong , Zheng Xue-Lian , Zhou Zong-Guang
Published: November 2007

Objectives: Tumors with high-frequency microsatellite instability (MSI-H) have unique biological behavior and the predictive role of microsatellite instability (MSI) status on survival of colorectal cancer is still debated. The prognostic significance of MSI status in sporadic stage II and III rectal cancer patients needs to be more precisely defined. So we investigated the relationship between MSI status and clinicopathological features and prognosis in these patients. Methods: DNAs from fresh-frozen paired samples of tumors and corresponding normal tissue from 128 stage II and III rectal cancer patients were analyzed for MSI by PCR amplification using markers recommended by a National Cancer Institute workshop on MSI. To assess prognostic significance, Cox proportional hazards modeling was used. Results: Twelve (9.3%) tumors in our study were MSI-H, 28 (21.9%) were low-frequency MSI (MSI-L) and 88 (68.8%) were microsatellite stable (MSS). Most of the MSI-H tumors compared with MSI-L and MSS tumors were found in female patients (p = 0.031), had mucinous histology (p = 0.023), high grade of differentiation (p = 0.002) and high level of preoperative serum carcinoembryonic antigen (p = 0.005). Rectal cancer patients with MSI-H did not show a better clinical outcome than those with MSI-L/MSS, neither in all cases (p = 0.986) nor in stage II and stage III disease analyzed separately (p = 0.705 and p = 0.664, respectively). Conclusions: Data provided here demonstrated there was high incidence of MSI-H and MSI was not a prognostic factor in sporadic stage II and III rectal cancers from the Chinese Han population included in this study. Tumor stage is more suitable than MSI status for prediction of individual survival in sporadic stage II and III rectal cancer patients.
Phase I Study of Paclitaxel and Uracil plus Tegafur Combination in Patients with Pretreated Metastatic Breast Cancer: Drug Sequencing Based on Preclinical Modelling Studies
Authors: Passardi A. , Maltoni R. , Milandri C. , Cecconetto L. , Massa I. , Zoli W. , Tesei A. , Fabbri F. , Nanni O. , Amadori D.
Published: November 2007

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. Methods: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 · day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3–13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT. Results: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity). Conclusions: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3–13, every 2 weeks.