bluuebunny/crossref_metadata_2025 huggingface dataset:
International symposium of memory management (ISMM 2008)
Authors: Jones Richard , Blackburn Steve
Published: October 2008

The ACM SIGPLAN International Symposium on Memory Management (ISMM) is a premier forum for research in the management of dynamically allocated memory. We interpret this remit widely: areas of interest include but are not limited to explicit storage allocation and deallocation; garbage collection algorithms and implementations; compiler analyses to aid memory management; interactions with languages, operating systems and hardware (especially the memory system); memory management related tools; and empirical studies of allocation and referencing behavior in programs that make significant use of dynamic memory.
Molecular Pathogenesis and Diagnostics of Bladder Cancer
Authors: Mitra Anirban P. , Cote Richard J.
Published: October 2008

Despite elaborate characterization of the risk factors, bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. Urothelial carcinoma is now recognized as a disease of alterations in several cellular processes. The more prevalent, less aggressive, recurrent, noninvasive tumors are characterized by constitutive activation of the Ras-MAPK pathway. The less common but more aggressive invasive tumors, which have a higher mortality rate, are characterized by alterations in the p53 and retinoblastoma pathways. Several diagnostic tests have attempted to identify these molecular alterations in tumor cells exfoliated in the urine, whereas prognostic tests have tried to identify aberrations so as to predict tumor behavior and identify therapeutic targets. The future of bladder cancer patient management will rely on the use of molecular tests to reliably diagnose the presence of disease, predict individual tumor behavior, and suggest potential targeted therapeutics.
Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat
Authors: La Merrill Michele , Baston David S. , Denison Michael S. , Birnbaum Linda S. , Pomp Daniel , Threadgill David W.
Published: October 2008

Diets high in fat are associated with increased susceptibility to obesity and metabolic syndrome. Increased adipose tissue that is caused by high-fat diets (HFD) results in altered storage of lipophilic toxicants like 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), which may further increase susceptibility to metabolic syndrome. Because both TCDD and HFD are associated with increased breast cancer risk, we examined their effects on metabolic syndrome-associated phenotypes in three mouse models of breast cancer: 7,12-dimethylbenz[a]anthracene (DMBA), Tg(MMTV-Neu)202Mul/J (HER2), and TgN(MMTV-PyMT)634Mul/J (PyMT), all on an FVB/N genetic background. Pregnant mice dosed with 1 μg/kg of TCDD or vehicle on gestational day 12.5 were placed on a HFD or low-fat diet (LFD) at parturition. Body weights, percent body fat, and fasting blood glucose were measured longitudinally, and triglycerides were measured at study termination. On HFD, all cancer models reached the pubertal growth spurt ahead of FVB controls. Among mice fed HFD, the HER2 model had a greater increase in body weight and adipose tissue from puberty through adulthood compared with the PyMT and DMBA models. However, the DMBA model consistently had higher fasting blood glucose levels than the PyMT and HER2 models. TCDD only impacted serum triglycerides in the PyMT model maintained on HFD. Because the estrogenic activity of the HFD was three times lower than that of the LFD, differential dietary estrogenic activities did not drive the observed phenotypic differences. Rather, the HFD-dependent changes were cancer model dependent. These results show that cancer models can have differential effects on metabolic syndrome-associated phenotypes even before cancers arise.
Cellular retinol-binding protein type III is a PPARγ target gene and plays a role in lipid metabolism
Authors: Zizola Cynthia F. , Schwartz Gary J. , Vogel Silke
Published: October 2008

Cellular retinol-binding protein (CRBP) type III (CRBP-III) belongs to the family of intracellular lipid-binding proteins, which includes the adipocyte-binding protein aP2. In the cytosol, CRBP-III binds retinol, the precursor of retinyl ester and the active metabolite retinoic acid. The goal of the present work is to understand the regulation of CRBP-III expression and its role in lipid metabolism. Using EMSAs, luciferase reporter assays, and chromatin immunoprecipitation assays, we found that CRBP-III is a direct target of peroxisome proliferator-activated receptor-γ (PPARγ). Moreover, CRBP-III expression was induced in adipose tissue of mice after treatment with the PPARγ agonist rosiglitazone. To examine a potential role of CRBP-III in regulating lipid metabolism in vivo, CRBP-III-deficient (C-III-KO) mice were maintained on a high-fat diet (HFD). Hepatic steatosis was decreased in HFD-fed C-III-KO compared with HFD-fed wild-type mice. These differences were partly explained by decreased serum free fatty acid levels and decreased free fatty acid efflux from adipose tissue of C-III-KO mice. In addition, the lack of CRBP-III was associated with reduced food intake, increased respiratory energy ratio, and altered body composition, with decreased adiposity and increased lean body mass. Furthermore, expression of genes involved in mitochondrial fatty acid oxidation in brown adipose tissue was increased in C-III-KO mice, and C-III-KO mice were more cold tolerant than wild-type mice fed an HFD. In summary, we demonstrate that CRBP-III is a PPARγ target gene and plays a role in lipid and whole body energy metabolism.
Four grams of glucose
Authors: Wasserman David H.
Published: October 2008

Four grams of glucose circulates in the blood of a person weighing 70 kg. This glucose is critical for normal function in many cell types. In accordance with the importance of these 4 g of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle.
Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-α and angiotensin II by β-hydroxy-β-methylbutyrate
Authors: Eley Helen L. , Russell Steven T. , Tisdale Michael J.
Published: October 2008

Both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with β-hydroxy-β-methylbutyrate (HMB; 50 μM). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-α/IFN-γ and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRΔ6, in response to TNF-α/IFN-γ, compared with myotubes expressing wild-type PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-α/IFN-γ and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.
Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism
Authors: van Straten E. M. E. , Huijkman N. C. A. , Baller J. F. W. , Kuipers F. , Plösch T.
Published: October 2008

Cholesterol is critical for several cellular functions and essential for normal fetal development. Therefore, its metabolism is tightly controlled during all life stages. The liver X receptors-α (LXRα; NR1H3) and -β (LXRβ; NR1H2) are nuclear receptors that are of key relevance in coordinating cholesterol and fatty acid metabolism. The aim of this study was to elucidate whether fetal cholesterol metabolism can be influenced in utero via pharmacological activation of LXR and whether this would have long-term effects on cholesterol homeostasis. Administration of the LXR agonist T0901317 to pregnant mice via their diet (0.015% wt/wt) led to induced fetal hepatic expression levels of the cholesterol transporter genes Abcg5/g8 and Abca1, higher plasma cholesterol levels, and lower hepatic cholesterol levels compared with controls. These profound changes during fetal development did not affect cholesterol metabolism in adulthood nor did they influence coping with a high-fat/high-cholesterol diet. This study shows that the LXR system is functional in fetal mice and susceptible to pharmacological activation. Despite massive changes in fetal cholesterol metabolism, regulatory mechanisms involved in cholesterol metabolism return to a “normal” state in offspring and allow coping with a high-fat/high-cholesterol diet.
Bis deficiency results in early lethality with metabolic deterioration and involution of spleen and thymus
Authors: Youn Dong-Ye , Lee Dong-Hyoung , Lim Mi-Hyun , Yoon Jung-Sook , Lim Ji Hee , Jung Seung Eun , Yeum Chung Eun , Park Cheol Whee , Youn Ho-Joong , Lee Jae-Seon , Lee Seong-Beom , Ikawa Masahito , Okabe Masaru , Tsujimoto Yoshihide , Lee Jeong-Hwa
Published: October 2008

Bcl-2 interacting cell death suppressor (Bis), also known as Bag3 or CAIR-1, is involved in antistress and antiapoptotic pathways. In addition to Bcl-2, Bis binds to several proteins, suggesting it has diverse functions in normal and pathological conditions. To better define the physiological function of Bis in vivo, we developed bis-deficient mice with a cre-loxP system. Targeted disruption of exon 4 of the bis gene was demonstrated by Southern blotting and PCR, and Western blotting showed that no intact or truncated Bis protein was synthesized in bis−/− mice. While heterozygotes were fertile and appeared normal, Bis-deficient mice showed growth retardation and died by 3 wk after birth. The relative weight of the thymus and spleen was reduced and the total numbers of white blood cells, splenocytes, and thymocytes were significantly reduced compared with wild-type littermates. Serum profiles indicated significant hypoglycemia as well as decrease in triglyceride and cholesterol levels. Expression profiles of metabolic genes indicated that gluconeogenesis and β-oxidation are activated in the liver of bis−/− mice. This activation, as well as a decrease in peripheral fat and an induction of fatty liver, appears to be an adaptive response to hypoglycemia. Our study reveals that the absence of Bis has considerable influences on postnatal growth and survival, possibly due to a nutritional impairment.
Balance of Increases and Decreases in Firing Rate of the Spontaneous Activity of Basal Ganglia High-Frequency Discharge Neurons
Authors: Elias Shlomo , Ritov Ya'acov , Bergman Hagai
Published: October 2008

Most neurons in the external and internal segments of the globus pallidus and the substantia nigra pars reticulata (GPe, GPi, and SNr) are characterized by a high-frequency discharge (HFD) rate (50–80 Hz) that, in most GPe neurons, is also interrupted by pauses. Almost all (∼90%) of the synaptic inputs to these HFD neurons are GABAergic and inhibitory. Nevertheless, their responses to behavioral events are usually dominated by increases in discharge rate. Additionally, there are no reports of prolonged bursts in the spontaneous activity of these cells that could reflect their disinhibition by GPe pauses. We recorded the spontaneous activity of 385 GPe, GPi, and SNr HFD neurons during a quiet-wakeful state from two monkeys. We developed three complementary methods to quantify the balance of increases and decreases in the spontaneous discharge of HFD neurons and validated them by simulations. Unlike the behavioral evoked responses, the spontaneous activity of pallidal and SNr neurons is not dominated by increases. Moreover, the activity of basal ganglia neurons does not include bursts that could reflect disinhibition by the spontaneous pauses of GPe neurons. These findings suggest that the discharge increase/decrease balance during a quiet-wakeful state better reflects the inhibitory input of the HFD basal ganglia neurons than during responses to behavioral events; however, the GPe pauses are not echoed by comparable bursts either in the GPe or in the output nuclei. Changes in the excitatory drive of these structures (e.g., during behavioral activity) thus may lead to a remarkable change in this balance.
Synthesis of High‐Thermal Stable Titanium Dioxide Nanoparticles
Authors: Rashidzadeh M.
Published: October 2008

Nanosized crystals of anatase phase TiO2 with high‐thermal stability was synthesized in the range of 15–17 nm via sol‐gel method using titanium n‐butoxide precursor. Synthesize was done at two different temperatures, that is, 200 and 300∘C and the final products were calcined at 400∘C. The final products were characterized by N2 adsorption, X‐ray diffraction, FT‐IR, and TEM and tested in a photoreactor using fluorescien as model molecule. For thermal stability investigation, the sample prepared at 300∘C was heated up to 800, 850, and 900∘C, the XRD results showed that the synthesized anatase phase was stable up to 850∘C. Photocatalytic activity of the prepared samples showed that the fluorescien degradation followed a pseudo‐first‐order kinetic.
Characterisation of Exponential Convergence to Nonequilibrium Limits for Stochastic Volterra Equations
Authors: Appleby John A. D. , Devin Siobhán , Reynolds David W.
Published: October 2008

This paper considers necessary and sufficient conditions for the solution
of a stochastically and deterministically perturbed Volterra equation to
converge exponentially to a nonequilibrium and nontrivial limit. Convergence
in an almost sure and pth mean sense is obtained.
Travelling Wave Solutions for the KdV‐Burgers‐Kuramoto and Nonlinear Schrödinger Equations Which Describe Pseudospherical Surfaces
Authors: Sayed S. M. , Elhamahmy O. O. , Gharib G. M.
Published: October 2008

We use the geometric notion of a differential system describing surfaces of a constant negative curvature and describe a family of pseudospherical
surfaces for the KdV‐Burgers‐Kuramoto and nonlinear Schrödinger equations with constant Gaussian curvature −1. Travelling wave solutions for the above equations are obtained by using a sech‐tanh method and Wu′s elimination method.
Using Mammographic Density to Improve Breast Cancer Screening Outcomes
Authors: Kavanagh Anne M. , Byrnes Graham B. , Nickson Carolyn , Cawson Jennifer N. , Giles Graham G. , Hopper John L. , Gertig Dorota M. , English Dallas R.
Published: October 2008

It is possible that the performance of mammographic screening would be improved if it is targeted at women at higher risk of breast cancer or who are more likely to have their cancer missed at screening, through more intensive screening or alternative screening modalities. We conducted a case-control study within a population-based Australian mammographic screening program (1,706 invasive breast cancers and 5,637 randomly selected controls). We used logistic regression to examine the effects of breast density, age, and hormone therapy use, all known to influence both breast cancer risk and the sensitivity of mammographic screening, on the risk of small (≤15 mm) and large (>15 mm) screen-detected and interval breast cancers. The risk of small screen-detected cancers was not associated with density, but the risk of large screen-detected cancers was nearly 3-fold for the second quintile and approximately 4-fold for the four highest density categories (third and fourth quintiles and the two highest deciles) compared with the lowest quintile. The risk of interval cancers increased monotonically across the density categories [highest decile odds ratio (OR), 4.65; 95% confidence interval (95% CI), 2.96-7.31]. The risk of small and large screen-detected cancers, but not interval cancers, increased with age. After adjusting for age and density, hormone therapy use was associated with a moderately elevated risk of interval cancers (OR, 1.43; 95% CI, 1.12-1.81). The effectiveness of the screening program could be improved if density were to be used to identify women most likely to have poor screening outcomes. There would be little additional benefit in targeting screening based on age and hormone therapy use. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2818–24)
Cyclin D1 Pro241Pro (CCND1-G870A) Polymorphism Is Associated with Increased Cancer Risk in Human Populations: A Meta-Analysis
Authors: Pabalan Noel , Bapat Bharati , Sung Lillian , Jarjanazi Hamdi , Francisco-Pabalan Ofelia , Ozcelik Hilmi
Published: October 2008

The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P ≤ 0.0001], Caucasians (OR, 1.16; 95% CI, 1.07-1.26; P = 0.0002), and Asians (OR, 1.26; 95% CI, 1.14-1.39; P ≤ 0.001). Among the nine cancer subtypes investigated, modestly significant risk (ORs, 1.08 to 1.51; P = 0.02 to 0.04) was detected in breast, colorectal, head and neck, and other cancers. Highly significant and increased risk was found to be associated with genitourinary (OR, 1.51; 95% CI, 1.20-1.89; P = 0.0004) and blood-related cancers (OR, 1.62; 95% CI, 1.28-2.05; P ≤ 0.0001). Individuals who are heterozygous for AG were found to be at increased risk in overall, ethnic groups, as well as breast and colorectal cancers. Significant dominant effects seem to prevail in the majority of the categories investigated, where some recessive effects were also detected. Overall, the risk effects associated with this polymorphism were small; however, due its common occurrence, it affects a large portion of the human population (AA, 25%; AG, 50%). Although the independent small risk associated with CCND1-A870G polymorphism is not clinically useful, its interaction with other genetic variants and environmental factors has been shown to be associated with further increase in cancer risk (OR, 1.6-7.1). In conclusion, our study strongly supports the increased cancer risk associated with CCND1-A870G polymorphism in the human population. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2773–81)
Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer
Authors: Brait Mariana , Begum Shahnaz , Carvalho André L. , Dasgupta Santanu , Vettore André L. , Czerniak Bogdan , Caballero Otávia L. , Westra William H. , Sidransky David , Hoque Mohammad Obaidul
Published: October 2008

Purpose: The aims of our study were to elucidate the role of methylation of a large panel of genes during multistage pathogenesis of bladder cancer and to correlate our findings with patient age and other clinicopathologic features.

Experimental Design: We studied the methylation status of 21 genes by quantitative methylation-specific PCR in an evaluation set of 25 tumor and 5 normal samples. Based on methylation frequency in tumors and normals in gene evaluation set, we selected 7 candidate genes and tested an independent set of 93 tumors and 26 normals. The presence or absence of methylation was evaluated for an association with cancer using cross-tabulations and χ2 or Fisher's exact tests as appropriate. All statistical tests were two-sided.

Results: Most primary tumors (89 of 93, 96%) had methylation of one or more genes of independent set; 53 (57%) CCNA1, 29 (31%) MINT1, 36 (39%) CRBP, 53 (57%) CCND2, 66 (71%) PGP9.5, 60 (65%) CALCA, and 78 (84%) AIM1. Normal uroepithelium samples from 26 controls revealed no methylation of the CCNA1 and MINT1 genes, whereas methylation of CRBP, CCND2, PGP9.5, and CALCA was detected at low levels. All the 7 genes in independent set were tightly correlated with each other and 3 of these genes showed increased methylation frequencies in bladder cancer with increasing age. PGP9.5 and AIM1 methylation correlated with primary tumor invasion.

Conclusion: Our results indicate that the methylation profile of novel genes in bladder cancers correlates with clinicopathologic features of poor prognosis and is an age-related phenomenon. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2786–94)
Congenital Abnormalities and Acute Leukemia among Children with Down Syndrome: A Children's Oncology Group Study
Authors: Linabery Amy M. , Blair Cindy K. , Gamis Alan S. , Olshan Andrew F. , Heerema Nyla A. , Ross Julie A.
Published: October 2008

Children with Down syndrome, due to their heightened risk of leukemia and increased prevalence of congenital abnormalities, comprise a valuable population in which to study etiology. A Children's Oncology Group study investigated the causes of childhood leukemia in children with Down syndrome diagnosed at ages 0 to 19 years during the period 1997-2002. Telephone interviews were completed with mothers of 158 cases [n = 97 acute lymphoblastic leukemia (ALL) and n = 61 acute myeloid leukemia (AML)] and 173 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed via unconditional logistic regression to evaluate the association between congenital abnormalities and acute leukemia overall, and ALL and AML analyzed separately. The results do not provide evidence for an association among the index children (ORCombined, 0.74; 95% CI, 0.45-1.23; ORALL, 0.67; 95% CI, 0.38-1.20; ORAML,1.03; 95% CI, 0.49-2.16) or their siblings (ORCombined, 1.23; 95% CI, 0.71-2.13; ORALL, 1.12; 95% CI, 0.60-2.09; ORAML, 1.60; 95% CI, 0.66-3.86), suggesting congenital malformations do not confer additional risk of leukemia beyond the risk attributable to trisomy 21 in this population. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2572–7)
Human Papillomavirus mRNA and p16 Detection as Biomarkers for the Improved Diagnosis of Cervical Neoplasia
Authors: Cuschieri Kate , Wentzensen Nicolas
Published: October 2008

Human papillomavirus (HPV) infection of the genital tract is very common and normally follows a benign clinical course; however, in an unfortunate minority of infected individuals, it can cause disease that sometimes leads to cancer. It is accepted that HPV DNA testing has a role in the management of cervical disease both in a prevaccination and postvaccination era; however, to improve the specificity of this approach, there is a requirement to develop and validate tools/assays that can identify women at risk for progressive disease. There is evidence to suggest that detection of viral gene expression both directly and indirectly may constitute a more specific approach for delineating clinically significant infection compared with HPV DNA–based assays. HPV oncogene expression and evidence of its deregulation can be monitored through direct detection of viral mRNA transcripts or through detection of the cellular protein p16. For both approaches, commercial assays have been introduced and numerous studies have been conducted. The present article describes the scientific theory underpinning these approaches, their amenability to routine-diagnostic specimens/settings, and the clinical data that has been garnered through their application thus far. Currently, there is promising data indicating that HPV mRNA and p16 might play an important role in future cervical cancer screening scenarios. Still, large randomized studies are necessary to confirm the preliminary data.

Methods: PubMed and OVID were interrogated with search terms “HPV RNA;” “HPV mRNA;” “HPV transcript—detection, testing, and methods;” “p16” AND “cervical cancer;” “p16” AND “CIN;” “p16” AND “histology”; “p16” AND “cytology;” “p16;” and “screening.” (Cancer Epidemiol Biomarkers Prev 2008;17(10):2536–45)
Micronuclei Related toAnti–B[a]PDE-DNA Adduct in Peripheral Blood Lymphocytes of Heavily Polycyclic Aromatic Hydrocarbon–Exposed Nonsmoking Coke-Oven Workers and Controls
Authors: Pavanello Sofia , Kapka Lucyna , Siwinska Ewa , Mielzyñska Danuta , Bolognesi Claudia , Clonfero Erminio
Published: October 2008

Micronuclei (MN) frequency associated to biologically effective dose of polycyclic aromatic hydrocarbons [PAH; anti-benzo[a]pyrene diolepoxide (B[a]PDE)-DNA] within the same subjects' peripheral blood lymphocytes (PBL) was evaluated. Study subjects were nonsmoking male Polish coke-oven workers (n = 49) and matched controls (n = 45) verified for PAH exposure by urinary 1-pyrenol. We found that coke-oven workers, heavily exposed to PAHs (80% workers exceeded the urinary 1-pyrenol biological exposure index value), presented significantly higher MN frequency in PBLs than controls (P < 0.01). Substantial difference was also found for adduct levels in PBLs (P < 0.01). Increase in MN levels was significantly related to anti–B[a]PDE-DNA formation, key adduct of the ultimate carcinogenic metabolite of B[a]P (n = 94; r = 0.47; P < 0.001). The dose-response relationship was improved when subjects with adduct levels above the 3rd tertile (≥4.35 adducts/108 nucleotides) were excluded (n = 61; r = 0.69; P < 0.001). Saturation of adduct/MN formation at high levels may disturb the underlying relationship. Linear multiple regression analysis, without subjects of 3rd tertile adduct level (n = 61), revealed that adduct formation (t = 4.61; P < 0.001), but not 1-pyrenol, was the significant determinant in increasing MN. In conclusion, the increase in MN frequency is mainly related to the specific anti–B[a]PDE-DNA formation within PBLs of the same subject. Our results substantiate, with the use of an early indicator of biological effect as well, that workers are at higher cancer risk than controls.(Cancer Epidemiol Biomarkers Prev 2008;17(10):2795–9)
5-Lipoxygenase and 5-Lipoxygenase-Activating Protein Gene Polymorphisms, Dietary Linoleic Acid, and Risk for Breast Cancer
Authors: Wang Jun , John Esther M. , Ingles Sue Ann
Published: October 2008

The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, −4900 A>G (rs4076128), and −3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, −1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP −4900 A>G polymorphism and dietary linoleic acid intake (P = 0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming ≤17.4 g/d of linoleic acid, ALOX5AP −4900 genotype was not associated with breast cancer risk (age- and race-adjusted odds ratio, 0.9; 95% confidence interval, 0.7-1.2). These results support a role for n-6 polyunsaturated fatty acids in breast carcinogenesis and suggest that epidemiologic studies on dietary fat and breast cancer should take into account genetic predisposition related to n-6 polyunsaturated fatty acid metabolism. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2748–54)
Physical Activity and Pancreatic Cancer Risk: A Systematic Review
Authors: Bao Ying , Michaud Dominique S.
Published: October 2008

Background: Physical activity has been associated with a lower risk for pancreatic cancer in several studies, but the overall epidemiologic evidence is not consistent. We therefore did a systematic review to evaluate the association between physical activity and pancreatic cancer risk.

Methods: We searched MEDLINE and EMBASE through April 2008 and examined the reference lists of the retrieved articles. We excluded studies that relied on job titles as surrogate measures for physical activity. We used a random-effects model to pool study-specific risk estimates comparing the highest versus the lowest category of physical activity.

Results: Total physical activity (occupational and leisure time) was not significantly associated with risk for pancreatic cancer [4 prospective studies; summary relative risk, 0.76, 95% confidence interval (95% CI), 0.53-1.09]. A decreased risk for pancreatic cancer was observed for occupational physical activity (3 prospective studies; relative risk, 0.75; 95% CI, 0.58-0.96) but not for leisure-time physical activity (14 prospective studies; relative risk, 0.94; 95% CI, 0.83-1.05). No association was found with light physical activity (2 prospective studies; relative risk, 1.01; 95% CI, 0.77-1.34), moderate physical activity (6 prospective studies; relative risk, 0.83; 95% CI, 0.58-1.18), or vigorous physical activity (7 prospective studies; relative risk, 0.94; 95% CI, 0.80-1.12).

Conclusions: This systematic review does not provide strong evidence for an association between physical activity and risk for pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2671–82)
PTPRJ Haplotypes and Colorectal Cancer Risk
Authors: Toland Amanda E. , Rozek Laura S. , Presswala Shafaq , Rennert Gad , Gruber Stephen B.
Published: October 2008

Recent studies from mouse mapping studies for cancer susceptibility have successfully led to the identification of a handful of susceptibility genes. Ptprj was identified as a strong candidate gene for mouse locus susceptibility to colorectal cancer 1, and one variant, rs1566734, showed evidence of preferential allelic imbalance in human colorectal tumors. Haplotypes in human PTPRJ have also been associated with protective effects for breast cancer risk. To determine if variants or haplotype in PTPRJ confer protective or risk effects for colorectal cancer (CRC), we genotyped rs1566734 and six additional PTPRJ haplotype tagging single nucleotide polymorphisms (SNP) in CRC cases and controls from the Molecular Epidemiology of Colorectal Cancer study. There was no evidence for cancer risk with rs1566734 in 1,897 cases and 1,954 controls with a homozygote odds ratio of 1.09 and 95% confidence interval of 0.85 to 1.39. The 6 tagging SNPs resulted in 6 main haplotypes (frequencies, >1%). None of the six tagSNPs individually showed significant evidence for risk; however, rs1503185 showed a nonsignificant protective effect. One haplotype was overrepresented in cases compared with controls, corresponding to a 34% increase in risk CRC, but there was no significant difference overall in haplotype frequencies between cases and controls (global test P statistic = 0.19). From this study, we observe no significant increase in risk for human CRC with variants or haplotypes in PTPRJ. Additional studies are warranted to study possible PTPRJ-interacting loci, which are observed with Scc1 in the mouse models for CRC susceptibility. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2782–5)
Chromogranin A as an Alternative to 5-Hydroxyindoleacetic Acid in the Evaluation of Symptoms during Treatment of Patients with Neuroendocrine Tumors
Authors: Korse Catharina M. , Bonfrer Johannes M.G. , Aaronson Neil K. , Hart Augustinus A.M. , Taal Babs G.
Published: October 2008

Background: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumors (NETs), but it has a low sensitivity and the 24-hour collection is inconvenient for patients. Chromogranin A (CgA) is a promising marker, but a thorough evaluation during follow-up is still lacking. Methods: 39 patients with metastatic gastrointestinal NETs were monitored during treatment with the long-acting octreotide SandostatinLAR®. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. Results: Correlations were found between CgA and physical functioning (p = 0.01) and quality of life (p = 0.03), while no significant correlations were observed between 5-HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p = 0.02), while no significant association was observed between 5-HIAA levels and survival time. Conclusion: Stronger correlations of CgA compared to 5-HIAA with physical functioning and wellbeing, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NETs.
Endopin Serpin Protease Inhibitors Localize with Neuropeptides in Secretory Vesicles and Neuroendocrine Tissues
Authors: Hwang Shin-Rong , Bundey Richard , Toneff Thomas , Hook Vivian
Published: October 2008

Background/Aims: The endopin serpin protease inhibitors have been identified by molecular studies as components of secretory vesicles that produce neuropeptides. Endopin 1 inhibits trypsin-like serine proteases, and endopin 2 inhibits cathepsin L that produces neuropeptides in secretory vesicles. To assess the secretory vesicle and neuroendocrine tissue distribution of these endopins, the goal of this study was to define specific antisera for each endopin isoform and to examine their localization with neuropeptides and in neuroendocrine tissues. Methods: This study utilized methods consisting of Western blots, immunoelectron microscopy, and immunofluorescence microscopy for evaluation of the localization of endopin protease inhibitors in neuroendocrine tissues. Results: Immunoelectron microscopy with these selective antisera demonstrated the localization of endopins 1 and 2 within secretory vesicles of adrenal medulla (bovine). Cellular immunofluorescence confocal microscopy illustrated the high level of colocalization of endopins 1 and 2 with enkephalin and NPY neuropeptides that are present in secretory vesicles of adrenal medullary chromaffin cells in primary culture. Tissue distribution studies (by Western blots) showed the expression of endopins 1 and 2 in bovine brain, pituitary, adrenal medulla, and other neuroendocrine tissues. Conclusions: These results implicate endopins 1 and 2 as endogenous protease inhibitors in neuropeptide-containing secretory vesicles and neuroendocrine tissues.
Mycobacterium tuberculosis Effects on Fibroblast Collagen Metabolism
Authors: González-Avila Georgina , Sandoval Cuauhtemoc , Herrera M. Teresa , Ruiz Victor , Sommer Bettina , Sada Eduardo , Ramos Carlos , Sarabia M. Carmen
Published: October 2008

Background: Type I collagen synthesis and degradation are important events during Mycobacterium tuberculosis (MTb) granuloma or cavity formation, and fibroblasts are cells involved in these processes. Objective: We examined the MTb effects on fibroblast collagen metabolism to understand the virulence factors involved in tuberculosis pathogenesis. Methods: Human lung fibroblasts were incubated with culture medium or sonicated MTb H37Ra (avirulent) or H37Rv (virulent) strains. The effects on collagen synthesis, fibroblast proliferation and collagenase activity were examined. Matrix metalloproteinase-1 (MMP-1), MMP-13 and tissue inhibitors of metalloproteinases (TIMP-1) mRNA levels were analyzed by quantitative real-time PCR amplification. Protein expression was explored by Western blot technique. Results: Collagen synthesis and fibroblast proliferation were significantly increased by H37Ra medium. In contrast, cells incubated with H37Rv medium showed an increase in collagenase activity. MMPs quantitative real-time PCR amplification revealed an increase on MMP-13 mRNA levels in fibroblasts cultured with H37Rv medium, with little effect observed on MMP-1 expression. Western blot assay demonstrated that H37Rv medium stimulated MMP-1 and MMP-13 proenzyme synthesis. This medium had a large effect on MMP-1 activation. TIMP-1 transcription was increased in cells incubated with medium and sonicated from H37Ra, although the highest TIMP-1 protein expression was found in fibroblasts cultured with sonicated H37Rv. Conclusions: These results suggest that MTb had direct effects on fibroblast collagen turnover, with differences in collagen synthesis and degradation depending on the strain.
End-of-Life Decision-Making and Terminal Sedation among Very Old Patients
Authors: De Gendt Cindy , Bilsen Johan , Mortier Freddy , Vander Stichele Robert , Deliens Luc
Published: October 2008

Background: About half of the persons who die in developed countries are very old (aged 80 years or older) and this proportion is still rising. In general, there is little information available concerning the circumstances and quality of the end of life of this group. Objective: This study aims (1) to describe the incidence and characteristics of medical end-of-life decisions with a possible or certain life-shortening effect (ELDs) and terminal sedation among very old patients who died nonsuddenly, (2) to describe the characteristics of the preceding decision-making process, and (3) to compare this with the deaths of younger patients. Methods: A sample of 5,005 death certificates was selected from all deaths in Flanders (Belgium) in the second half of 2001 (before euthanasia was legalized). Questionnaires were mailed to the certifying physicians. Results: Response rate was 58.9%. An ELD was made for 53.6% very old (aged 80+) patients who died nonsuddenly (vs. 63.3% for the younger patients). Use of life-ending drugs occurred among 1.1% (six times less frequently than in younger patients), with no euthanasia cases, pain and symptom alleviation with a possible life-shortening effect among 27.3% (two times less frequently), and withholding or withdrawing life-prolonging treatments among 25.2% (slightly more frequently). Terminal sedation occurred among 6.9% of the cases, two times less frequently than for the younger patients. ELDs were not often discussed with very old patients. Among competent patients this was less than compared with younger patients. Conclusion: ELDs are less common for very old than for younger patients. Physicians seem to have a more reluctant attitude towards the use of lethal drugs, terminal sedation and participation in decision-making when dealing with very old patients. Advance care planning should increase the involvement of very old competent and noncompetent patients in end-of-life decision-making.
Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication
Authors: Chasman Daniel I. , Paré Guillaume , Zee Robert Y.L. , Parker Alex N. , Cook Nancy R. , Buring Julie E. , Kwiatkowski David J. , Rose Lynda M. , Smith Joshua D. , Williams Paul T. , Rieder Mark J. , Rotter Jerome I. , Nickerson Deborah A. , Krauss Ronald M. , Miletich Joseph P. , Ridker Paul M
Published: October 2008

Background—

Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods and Results—

We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (Apo) A1, and ApoB. Genome-wide associations (
P
<5�10
−8
) were found at the
PCSK9
gene, the
APOB
gene, the
LPL
gene, the
APOA1-APOA5
locus, the
LIPC
gene, the
CETP
gene, the
LDLR
gene, and the
APOE
locus. In addition, genome-wide associations with triglycerides at the
GCKR
gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the
SORT1
gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.

Conclusion—

Genome-wide associations at the
GCKR
gene and near the
SORT1
gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.
Determinants of U.S. Exports to China
Authors: Bosworth Barry , Collins Susan M.
Published: October 2008

This paper examines U.S. goods trade with China, focusing on the performance of exports. Throughout the analysis, we explore whether U.S. trade is unusual by contrasting it with trade from Japan and the EU-15.1 The issue is examined from three perspectives: the commodity composition of exports, the role of multinational corporations (MNCs), and the determinants of trade as specified in a formal “gravity model.” As an initial point of departure, we show that the commodity composition of U.S. exports to China is similar to the pattern of exports to the world as a whole, and that the operations of U.S. MNCs have only minor implications for trade with China. Consequently, we emphasize the estimation of a set of “gravity equations” that explore the role of market size and distance from the United States. Distance exerts a surprisingly large effect on trade. Finally, although exports to China may be a small share of U.S. GDP, they are relatively substantial compared to U.S. exports to other countries. In other words, the measure of U.S. trade performance in China is distorted by the low level of its exports to all countries. We present evidence that the United States underperforms as an exporter relative to a peer group of high-income European countries and Japan.
Evidence for Morphoprosodic Alignment in Reduplication
Authors: Kennedy Robert
Published: October 2008

Morphoprosodic Alignment (MPA) is a nontemplatic model of reduplication designed to account for languages with multiple reduplicative subpatterns. The premise of MPA is that reduplicative morphemes can be stem-internal or stem-external and that this distinction is visible to the phonological component through general constraints on the association of stem-internal and stem-external morphemes to prosodic categories. I illustrate the model with Moronene, Klamath, and Gooniyandi, each of which has several reduplicative morphemes. MPA meets the challenge for an optimality-theoretic model to account for such systems without resorting to morpheme-specific indexed constraints or cophonological constraint hierarchies.
Evaluations of BDA Scheme Using the Advanced Research WRF (ARW) Model
Authors: Xiao Qingnong , Chen Liqiang , Zhang Xiaoyan
Published: October 2008

A tropical cyclone bogus data assimilation (BDA) scheme is built in the Weather Research and Forecasting three-dimensional variational data assimilation system (WRF 3D-VAR). Experiments were conducted (21 experiments with BDA in parallel with another 21 without BDA) to assess its impacts on the predictions of seven Atlantic Ocean basin hurricanes observed in 2004 (Charley, Frances, Ivan, and Jeanne) and in 2005 (Katrina, Rita, and Wilma). In addition, its performance was compared with the Geophysical Fluid Dynamics Laboratory (GFDL) hurricane initialization scheme in a case study of Hurricane Humberto (2007). It is indicated that hurricane initialization with the BDA technique can improve the forecast skills of track and intensity in the Advanced Research WRF (ARW). Among the three hurricane verification parameters [track, central sea level pressure (CSLP), and maximum surface wind (MSW)], BDA improves CSLP the most. The improvement of MSW is also considerable. The track has the smallest, but still noticeable, improvement. With WRF 3D-VAR, the initial vortex produced by BDA is balanced with the dynamical and statistical balance in the 3D-VAR system. It has great potential for improving the hurricane intensity forecast. The case study on Hurricane Humberto (2007) shows that BDA performs better than the GFDL bogus scheme in the ARW forecast for the case. Better definition of the initial vortex is the main reason for the advanced skill in hurricane track and intensity forecasting in this case.
Sodium-Lithium Countertransport Activity in Healthy, Dyslipidemic, and Hypertensive Individuals
Authors: Savopoulos Christos G. , Hatzitolios Apostolos I. , Katsiki Niki A. , Baltatzi Maria , Kosmidou Maria , Raikos Nikolaos , Mikhailidis Dimitri P. , Ziakas Antonios G. , Kaiafa Georgia , Tsesmeli Niki
Published: October 2008

The aim of our study was to investigate the role of dyslipidemia on red blood cell sodium-lithium countertransport activity in healthy and hypertensive individuals. A total of 128 Caucasian individuals, aged 20 to 60 years old, were divided into 4 groups: dyslipidemic/ hypertensive, dyslipidemic/normotensive, normolipidemic/hypertensive, and normolipidemic/ normotensive (controls). Sodiumlithium countertransport activity was determined based on the Canessa et al method. Sodium-lithium countertransport activity was significantly higher in all patient groups compared with controls ( P < .001) and similar in the 3 patient groups. Sodium-lithium countertransport activity was significantly and positively associated with triglyceride levels ( P < .001), body mass index ( P < .001), total cholesterol levels ( P = .001), and systolic ( P = .001) and diastolic blood pressure ( P = .001). In multivariate regression analysis, triglycerides made the largest contribution to sodiumlithium countertransport variation among the variables tested ( R 2 = 0.273). Our results suggest that dyslipidemia affects sodium-lithium countertransport activity independently of essential hypertension and even to a greater extent than hypertension.