bluuebunny/crossref_metadata_2025 huggingface dataset:
Depletion of the ATPase NSF from Golgi membranes with hypo-S-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole
Authors: Mukhopadhyay Somshuvra , Lee Jason , Sehgal Pravin B.
Published: September 2008

Investigations of regulated S-nitrosylation and denitrosylation of vasorelevant proteins are a newly emergent area in vascular biology. We previously showed that monocrotaline pyrrole (MCTP)-induced megalocytosis of pulmonary arterial endothelial cells (PAECs), which underlies the development of pulmonary arterial hypertension, was associated with a Golgi blockade characterized by the trapping of diverse vesicle tethers, soluble N-ethylmaleimide-sensitive factor (NSF)-attachment protein receptors (SNAREs), and soluble NSF-attachment proteins (SNAPs) in the Golgi; reduced trafficking of caveolin-1 (cav-1) and endotheial nitric oxide (NO) synthase (eNOS) from the Golgi to the plasma membrane; and decreased caveolar NO. We have investigated whether NSF, the ATPase involved in all SNARE disassembly, might be the upstream target of MCTP and whether MCTP might regulate NSF by S-nitrosylation. Immunofluorescence microscopy and Golgi purification techniques revealed the discordant decrease of NSF by ∼50% in Golgi membranes after MCTP despite increases in α-SNAP, cav-1, eNOS, and syntaxin-6. The NO scavenger (4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide failed to affect the initiation or progression of MCTP megalocytosis despite a reduction of 4,5-diaminofluorescein diacetate fluorescence and inhibition of S-nitrosylation of eNOS as assayed using the biotin-switch method. Moreover, the latter assay not only revealed constitutive S-nitrosylation of NSF, eNOS, cav-1, and clathrin heavy chain (CHC) in PAECs but also a dramatic 70–95% decrease in the S-nitrosylation of NSF, eNOS, cav-1, and CHC after MCTP. These data point to depletion of NSF from Golgi membranes as a mechanism for Golgi blockade after MCTP and to denitrosylation of vasorelevant proteins as critical to the development of endothelial cell megalocytosis.
Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences
Authors: Atkinson Jeffrey
Published: September 2008

With age, the calcium content of the arterial wall increases. Calcification occurs at two main levels: intimal plaques and the medial elastic fiber network. The latter has been referred to as medial elastocalcinosis and is the subject of this review. The mechanisms involved in elastocalcinosis are complex and involve polar, apolar, and active processes. Vascular calcification may be species specific to humans. As laboratory animals, such as the rat, grow old, they suffer from only very mild arterial calcification. Different animal models of induction of massive arterial calcification by pharmacological and other means exist. Although extrapolation from such models to the clinical situation in terms of etiology is difficult, such models could be useful in the nonclinical study of the pathophysiological consequences of vascular calcification. Vascular calcification modifies arterial wall stiffness, and this could have clinically significant consequences on cardiac function and downstream circulatory control.
Ionic Factors Governing Rebound Burst Phenotype in Rat Deep Cerebellar Neurons
Authors: Molineux Michael L. , Mehaffey W. Hamish , Tadayonnejad Reza , Anderson Dustin , Tennent Adrien F. , Turner Ray W.
Published: September 2008

Large diameter cells in rat deep cerebellar nuclei (DCN) can be distinguished according to the generation of a transient or weak rebound burst and the expression of T-type Ca2+ channel isoforms. We studied the ionic basis for the distinction in burst phenotypes in rat DCN cells in vitro. Following a hyperpolarization, transient burst cells generated a high-frequency spike burst of ≤450 Hz, whereas weak burst cells generated a lower-frequency increase (<140 Hz). Both cell types expressed a low voltage–activated (LVA) Ca2+ current near threshold for rebound burst discharge (−50 mV) that was consistent with T-type Ca2+ current, but on average 7 times more current was recorded in transient burst cells. The number and frequency of spikes in rebound bursts was tightly correlated with the peak Ca2+ current at −50 mV, showing a direct relationship between the availability of LVA Ca2+ current and spike output. Transient burst cells exhibited a larger spike depolarizing afterpotential that was insensitive to blockers of voltage-gated Na+ or Ca2+ channels. In comparison, weak burst cells exhibited larger afterhyperpolarizations (AHPs) that reduced cell excitability and rebound spike output. The sensitivity of AHPs to Ca2+ channel blockers suggests that both LVA and high voltage–activated (HVA) Ca2+ channels trigger AHPs in weak burst compared with only HVA Ca2+ channels in transient burst cells. The two burst phenotypes in rat DCN cells thus derive in part from a difference in the availability of LVA Ca2+ current following a hyperpolarization and a differential activation of AHPs that establish distinct levels of membrane excitability.
Evolution of ventricular myocyte electrophysiology
Authors: Rosati Barbara , Dong Min , Cheng Lan , Liou Shian-Ren , Yan Qinghong , Park Ji Young , Shiang Elaine , Sanguinetti Michael , Wang Hong-Sheng , McKinnon David
Published: September 2008

The relative importance of regulatory versus structural evolution for the evolution of different biological systems is a subject of controversy. The primacy of regulatory evolution in the diversification of morphological traits has been promoted by many evolutionary developmental biologists. For physiological traits, however, the role of regulatory evolution has received less attention or has been considered to be relatively unimportant. To address this issue for electrophysiological systems, we examined the importance of regulatory and structural evolution in the evolution of the electrophysiological function of cardiac myocytes in mammals. In particular, two related phenomena were studied: the change in action potential morphology in small mammals and the scaling of action potential duration across mammalian phylogeny. In general, the functional properties of the ion channels involved in ventricular action potential repolarization were found to be relatively invariant. In contrast, there were large changes in the expression levels of multiple ion channel and transporter genes. For the Kv2.1 and Kv4.2 potassium channel genes, which are primary determinants of the action potential morphology in small mammals, the functional properties of the proximal promoter regions were found to vary in concordance with species-dependent differences in mRNA expression, suggesting that evolution of cis-regulatory elements is the primary determinant of this trait. Scaling of action potential duration was found to be a complex phenomenon, involving changes in the expression of a large number of channels and transporters. In this case, it is concluded that regulatory evolution is the predominant mechanism by which the scaling is achieved.
MTHFR Genotype and Colorectal Adenoma Recurrence: Data from a Double-blind Placebo-controlled Clinical Trial
Authors: Levine A. Joan , Wallace Kristin , Tsang Shirley , Haile Robert W. , Saibil Fred , Ahnen Dennis , Cole Bernard F. , Barry Elizabeth L. , Munroe David J. , Ali Iqbal U. , Ueland Per , Baron John A.
Published: September 2008

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double- blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared with those with two wild-type alleles, the relative risk for advanced adenoma was 0.75 (95% CI, 0.36-1.55) for the MTHFR 677 TT genotype and 1.16 (95% CI, 0.58-2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2409–15)
Benzo(a)pyrene Diol Epoxide-Induced Chromosome 9p21 Aberrations Are Associated with Increased Risk of Bladder Cancer
Authors: Gu Jian , Horikawa Yohei , Chen Meng , Dinney Colin P. , Wu Xifeng
Published: September 2008

Purpose: Loss of chromosome 9p21 is one of the most frequent genomic alterations in bladder cancer. Alterations of 9p21 and p16 are also frequently seen in the epithelial cells of chronic smokers. We hypothesize that 9p21 is a molecular target of benzo(a)pyrene diol epoxide (BPDE), the metabolic product of tobacco carcinogen benzo(a)pyrene, and 9p21 BPDE sensitivity is a genetic susceptibility factor for bladder cancer.

Material and Methods: In this case-control study of 203 bladder cancer cases and 198 matched healthy controls, we compared the frequencies of BPDE-induced 9p21 aberrations in cultured peripheral blood lymphocytes using fluorescent in situ hybridization and evaluated the association between 9p21 BPDE sensitivity and bladder cancer risk.

Results: We found that BPDE-induced chromosome 9p21 aberrations were significantly higher in peripheral blood lymphocytes of bladder cancer cases (20.76 ± 6.97 per 1,000) than those of controls (16.58 ± 7.07 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control centromere locus on chromosome 9. Using the median aberration value in the controls as a cutoff point to dichotomize BPDE sensitivity and after adjustment by age, sex, ethnicity, and smoking status, 9p21 BPDE sensitivity was associated with a significantly increased risk of bladder cancer (odds ratio, 5.29; 95% confidence interval, 3.26-8.59), whereas the odds ratio for the CEP9 locus was 0.99 (95% confidence interval, 0.66-1.50). There was also a dose-response relationship between the 9p21 BPDE sensitivity and increased risk for bladder cancer.

Conclusion: 9p21 may be a molecular target for BPDE damage in bladder cancer cases and 9p21 BPDE sensitivity may be a marker of bladder cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2445–50)
Prognostic Value of Signal Transducers and Activators of Transcription 3 in Breast Cancer
Authors: Sheen-Chen Shyr-Ming , Huang Chao-Cheng , Tang Rei-Ping , Chou Fong-Fu , Eng Hock-Liew
Published: September 2008

Introduction: Constitutively activated signal transducers and activators of transcription (STAT) proteins are found in various types of tumors. However, there is still very limited information about the role of STATs in breast cancer. The power of tissue microarray technique is the capability of doing a series of analyses of thousands specimens in a parallel fashion with minimal damage to the origin blocks. This study was designed with the application of tissue microarray to analyze the STAT3 status in breast cancer.

Materials and Methods: Archival tissue specimens from 102 patients with primary invasive breast cancer were selected, and STAT3 expression was analyzed by immunohistochemical staining with tissue microarray. The data of primary tumor staging, age, estrogen receptor status, lymph node status, histologic grading, and tumor-node-metastasis staging were also collected.

Results: By multivariate analysis, the STAT3 expression turned out to be significantly related to the overall 5-year survival rate (P = 0.024).

Conclusion: Immunohistochemical staining with tissue microarray was convenient and feasible for the analysis of STAT3 expression status in breast cancer. Our preliminary results are promising and deserve further evaluation. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2286–90)
Promoter Hypermethylation of the p16 Gene Is Associated with Poor Prognosis in Recurrent Early-Stage Hepatocellular Carcinoma
Authors: Ko Eunkyung , Kim Yujin , Kim Sung-Joo , Joh Jae-Won , Song SangYong , Park Cheol-Keun , Park Joobae , Kim Duk-Hwan
Published: September 2008

Despite significant advances in the detection and treatment of hepatocellular carcinoma, the prognosis of patients with hepatocellular carcinoma remains very poor, in part due to the high incidence of recurrence. This study was aimed at identifying a prognostic indicator of recurrence in patients with hepatocellular carcinoma. We retrospectively analyzed CpG island hypermethylation of the p14, p15, p16, GSTP1, integrin α4, SYK, and CDH1 genes in fresh-frozen tissues from 265 patients with hepatocellular carcinoma using the methylation-specific PCR. The expression levels of p16 and p53 were evaluated by immunohistochemistry. CpG island hypermethylation was detected in 6% for p14, 21% for p15, 67% for p16, 75% for GSTP1, 23% for integrin α4, 12% for SYK, and 57% for CDH1. Recurrence was observed in 102 (38%) of the 265 patients. There was no association between the risk for recurrence and hypermethylation of any gene studied. However, p16 methylation was associated with a poor survival after surgery for recurrent stage I to II hepatocellular carcinomas (hazard ratio, 4.05; 95% confidence interval, 1.15-14.20; P = 0.03). In addition, the hazard of failure after recurrence was about 3.80 (95% confidence interval, 1.03-14.20; P = 0.04) times higher in patients with p16 methylation than in those without. Negative expression of p16 at a protein level was also associated with poor survival in recurrent stage I to II hepatocellular carcinomas, but p53 expression did not have a synergistic effect on the poor prognosis. In conclusion, the present study suggests that p16 methylation may be associated with a poor prognosis in recurrent early-stage hepatocellular carcinomas. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2260–7)
Mortality among HIV-1– and Human Herpesvirus Type 8–Affected Mother-Infant Pairs in Zambia
Authors: Wojcicki Janet , Mwanahamuntu Mulindi , Minhas Veenu , Djokic Boris , Kankasa Chipepo , Klaskala Winslow , Brayfield Brad , Phiri Saul , Wood Charles , Mitchell Charles D.
Published: September 2008

Objective: To determine the respective trends in mortality of Zambian mother-infant pairs based on maternal infection with HIV-1 and human herpesvirus type 8 (HHV-8).

Methods: A prospective cohort study was done on Zambian mother-infant pairs, stratified by maternal serologic status and followed from 6 weeks postdelivery for 48 months. Statistical analysis of the differences in the calculated mortality rates among the four groups was done using Stata 7.0. Kaplan-Meier analysis and Cox proportional hazard models were used to measure subject survival time.

Results: Between September 1998 and March 2002, a total of 1,425 mother-infant pairs were enrolled. The crude mortality rate among children born to dually infected mothers was ∼9 times higher (245.90 deaths per 1,000 live births) when compared with the death ratio of children born to seronegative mothers (24.63 deaths per 1,000 live births). The incidence rate for death was 0.34/1,000 in infants of co-infected mothers in comparison with 0.32/1,000 among HIV-1–infected mothers, 0.0336/1,000 among uninfected mothers, and 0.0403/1,000 among HHV-8–infected mothers (χ2 = 154.56; P < 0.01). Infants of co-infected mothers had a comparable risk of death in comparison with infants infected with HIV-1 alone {hazard ratio, 9.91 [95% confidence interval (95% CI), 5.08-19.37] for co-infected versus 9.26 [95% CI, 4.75-18.07] for HIV-1–infected alone}. Infants of mothers infected only with HHV-8 also had comparable survival in comparison with uninfected infants (hazard ratio, 1.21; 95% CI, 0.56-2.61).

Conclusion: Infants born to mothers dually infected with both HIV-1 and HHV-8 have comparable survival with infants exposed to HIV-1 alone. Infants born to mothers infected only with HHV-8 have comparable survival with uninfected infants. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2238–43)
Genetic Susceptibility to Renal Cell Carcinoma: The Role of DNA Double-Strand Break Repair Pathway
Authors: Margulis Vitaly , Lin Jie , Yang Hushan , Wang Wei , Wood Christopher G. , Wu Xifeng
Published: September 2008

Alterations in DNA repair genes have been shown to cause a reduction in host DNA repair capacity and may influence host susceptibility to carcinogenesis. The double-strand break repair is a major DNA-repair pathway. This study tested the hypothesis that common sequence variants of the double-strand break pathway genes predispose susceptible individuals to an increased risk for renal cell carcinoma. Toward this end, we evaluated the associations of 13 single-nucleotide polymorphisms in 10 candidate genes involved in the double-strand break pathway with renal cell carcinoma risk in a population-based case-control study that included 326 Caucasian renal cell carcinoma patients and 335 controls. Using the homozygous wild type as the reference group, we observed a significantly increased renal cell carcinoma risk associated with the homozygous variant genotype of NBS1 (rs1805794; odds ratio, 2.13; 95% confidence interval (95% CI), 1.17-3.86). Carrying of at least one copy of the variant XRCC4 allele was also associated with a significantly increased risk (rs1805377; odds ratio, 1.56; 95% CI, 1.08-2.26). Importantly, in pathway analysis, compared with the reference group (1 or less adverse alleles), individuals with two (odds ratio, 1.26; 95% CI, 0.83-1.91), three (odds ratio, 1.00; 95% CI, 0.64-1.56), and more than three adverse alleles (odds ratio, 1.75; 95% CI, 1.03-2.98) were at increased risk for renal cell carcinoma with significant association in subjects carrying more than 3 adverse alleles. Results from this study provide evidence that individuals with a higher number of genetic variations in the DBS repair pathway are at an increased risk for renal cell carcinoma. These findings require further validation in independent populations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2366–73)
Urinary Lead Exposure and Breast Cancer Risk in a Population-Based Case-Control Study
Authors: McElroy Jane A. , Shafer Martin M. , Gangnon Ronald E. , Crouch Luis A. , Newcomb Polly A.
Published: September 2008

Background: Lead is a toxic nonessential metal with widespread exposure starting in utero. Lead has been reclassified in 2004 by the International Agency for Research on Cancer Working Group from a “possible” to a “probable” human carcinogen. Lead may be a facilitative or permissive carcinogen, which means that lead may permit or augment the genotoxic effects of other exposures.

Methods: This population-based study in Wisconsin gathered survey data and home-collected urine specimens from 246 women, ages 20 to 69 years, with incident invasive breast cancer identified from the Wisconsin state registry and 254 age-matched control subjects from population lists from September 2004 to February 2005. We measured urinary lead concentrations by inductively coupled plasma mass spectrometry, adjusted the values by specific gravity, and conducted interviews by telephone to obtain information on known and suspected breast cancer risk factors.

Results: Women in the highest quartile of specific gravity–adjusted lead level (≥1.10 μg/L) had twice the breast cancer risk of those in the lowest quartile (<0.42 μg/L; odds ratio, 1.99; 95% confidence interval, 1.1-3.6) after adjustment for established risk factors. Excluding women who were currently taking nonsteroidal aromatase inhibitors (n = 52), we did not observe any increased breast cancer risk after adjustment for established risk factors.

Conclusion: Our population-based case-control study suggests that lead exposure, as determined by specific gravity–adjusted urinary lead concentrations, is not associated with a significant increased risk for breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2311–7)
Genomic DNA Methylation among Women in a Multiethnic New York City Birth Cohort
Authors: Terry Mary Beth , Ferris Jennifer S. , Pilsner Richard , Flom Julie D. , Tehranifar Parisa , Santella Regina M. , Gamble Mary V. , Susser Ezra
Published: September 2008

One plausible mechanism for the environment to alter cancer susceptibility is through DNA methylation. Alterations in DNA methylation can lead to genomic instability and altered gene transcription. Genomic DNA methylation levels have been inversely associated with age, suggesting that factors throughout life may be associated with declines in DNA methylation. Using information from a multiethnic New York City birth cohort (born between 1959 and 1963), we examined whether genomic DNA methylation, measured in peripheral blood mononuclear cells, was associated with smoking exposure and other epidemiologic risk factors across the life course. Information on prenatal and childhood exposures was collected prospectively through 1971, and information on adult exposures and blood specimens were collected in adulthood from 2001 to 2007. Methylation levels of leukocyte DNA were determined using a [3H]-methyl acceptance assay where higher values of disintegrations per minute per microgram DNA indicate less DNA methylation. Genomic methylation of leukocyte DNA differed by ethnicity (66% of Blacks, 48% of Whites, and 29% of Hispanics were above the median level of disintegrations per minute per microgram DNA; P = 0.03). In multivariable modeling, DNA methylation was statistically significantly associated with maternal smoking during pregnancy, longer birth length, later age at menarche, nulliparity, and later age at first birth. These data, if replicated in larger samples, suggest that risk factors across the life course may be associated with DNA methylation in adulthood. Larger studies and studies that measure within-individual changes in DNA methylation over time are a necessary next step. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2306–10)
Genetic Variation in Genes for the Xenobiotic-Metabolizing EnzymesCYP1A1, EPHX1, GSTM1, GSTT1, andGSTP1and Susceptibility to Colorectal Cancer in Lynch Syndrome
Authors: Pande Mala , Amos Christopher I. , Osterwisch Daniel R. , Chen Jinyun , Lynch Patrick M. , Broaddus Russell , Frazier Marsha L.
Published: September 2008

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2393–401)
Talc Use, Variants of theGSTM1, GSTT1, andNAT2Genes, and Risk of Epithelial Ovarian Cancer
Authors: Gates Margaret A. , Tworoger Shelley S. , Terry Kathryn L. , Titus-Ernstoff Linda , Rosner Bernard , De Vivo Immaculata , Cramer Daniel W. , Hankinson Susan E.
Published: September 2008

Epidemiologic evidence suggests a possible association between genital use of talcum powder and risk of epithelial ovarian cancer; however, the biological basis for this association is not clear. We analyzed interactions between talc use and genes in detoxification pathways [glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and N-acetyltransferase 2 (NAT2)] to assess whether the talc/ovarian cancer association is modified by variants of genes potentially involved in the response to talc. Our analysis included 1,175 cases and 1,202 controls from a New England-based case-control study and 210 cases and 600 controls from the prospective Nurses' Health Study. We genotyped participants for the GSTM1 and GSTT1 gene deletions and three NAT2 polymorphisms. We used logistic regression to analyze the main effect of talc use, genotype, and gene-talc interactions in each population and pooled the estimates using a random-effects model. Regular talc use was associated with increased ovarian cancer risk in the combined study population (RR, 1.36; 95% CI, 1.14-1.63; Ptrend < 0.001). Independent of talc, the genes examined were not clearly associated with risk. However, the talc/ovarian cancer association varied by GSTT1 genotype and combined GSTM1/GSTT1 genotype. In the pooled analysis, the association with talc was stronger among women with the GSTT1-null genotype (Pinteraction = 0.03), particularly in combination with the GSTM1-present genotype (Pinteraction = 0.03). There was no clear evidence of an interaction with GSTM1 alone or NAT2. These results suggest that women with certain genetic variants may have a higher risk of ovarian cancer associated with genital talc use. Additional research is needed on these interactions and the underlying biological mechanisms. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2436–44)
Fruit and Vegetable Consumption and Risk of Bladder Cancer: A Prospective Cohort Study
Authors: Larsson Susanna C. , Andersson Swen-Olof , Johansson Jan-Erik , Wolk Alicja
Published: September 2008

Fruit and vegetable consumption has been inconsistently associated with risk of bladder cancer. We used data from a prospective population-based cohort study of 82,002 Swedish women and men to examine the association between fruit and vegetable consumption and bladder cancer incidence. Diet was assessed with a validated food frequency questionnaire. During a mean follow-up of 9.4 years, 485 incident cases of bladder cancer were identified in the Swedish cancer registries. We found no statistically significant association between intakes of total fruits and vegetables, total fruits, or total vegetables and bladder cancer risk after adjustment for age, sex, education, and cigarette smoking. The multivariate rate ratios (95% confidence intervals) comparing the highest with the lowest quartile of intake were 0.80 (0.60-1.05) for total fruits and vegetables, 0.93 (0.69-1.25) for fruits, and 0.89 (0.67-1.19) for vegetables. Likewise, no associations were observed for citrus fruits, cruciferous vegetables, or green leafy vegetables. The associations did not differ by sex or smoking status. In conclusion, findings from this prospective study suggest that fruit and vegetable intakes are not likely to be appreciably associated with the risk of bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2519–22)
No Association of MMP-7, MMP-8, and MMP-21 Polymorphisms with the Risk of Hepatocellular Carcinoma in a Chinese Population
Authors: Qiu Wei , Zhou Gangqiao , Zhai Yun , Zhang Xiumei , Xie Weimin , Zhang Hongxing , Yang Hao , Zhi Lianteng , Yuan Xiaoyan , Zhang Xiaoai , He Fuchu
Published: September 2008

Previous studies have suggested that the functional polymorphisms in the promoters of matrix metalloproteinases (MMP) genes were associated with the risk of cancers, but no study has ever explored these polymorphisms as risk factors for hepatocellular carcinoma. Recently, we firstly examined whether seven functional polymorphisms in the promoters of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, and MMP-13 have any bearing on the risk of hepatocellular carcinoma, but we found none. In this study, we focused on an additional six MMP polymorphisms, including four functional polymorphisms in the promoters of MMP-7 (A-181G and C-153T) and MMP-8 (C-799T and A-381G), and two nonsynonymous polymorphisms in MMP-10 (A180G) and MMP-21 (C572T). With the polymorphism validation, we found that only MMP-7 A-181G, MMP-8 C-799T, and MMP-21 C572T were polymorphic. These three polymorphisms were then genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PRC-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk of hepatocellular carcinoma was observed with the three polymorphisms in the overall sample, hepatitis B virus carriers, and non–hepatitis B virus carriers after correction for multiple comparisons. Furthermore, when the analyses were stratified by age, sex, status of smoking and drinking, pack-years of smoking, and family history of hepatocellular carcinoma, there was also no significant association between these polymorphisms and hepatocellular carcinoma risk. Our findings suggest that the polymorphisms MMP-7 A-181G, MMP-8 C-799T, and MMP-21 C572T may not play a major role in mediating susceptibility to hepatocellular carcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2514–8)
Linking Tobacco Control Policies and Practices to Early Cancer Endpoints: Surveillance as an Agent for Change
Authors: Hartman Anne M. , Thun Michael J. , Ballard-Barbash Rachel ,   for the Organizing Committee
Published: September 2008

State tobacco control programs provide an important laboratory for the development, implementation, and evaluation of comprehensive tobacco control interventions. Studies have shown that states and municipalities with aggressive tobacco control programs have experienced more rapid decreases in per capita cigarette sales, smoking prevalence, lung cancer, and heart disease than entities without such programs. Despite strong evidence that population-level interventions are critical in achieving large and sustained reductions in tobacco use, states do not fund tobacco control efforts at levels recommended by the Centers for Disease Control and Prevention. Research on the effectiveness and cost effectiveness of these activities is essential to inform and strengthen tobacco control at the state level. A workshop, co-organized by the American Cancer Society, the National Cancer Institute, the American Association for Cancer Research, and the Centers for Disease Control and Prevention, was held in Philadelphia in December, 2007, to discuss the topic “Linking tobacco control policies and practices to early cancer endpoints: surveillance as an agent for change.” Participants represented three different disciplines. Tobacco surveillance researchers described the data currently collected on state-level tobacco control policies, protobacco countermeasures by the industry, public attitudes toward tobacco use, and measures of smoking prevalence and consumption. Cancer registry experts described the geographic coverage of high quality, population-based cancer registries. Mathematical modeling experts discussed various modeling approaches that can be used to relate upstream tobacco promotion and control activities to downstream measures such as public attitudes, changes in tobacco use, and trends in tobacco-related diseases. The most important recommendation of the Workshop was a call for national leadership to enhance the collection and integration of data from multiple sources as a resource to further study and strengthen the scientific basis for tobacco control. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2215–9)
Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation
Authors: Jaggi Meena , Chauhan Subhash C. , Du Cheng , Balaji K.C.
Published: September 2008

In recent years, the use of natural products for cancer prevention and treatment has received considerable attention. Bryostatin 1 is a natural macrocyclic lactone and a protein kinase D (PKD) modulator with potent antineoplastic properties that has been used to treat human cancers in clinical trials with limited success. Further understanding the mechanistic basis of Bryostatin 1 action may provide opportunities to improve clinical results of treatment with Bryostatin 1. We identified that PKD1, founding member of PKD family of serine/threonine kinases, modulates E-cadherin/β-catenin activity, which plays an important role in cell integrity, polarity, growth, and morphogenesis. An aberrant expression and localization of E-cadherin/β-catenin has been strongly associated with cancer progression and metastasis. In this study, we examined the effect of Bryostatin 1 treatment on PKD1 activation, β-catenin translocation and transcription activity, and malignant phenotype of prostate cancer cells. Initial activation of PKD1 with Bryostatin 1 leads to colocalization of the cytoplasmic pool of β-catenin with PKD1, trans-Golgi network markers, and proteins involved in vesicular trafficking. Activation of PKD1 by Bryostatin 1 decreases nuclear β-catenin expression and β-catenin/TCF transcription activity. Activation of PKD1 alters cellular aggregation and proliferation in prostate cancer cells associated with subcellular redistribution of E-cadherin and β-catenin. For the first time, we have identified that Bryostatin 1 modulates β-catenin signaling through PKD1, which identifies a novel mechanism to improve efficacy of Bryostatin 1 in clinical settings. [Mol Cancer Ther 2008;7(9):2703–12]
Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides
Authors: de Wolf Cornelia , Jansen Robert , Yamaguchi Hiroaki , de Haas Marcel , van de Wetering Koen , Wijnholds Jan , Beijnen Jos , Borst Piet
Published: September 2008

We have studied the potential contribution of ABCG2 (breast cancer resistance protein) to resistance to nucleoside analogues. In cells transfected with DNA constructs resulting in overexpression of human or mouse ABCG2, we found resistance against cladribine, clofarabine, fludarabine, 6-mercaptopurine, and 6-mercaptopurine riboside in both MDCKII and HEK293 cells and against gemcitabine only in HEK293 cells. With Transwell studies in MDCK cells and transport experiments with vesicles from Sf9 and HEK293 cells, we show that ABCG2 is able to transport not only the nucleotide CdAMP, like several other ATP-binding cassette transporters of the ABCC (multidrug resistance protein) family, but also the nucleoside cladribine itself. Expression of ABCG2 in cells results in a substantial decrease of intracellular CdATP, explaining the resistance against cladribine. The high transport rate of cladribine and clofarabine by ABCG2 deduced from Transwell experiments raises the possibility that this transporter could affect the disposition of nucleoside analogues in patients or cause resistance in tumors. [Mol Cancer Ther 2008;7(9):3092–102]
Repeat Hepatic Resection Using a Radiofrequency-Assisted Technique
Authors: El-Gendi Ahmed M. , Khorsandi Shirin E. , Pai Madhava , Zacharoulis Dimitris , Nicholls Joanna P. , Spalding Duncan R.C. , Jiao Long R. , Habib Nagy A.
Published: September 2008

Background: Repeat hepatic resection for recurrent primary or secondary liver cancer is performed due to advances in resection techniques and evidence of survival benefit. This paper presents the safety and efficacy of repeat radiofrequency-assisted hepatic resection to highlight the utility of the technique. Methods: 264 consecutive hepatic resections performed on 218 patients were identified. The subset of patients with recurrent disease (n = 24) suitable for repeat hepatic resection had their records reviewed. Results: Including initial (n = 24), second (n = 24) and third hepatic resection (n = 6), a total of 54 hepatic resections were performed in 24 patients.Non-anatomical resection in the form of metastatectomy was the most common procedure. There were no post-operative deaths. Four patients (17%) had complications after their second resection and 1 (17%) after the third resection. There were no cases of bile leak or liver failure. The proportion of repeat hepatic resection for recurrent disease was high: 50% of recurrences were suitable for further resection after initial resection and 43% after second resection. Conclusion: Radiofrequency-assisted repeat hepatic resection is a safe procedure and may increase the proportion of patients who can be considered for a curative repeat hepatic resection.
Monaural Tinnitus from a Contralateral Inferior Colliculus Hemorrhage
Authors: Stimmer H. , Borrmann A. , Löer C. , Arnold W. , Rummeny E.J.
Published: September 2008

A 48-year-old man presented with sudden right ear tinnitus and showed no other otoneurologic signs or symptoms. Auditory brainstem response revealed prolonged III–V interpeak latencies from stimulating either ear. MRI revealed a small, circumscribed lesion of the left inferior colliculus, probably from an acute hemorrhage leading to a small cavernous malformation. Circumscribed lesions of the inferior colliculus are rare with no prior reports of contralateral tinnitus.
Ascorbic Acid Enhances Adipogenesis of Bone Marrow-Derived Mesenchymal Stromal Cells
Authors: Weiser Barbara , Sommer Florian , Neubauer Markus , Seitz Annina , Tessmar Joerg , Goepferich Achim , Blunk Torsten
Published: September 2008

A prerequisite to successfully engineer cell-based adipose tissue surrogates is the evaluation of in vitro culture conditions that facilitate expansion of primary precursor cells under retention of their adipogenic potential and that enable a large fraction of the heterogeneous cell pool to undergo adipogenesis upon respective stimuli. Ascorbic acid (AA) was reported to enhance differentiation of precursor cells into various mesenchymal cell types. Thus, the aim of the current study was to evaluate the influence of AA on hormonally induced adipogenesis of bone marrow-derived mesenchymal stromal cells (BMSCs) in vitro when supplemented during cell propagation and/or adipogenic differentiation. BMSCs were isolated from rat bone marrow, propagated, and hormonally induced to undergo adipogenesis. Supplementation of AA from the time of induction increased the fraction of BMSCs differentiating into adipocytes and glycerol-3-phosphate dehydrogenase activity up to 2-fold. Furthermore, administration of AA already during propagation had an even larger effect with an up to 8-fold increase in adipogenic markers. Assessment of collagen accumulation suggested that the observed effects might be attributed to an enhanced collagen synthesis during propagation. The presented results demonstrate AA as a potent medium component able to enhance adipogenic conversion of BMSCs, especially when administered during cell propagation.
Lysosomal Targeting and Trafficking of Acid Sphingomyelinase to Lipid Raft Platforms in Coronary Endothelial Cells
Authors: Jin Si , Yi Fan , Zhang Fan , Poklis Justin L. , Li Pin-Lan
Published: September 2008

Objective—

The purpose of this study was to determine whether lysosome trafficking and targeting of acid sphingomyelinase (ASMase) to this organelle contribute to the formation of lipid raft (LR) signaling platforms in the membrane of coronary arterial endothelial cells (CAECs).

Methods and Results—

By measurement of fluorescent resonance energy transfer (FRET), it was found that in FasL-stimulated CAECs, membrane lamp1 (a lysosome marker protein) or Fas and GM1 (a LR marker) were trafficking together. Cofocal colocalization assay showed that ceramide was enriched in these LR platforms. Further studies demonstrated that these ceramide molecules in LR platforms were colocalized with ASMase, a ceramide producing enzyme. Fluorescence imaging of living CAECs loaded with lysosomal specific dyes demonstrated that lysosomes fused with membrane on FasL stimulation. In the presence of lysosome function inhibitors, bafilomycin (Baf) or glycyl-
l
-phenylalanine-β-naphthylamide (GPN), these FasL-induced changes were abolished. Moreover, this FasL-induced formation of LR platforms was also blocked in ECs transfected with siRNA of sortilin, an intracellular transporter for targeting of ASMase to lysosomes. Functionally, FasL-induced impairment of vasodilator response was reversed by lysosomal inhibitors or sortilin gene silencing.

Conclusions—

Lysosomal trafficking and targeting of ASMase are importantly involved in LRs clustering in ECs membrane, leading to the formation of signaling platforms or signalosomes.
Effects of the Direct Lipoprotein-Associated Phospholipase A
2
Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque
Authors: Serruys Patrick W. , García-García Héctor M. , Buszman Pawel , Erne Paul , Verheye Stefan , Aschermann Michael , Duckers Henrikus , Bleie Oyvind , Dudek Dariusz , Bøtker Hans Erik , von Birgelen Clemens , D'Amico Don , Hutchinson Tammy , Zambanini Andrew , Mastik Frits , van Es Gerrit-Anne , van der Steen Antonius F.W. , Vince D. Geoffrey , Ganz Peter , Hamm Christian W. , Wijns William , Zalewski Andrew
Published: September 2008

Background—

Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture.

Methods and Results—

This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA
2
inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL;
P
=0.37). In contrast, Lp-PLA
2
activity was inhibited by 59% with darapladib (
P
<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (
P
=0.22) or plasma high-sensitivity C-reactive protein (
P
=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm
3
;
P
=0.009), whereas darapladib halted this increase (−0.5±13.9 mm
3
;
P
=0.71), resulting in a significant treatment difference of −5.2 mm
3
(
P
=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (
P
=0.95).

Conclusions—

Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA
2
inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA
2
inhibition may represent a novel therapeutic approach.
Effects of Continuous Aortic Flow Augmentation in Patients With Exacerbation of Heart Failure Inadequately Responsive to Medical Therapy
Authors: Greenberg Barry , Czerska Barbara , Delgado Reynolds M. , Bourge Robert , Zile Michael R. , Silver Marc , Klapholz Marc , Haeusslein Ernest , Mehra Mandeep R. , Mather Paul , Abraham William T. , Neaton James D. , Brown B. Scott , Parker Irene C. , Konstam Marvin A.
Published: September 2008

Background—

Prior investigations suggest that superimposing continuous flow on aortic flow (continuous aortic flow augmentation) produces vasodilation, cardiac unloading, and improved cardiac performance.

Methods and Results—

We compared percutaneous continuous aortic flow augmentation (flow ≤1.5 L/min for up to 96 hours) plus medical therapy versus medical therapy alone by randomizing 168 patients (device, n=109; control, n=59) hospitalized with heart failure, reduced left ventricular ejection fraction and cardiac index, elevated pulmonary capillary wedge pressure, and renal impairment or substantial diuretic requirement despite intravenous inotropes/vasodilators. The primary composite efficacy end point included pulmonary capillary wedge pressure (72 to 96 hours) and days alive out of hospital off mechanical support over 35 days. The population’s illness severity posed unique challenges. Enrollment ended early because of an inability to demonstrate significant benefit on the primary composite end point (device, 17.4%; control, 13.6%;
P
=0.45) in the face of excess device group bleeding. Pulmonary capillary wedge pressure decreased from 28.8±6.3 mm Hg (mean±SD) to 24.9±7.2 mm Hg (average, 72 to 96 hours) and 28.9±7.1 to 26.5±6.2 mm Hg in the device and control groups, respectively (between-group
P
=0.074). Cardiac index progressively increased in the device (2.05±0.53 to 2.44±0.52 L · min
−1
· m
−2
) but not the control (between-group
P
<0.0001) group. Thirty-five–day Kansas City Cardiomyopathy Questionnaire Overall Summary scores increased by 38.4±22.7 and 31.2±26.0 points in the device and control groups (between-group
P
=0.10). Through 65 days, device-to-control hazard ratios were as follows: all-cause mortality, 1.05 (95% confidence interval, 0.60 to 1.82); death or heart failure hospitalization, 0.87 (95% confidence interval, 0.57 to 1.33); and heart failure hospitalization, 0.66 (95% confidence interval, 0.38 to 1.13). Major bleeds occurred in 16.5% in the device (7.3% treatment related) and 5.1% in the control (
P
=0.05) group.

Conclusions—

Continuous aortic flow augmentation improved cardiac performance, improving cardiac index and pulmonary capillary wedge pressure, but statistical significance for the primary efficacy end point was not attained. Hemodynamic and clinical observations provide direction toward additional studies to further investigate the clinical effects of this treatment.
Mitogen-Activated Protein Kinases Mediate Upregulation of Hypothalamic Angiotensin II Type 1 Receptors in Heart Failure Rats
Authors: Wei Shun-Guang , Yu Yang , Zhang Zhi-Hua , Weiss Robert M. , Felder Robert B.
Published: September 2008

In heart failure (HF), angiotensin II type 1 receptor (AT
1
-R) expression is upregulated in brain regions regulating sympathetic drive, blood pressure, and body fluid homeostasis. However, the mechanism by which brain AT
1
-R are upregulated in HF remains unknown. The present study examined the hypothesis that the angiotensin II (Ang II)–triggered mitogen-activated protein kinases (MAPKs) p44/42, p38, and c-Jun N-terminal kinase contribute to upregulation of the AT
1
-R in the hypothalamus of rats with HF. AT
1
-R protein, AT
1
-R mRNA, and AT
1
-R immunoreactivity increased in the paraventricular nucleus of hypothalamus and the subfornical organ of rats with ischemia-induced HF compared with sham-operated controls. Phosphorylated p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK also increased in paraventricular nucleus and subfornical organ. A 4-week ICV infusion of the AT
1
-R antagonist losartan decreased AT
1
-R protein and phosphorylation of p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK in the HF rats. A 4-week ICV infusion of the p44/42 MAPK inhibitor PD98059 or the c-Jun N-terminal kinase inhibitor SP600125 significantly decreased AT
1
-R protein and AT
1
-R immunoreactivity in the paraventricular nucleus and subfornical organ, but the p38 MAPK inhibitor SB203580 did not. Treatment with ICV losartan, PD98059, and SP600125 had no effect on AT
1
-R expression by Western blot in sham-operated rats. In untreated HF rats 4 weeks after coronary ligation, a 3-hour ICV infusion of PD98059, SP600125, or losartan reduced AT
1
-R mRNA in paraventricular nucleus and subfornical organ. These data indicate that MAPK plays an important role in the upregulation of AT
1
-R in the rat forebrain in HF and suggest that Ang II upregulates its own receptor by this mechanism.