bluuebunny/crossref_metadata_2025 huggingface dataset:
A Simulation Model to Predict the Impact of Prophylactic Surgery and Screening on the Life Expectancy of BRCA1 and BRCA2 Mutation Carriers
Authors: Sigal Bronislava M. , Munoz Diego F. , Kurian Allison W. , Plevritis Sylvia K.
Published: July 2012

Background: Women with inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes are recommended to undergo a number of intensive cancer risk-reducing strategies, including prophylactic mastectomy, prophylactic oophorectomy, and screening. We estimate the impact of different risk-reducing options at various ages on life expectancy.

Methods: We apply our previously developed Monte Carlo simulation model of screening and prophylactic surgery in BRCA1/2 mutation carriers. Here, we present the mathematical formulation to compute age-specific breast cancer incidence in the absence of prophylactic oophorectomy, which is an input to the simulation model, and provide sensitivity analysis on related model parameters.

Results: The greatest gains in life expectancy result from conducting prophylactic mastectomy and prophylactic oophorectomy immediately after BRCA1/2 mutation testing; these gains vary with age at testing, from 6.8 to 10.3 years for BRCA1 and 3.4 to 4.4 years for BRCA2 mutation carriers. Life expectancy gains from delaying prophylactic surgery by 5 to 10 years range from 1 to 9.9 years for BRCA1 and 0.5 to 4.2 years for BRCA2 mutation carriers. Adding annual breast screening provides gains of 2.0 to 9.9 years for BRCA1 and 1.5 to 4.3 years for BRCA2. Results were most sensitive to variations in our assumptions about the magnitude and duration of breast cancer risk reduction due to prophylactic oophorectomy.

Conclusions: Life expectancy gains depend on the type of BRCA mutation and age at interventions. Sensitivity analysis identifies the degree of breast cancer risk reduction due to prophylactic oophorectomy as a key determinant of life expectancy gain.

Impact: Further study of the impact of prophylactic oophorectomy on breast cancer risk in BRCA1/2 mutation carriers is warranted. Cancer Epidemiol Biomarkers Prev; 21(7); 1066–77. ©2012 AACR.
Parental Age, Family Size, and Offspring's Risk of Childhood and Adult Acute Leukemia
Authors: Larfors Gunnar , Hallböök Helene , Simonsson Bengt
Published: July 2012

Background: An association between childhood acute leukemia and advanced parental age was observed more than 50 years ago, and the association has been repeated in several, but not all, subsequent studies. In contrast to the many studies addressing childhood leukemia, few have included adult patients.

Methods: In this register-based case–control study, we examined the association between parental age and incidence of acute leukemia in 2,660 childhood cases and 4,412 adult cases of acute leukemia, compared with 28,288 age-matched controls selected from a population-based register. Relative risks were estimated with conditional logistic regression.

Results: We found a small increased risk of childhood acute lymphoblastic leukemia with increasing paternal age (adjusted OR, 1.05 per 5-year increase in age). Risk estimates were similar for childhood acute myeloid leukemia (AML), whereas no association was found with adult leukemia. Meanwhile, we observed a decreased risk of adult AML with increasing number of siblings, both older and younger.

Conclusions: The results support the idea of a prenatal etiology of leukemia but indicate that parental age effects are limited to childhood cases.

Impact: This is the first large study on parental age and leukemia risk, which includes adult cases. The finding on family size and risk of adult AML needs to be validated in future studies. Cancer Epidemiol Biomarkers Prev; 21(7); 1185–90. ©2012 AACR.
Reproducibility of the Nicotine Metabolite Ratio in Cigarette Smokers
Authors: St.Helen Gideon , Novalen Maria , Heitjan Daniel F. , Dempsey Delia , Jacob Peyton , Aziziyeh Adel , Wing Victoria C. , George Tony P. , Tyndale Rachel F. , Benowitz Neal L.
Published: July 2012

Background: The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (i) the stability of NMR in plasma, saliva, and blood in various storage conditions, (ii) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (iii) the reproducibility of plasma NMR in ad libitum cigarette smokers.

Methods: We analyzed data from four clinical studies. In studies 1 and 2, we assessed NMR stability in saliva and plasma samples at room temperature (∼22°C) over 14 days and in blood at 4°C for up to 72 hours. In studies 2 and 3, we used Bland–Altman analysis to assess agreement between blood, plasma, saliva, and urine NMRs. In study 4, plasma NMR was measured on six occasions over 44 weeks in 43 ad libitum smokers.

Results: Reliability coefficients for stability tests of NMR in plasma and saliva at room temperature were 0.97 and 0.98, respectively, and 0.92 for blood at 4°C. Blood NMR agreed consistently with saliva and plasma NMRs but showed more variability in relation to urine NMR. The reliability coefficient for repeated plasma NMR measurements in smokers was 0.85.

Conclusion: The NMR is stable in blood, plasma, and saliva at the conditions tested. Blood, plasma, and saliva NMRs are similar whereas urine NMR is a good proxy for these NMR measures. Plasma NMR was reproducible over time in smokers.

Impact: One measurement may reliably estimate a smoker's NMR for use as an estimate of the rate of nicotine metabolism. Cancer Epidemiol Biomarkers Prev; 21(7); 1105–14. ©2012 AACR.
Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer
Authors: Hvidtfeldt Ulla A. , Gunter Marc J. , Lange Theis , Chlebowski Rowan T. , Lane Dorothy , Farhat Ghada N. , Freiberg Matthew S. , Keiding Niels , Lee Jennifer S. , Prentice Ross , Tjønneland Anne , Vitolins Mara Z. , Wassertheil-Smoller Silvia , Strickler Howard D. , Rod Naja H.
Published: July 2012

Background: Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.

Methods: We combined data from two case–cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.

Results: A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2–76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9–68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6–273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8–161.1) for BMI when restricted to estrogen receptor positive (ER+) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8–284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER+ breast cancers.

Conclusions: The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.

Impact: The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk. Cancer Epidemiol Biomarkers Prev; 21(7); 1203–12. ©2012 AACR.
Use of Lung Cancer Screening Tests in the United States: Results from the 2010 National Health Interview Survey
Authors: Doria-Rose V. Paul , White Mary C. , Klabunde Carrie N. , Nadel Marion R. , Richards Thomas B. , McNeel Timothy S. , Rodriguez Juan L. , Marcus Pamela M.
Published: July 2012

Background: Before evidence of efficacy, lung cancer screening was being ordered by many physicians. The National Lung Screening Trial (NLST), which showed a 20% reduction in lung cancer mortality among those randomized to receive low-dose computed tomography (LDCT), will likely lead to increased screening use.

Methods: We estimated the prevalence of chest X-ray and CT use in the United States using data from the 2010 National Health Interview Survey (NHIS). Subjects included 15,537 NHIS respondents aged ≥40 years without prior diagnosis of lung cancer. Estimates of the size of the U. S. population by age and smoking status were calculated. Multivariate logistic regression examined predictors of test use adjusting for potential confounders.

Results: Twenty-three percent of adults reported chest X-ray in the previous year and 2.5% reported chest X-ray specifically to check for lung cancer; corresponding numbers for chest CT were 7.5% and 1.3%. Older age, black race, male gender, smoking, respiratory disease, personal history of cancer, and having health insurance were associated with test use. Approximately, 8.7 million adults in the United States would be eligible for LDCT screening according to NLST eligibility criteria.

Conclusions and Impact: Monitoring of trends in the use of lung screening tests will be vital to assess the impact of NLST and possible changes in lung cancer screening recommendations and insurance coverage in the future. Education of patients by their physicians, and of the general public, may help ensure that screening is used appropriately, in those most likely to benefit. Cancer Epidemiol Biomarkers Prev; 21(7); 1049–59. ©2012 AACR.
Frontiers in Cancer Epidemiology: A Challenge to the Research Community from the Epidemiology and Genomics Research Program at the National Cancer Institute
Authors: Khoury Muin J. , Freedman Andrew N. , Gillanders Elizabeth M. , Harvey Chinonye E. , Kaefer Christie , Reid Britt C. , Rogers Scott , Schully Sheri D. , Seminara Daniela , Verma Mukesh
Published: July 2012

The Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI) is developing scientific priorities for cancer epidemiology research in the next decade. We would like to engage the research community and other stakeholders in a planning effort that will include a workshop in December 2012 to help shape new foci for cancer epidemiology research. To facilitate the process of defining the future of cancer epidemiology, we invite the research community to join in an ongoing web-based conversation at http://blog-epi.grants.cancer.gov/ to develop priorities and the next generation of high-impact studies. Cancer Epidemiol Biomarkers Prev; 21(7); 999–1001. ©2012 AACR.
A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer
Authors: Rosen Lee S. , Hurwitz Herbert I. , Wong Michael K. , Goldman Jonathan , Mendelson David S. , Figg William D. , Spencer Shawn , Adams Bonne J. , Alvarez Delia , Seon Ben K. , Theuer Charles P. , Leigh Bryan R. , Gordon Michael S.
Published: July 2012

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors.

Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.

Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months.

Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820–9. ©2012 AACR.
Phase I Study of Aurora A Kinase Inhibitor MLN8237 in Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics, and Bioavailability of Two Oral Formulations
Authors: Dees E. Claire , Cohen Roger B. , von Mehren Margaret , Stinchcombe Thomas E. , Liu Hua , Venkatakrishnan Karthik , Manfredi Mark , Fingert Howard , Burris Howard A. , Infante Jeffrey R.
Published: July 2012

Purpose: This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors.

Experimental Design: Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed.

Results: Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5–150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months.

Conclusions: This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies. Clin Cancer Res; 18(17); 4775–84. ©2012 AACR.
Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors
Authors: Leijen Suzanne , Middleton Mark R. , Tresca Patricia , Kraeber-Bodéré Françoise , Dieras Veronique , Scheulen Max E. , Gupta Avinash , Lopez-Valverde Vanesa , Xu Zhi-Xin , Rueger Ruediger , Tessier Jean J.L. , Shochat Eliezer , Blotner Steve , Naegelen Valerie Meresse , Schellens Jan H.M. , Eberhardt Wilfried Ernst Erich
Published: July 2012

Purpose: This phase I study of the mitogen-activated protein/extracellular signal–regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors.

Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule.

Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal–regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15.

Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794–805. ©2012 AACR.
Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer
Authors: Adams Sylvia , Kozhaya Lina , Martiniuk Frank , Meng Tze-Chiang , Chiriboga Luis , Liebes Leonard , Hochman Tsivia , Shuman Nicholas , Axelrod Deborah , Speyer James , Novik Yelena , Tiersten Amy , Goldberg Judith D. , Formenti Silvia C. , Bhardwaj Nina , Unutmaz Derya , Demaria Sandra
Published: July 2012

Purpose: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases.

Experimental Design: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives.

Results: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%–56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines.

Conclusion: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses. Clin Cancer Res; 18(24); 6748–57. ©2012 AACR.
Protein Kinase Casein Kinase 2–Mediated Upregulation of N-Cadherin Confers Anoikis Resistance on Esophageal Carcinoma Cells
Authors: Ko Hyeonseok , Kim Seongrak , Jin Cheng-Hao , Lee Eunjung , Ham Sunyoung , Yook Jong In , Kim Kunhong
Published: July 2012

Previously, we reported that high PKCK2 activity could protect cancer cells from death receptor–mediated apoptosis through phosphorylation of procaspase-2. Because anoikis is another form of apoptosis, we asked whether PKCK2 could similarly confer resistance to anoikis on cancer cells. Human esophageal squamous cancer cell lines with high PKCK2 activity (HCE4 and HCE7) were anoikis-resistant, whereas cell lines with low PKCK2 activity (TE2 and TE3) were anoikis-sensitive. Because the cells showed different sensitivity to anoikis, we compared the expression of cell adhesion molecules between anoikis-sensitive TE2 and anoikis-resistant HCE4 cells using cDNA microarray. We found that E-cadherin is expressed only in TE2 cells; whereas N-cadherin is expressed instead of E-cadherin in HCE4 cells. To examine whether PKCK2 activity could determine the type of cadherin expressed, we first increased intracellular PKCK2 activity in TE2 cells by overexpressing the PKCK2α catalytic subunit using lentivirus and found that high PKCK2 activity could switch cadherin expression from type E to N and confer anoikis resistance. Conversely, a decrease in PKCK2 activity in HCE4 cells by knockdown of PKCK2α catalytic subunit using shRNA induced N- to E-cadherin switching and the anoikis-resistant cells became sensitive. In addition, N-cadherin expression correlated with PKB/Akt activation and increased invasiveness. We conclude that high intracellular PKCK2 activity confers anoikis resistance on esophageal cancer cells by inducing E- to N-cadherin switching. Mol Cancer Res; 10(8); 1032–8. ©2012 AACR.
Lack of ABCG2 Shortens Latency of BRCA1-Deficient Mammary Tumors and This Is Not Affected by Genistein or Resveratrol
Authors: Zander Serge A.L. , Kersbergen Ariena , Sol Wendy , Gonggrijp Maaike , van de Wetering Koen , Jonkers Jos , Borst Piet , Rottenberg Sven
Published: July 2012

In addition to their role in drug resistance, the ATP-binding cassette (ABC) transporters ABCG2 and ABCB1 have been suggested to protect cells from a broad range of substances that may foster tumorigenesis. Phytoestrogens or their metabolites are substrates of these transporters and the influence of these compounds on breast cancer development is controversial. Estrogen-like properties might accelerate tumorigenesis on the one hand, whereas their proposed health-protective properties might antagonize tumorigenesis on the other. To address this issue, we used a newer generation mouse model of BRCA1-mutated breast cancer and examined tumor latency in K14cre;Brca1F/F; p53F/F, Abcb1a/b−/−;K14cre;Brca1F/F; p53F/F, or Abcg2−/−;K14cre;Brca1F/F; p53F/F animals, fed with genistein- or resveratrol-supplemented diets. Ovariectomized K14cre;Brca1F/F; p53F/F animals were included to evaluate whether any estrogen-mimicking effects can restore mammary tumor development in the absence of endogenous estrogens. Compared with the ABC transporter proficient model, ABCG2-deficient animals showed a reduced median tumor latency of 17.5 days (P < 0.001), whereas no significant difference was observed for ABCB1-deficient animals. Neither genistein nor resveratrol altered this latency reduction in Abcg2−/−;K14cre;Brca1F/F; p53F/F animals. Ovariectomy resulted in nearly complete loss of mammary tumor development, which was not restored by genistein or resveratrol. Our results show that ABCG2 contributes to the protection of genetically instable epithelial cells against carcinogenesis. Diets containing high levels of genistein or resveratrol had no effect on mammary tumorigenesis, whether mice were lacking ABCG2 or not. Because genistein and resveratrol only delayed skin tumor development of ovariectomized animals, we conclude that these phytoestrogens are no effective modulators of mammary tumor development in our mouse model. Cancer Prev Res; 5(8); 1053–60. ©2012 AACR.
Differential Expression of SLC9A9 and Interacting Molecules in the Hippocampus of Rat Models for Attention Deficit/Hyperactivity Disorder
Authors: Zhang-James Yanli , Middleton Frank A. , Sagvolden Terje , Faraone Stephen V.
Published: July 2012

SLC9A9 [solute carrier family 9, member 9, also known as Na+/H+ exchanger member 9 (NHE9)], has been implicated in human attention deficit/hyperactivity disorder (ADHD), autism, and rat studies of hyperactivity and inattentiveness. SLC9A9 is a membrane protein that regulates the luminal pH of the recycling endosome. We recently reported the interactions of SLC9A9 with two molecules: calcineurin homologous protein (CHP) and receptor for activated C-kinase 1 (RACK1). We also reported two novel SLC9A9 mutations and abnormal gene expression profiles in the brains of an inattentive type rat model of ADHD (WKY/NCrl rat). In this study, we further examined the expression and relationship of SLC9A9 and 9 additional genes (CHP, RACK1, CaM, PPP3R1, PPP1R10, PKCm, CaMKI, NR2B, PLCb1) that may directly or indirectly interact with SLC9A9 in the hippocampus of the WKY/NCrl rat and the spontaneously hypertensive rat (SHR) model of the combined type of ADHD. We found that the expression levels of these genes were significantly correlated, suggesting that they may be coregulated. Principal component analysis identified two main factors that accounted for 94% of the expression variance of the 10 genes. Significant differences were found for both factors across the 3 different rat strains. The two ADHD rat models (WKY/NCrl and SHR), although different from each other in adulthood, showed similar profiles in adolescence. Both models were significantly different from WKY/NHsd control rats at both ages. The expression abnormalities of each gene were evaluated and their roles in cell signaling processes such as calcium signaling and protein phosphorylation are discussed. Our results suggest that abnormalities in SLC9A9-mediated signaling pathways could contribute to the ADHD phenotype of two rat models (WKY/NCrl and SHR/NCrl), and that the perturbation of the SLC9A9 network is age-dependent.
Schizophrenia and Substance Abuse Comorbidity: Nicotine Addiction and the Neonatal Quinpirole Model
Authors: Brown Russell W. , Maple Amanda M. , Perna Marla K. , Sheppard A. Brianna , Cope Zackary A. , Kostrzewa Richard M.
Published: July 2012

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D2/D3 receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D2 receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.
Fetal Presentation of Long QT Syndrome – Evaluation of Prenatal Risk Factors: A Systematic Review
Authors: Ishikawa Satoshi , Yamada Takashi , Kuwata Tomoyuki , Morikawa Mamoru , Yamada Takahiro , Matsubara Shigeki , Minakami Hisanori
Published: July 2012

Objective: This systematic review evaluated the existence of risk factors for the fetal manifestation of long QT syndrome (LQTS). Methods: Prenatal cardiac findings suggestive of fetal LQTS were studied using 30 English literature reports extracted from the Pubmed database (1979 to December 2011) using the search terms ‘long QT syndrome’, ‘fetal arrhythmia’ and ‘congenital heart disease’. Results: LQTS accounted for 15–17% of fetal bradycardias <110 bpm among fetuses with a normally structured heart. Of the patients with significant prenatal findings of LQTS, 17–35% exhibited a reduced baseline fetal heart rate (FHR) of 110–120 bpm on electronic cardiotocography. Other prenatal signs were sinus or intermittent bradycardia <110 bpm arising from atrioventricular block, tachyarrhythmias, pleural effusion and hydrops. More than 30% of Japanese infants with LQTS born at or after the mid-1980s exhibited the above-mentioned in utero signs. Conclusions: Fetal factors including a slightly reduced baseline FHR of 110–120 bpm, bradycardia <110 bpm, tachyarrhythmias or clinical signs of heart failure, such as pleural effusion and hydrops, were associated with a higher frequency of LQTS. The use of these signs may help to increase the perinatal diagnosis of LQTS.
Depressive-Like Behavior in Adolescents after Maternal Separation: Sex Differences, Controllability, and GABA
Authors: Leussis Melanie P. , Freund Nadja , Brenhouse Heather C. , Thompson Britta S. , Andersen Susan L.
Published: July 2012

Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments.
Spontaneous Renal Artery Dissection Diagnosed by Unenhanced Magnetic Resonance Angiography: Case Report
Authors: Casciani Emanuele , Polettini Elisabetta , Masselli Gabriele , Stirati Giovanni , Gualdi Gianfranco
Published: July 2012

A 47-year-old patient is presented who was admitted to the emergency department with complaints of right-sided flank pain and hypertension. His creatinine and glomerular filtration rate were 2.5 mg/dl and 37 ml/min respectively, so that contrast media administration was contraindicated. The unenhanced magnetic resonance angiography image obtained with 3D in-flow inversion recovery sequence showed right renal artery dissection, without aortic dissection. Selective renal angiography confirmed the diagnosis and a stent was placed in the renal artery. The patient was free of pain after stenting, with normalized laboratory values and blood pressure.
Differential Regulation by Toll-Like Receptor Agonists Reveals That MCPIP1 Is the Potent Regulator of Innate Immunity in Bacterial and Viral Infections
Authors: Blazusiak E. , Florczyk D. , Jura J. , Potempa J. , Koziel J.
Published: July 2012

Toll-like receptors (TLRs) are key molecules in innate immunity that recognize a variety of pathogen-associated molecular patterns. Activation of TLRs by their agonists initiates several signaling cascades, which eventually result in the expression of immune modifiers. Despite the fact that MCPIP1 is reported as an important immune regulator involved in macrophage activation, modulation of its expression by all known TLR agonists has never been documented. In this study, we present for the first time that in human monocyte-derived macrophages all TLR agonists, except CpG, markedly induced the expression of MCPIP1. The level of the induced transcript, as well as the protein and time of their appearance varied depending on the agonist. Furthermore, we confirmed the strong and differential upregulation of MCPIP1 during bacteria, virus and fungus infection. MCPIP1 belongs to a group of early-response genes; however, in the present study, we show for the first time the sustained high level of MCPIP1 expression during long-term Staphylococcus aureus infection. Taken together, our results implicate MCPIP1 as a potent regulator of innate immunity, which can be strongly engaged in the pathogenesis of acute and chronic infective diseases.
Association of a Genetic Risk Score With Prevalent and Incident Myocardial Infarction in Subjects Undergoing Coronary Angiography
Authors: Patel Riyaz S. , Sun Yan V. , Hartiala Jaana , Veledar Emir , Su Shaoyong , Sher Salman , Liu Ying X. , Rahman Ayaz , Patel Ronak , Rab S. Tanveer , Vaccarino Viola , Zafari A. Maziar , Samady Habib , Tang W.H. Wilson , Allayee Hooman , Hazen Stanley L. , Quyyumi Arshed A.
Published: July 2012

Background—

Genome-wide association studies have identified multiple variants associating with coronary artery disease (CAD) and myocardial infarction (MI). Whether a combined genetic risk score (GRS) is associated with prevalent and incident MI in high-risk subjects remains to be established.

Methods and Results—

In subjects undergoing cardiac catheterization (n=2597), we identified cases with a history of MI onset at age <70 years and controls ≥70 years without prior MI and followed them for incident MI and death. Genotyping was performed for 11 established CAD/MI variants, and a GRS was calculated based on average number of risk alleles carried at each locus weighted by effect size. Replication of association findings was sought in an independent angiographic cohort (n=2702). The GRS was significantly associated with prevalent MI, occurring before age 70, compared with older controls (≥70 years of age) with no history of MI (
P
<0.001). This association was successfully replicated in a second cohort, yielding a pooled
P
value of <0.001. The GRS modestly improved the area-under–the–curve statistic in models of prevalent MI with traditional risk factors; however, the association was not statistically significant when elderly controls without MI but with s\ angiographic CAD were examined (pooled
P
=0.11). Finally, during a median 2.5-year follow-up, only a nonsignificant trend was noted between the GRS and incident events, which was also not significant in the replication cohort.

Conclusions—

A GRS of 11 CAD/MI variants is associated with prevalent MI but not near-term incident adverse events in 2 independent angiographic cohorts. These findings have implications for understanding the clinical use of genetic risk scores for secondary as opposed to primary risk prediction.
Aging and Atherosclerosis
Authors: Wang Julie C. , Bennett Martin
Published: July 2012

Atherosclerosis is classed as a disease of aging, such that increasing age is an independent risk factor for the development of atherosclerosis. Atherosclerosis is also associated with premature biological aging, as atherosclerotic plaques show evidence of cellular senescence characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction. Not only is cellular senescence associated with atherosclerosis, there is growing evidence that cellular senescence promotes atherosclerosis. This review examines the pathology of normal vascular aging, the evidence for cellular senescence in atherosclerosis, the mechanisms underlying cellular senescence including reactive oxygen species, replication exhaustion and DNA damage, the functional consequences of vascular cell senescence, and the possibility that preventing accelerated cellular senescence is a therapeutic target in atherosclerosis.
Research Radar Analyses of the Internal Boundary Layer over Cape Canaveral, Florida, during the Landfall of Hurricane Frances (2004)
Authors: Hirth Brian D. , Schroeder John L. , Weiss Christopher C. , Smith Douglas A. , Biggerstaff Michael I.
Published: July 2012

The structure of the coastal internal boundary layer (IBL) during a landfalling hurricane has important ramifications on operational forecasting, structural design, and poststorm damage assessment. Despite these important issues, the mean IBL structure at the coastline during landfall is poorly understood. Knowledge of the vertical kinematic structure within tropical cyclones over water has improved greatly through aircraft reconnaissance missions and the advent of GPS dropsondes and stepped frequency microwave radiometers. Unfortunately, reconnaissance and research aircraft are limited to overwater missions, resulting in a poor understanding of vertical kinematic structure near the coastal interface, where changes in IBL structure are expected due to changes in surface roughness. Composite single- and dual-Doppler radar observations collected by the Shared Mobile Atmospheric Research and Teaching Radars during the landfall of Hurricane Frances (2004) are presented. Data analyses from the Cape Canaveral, Florida, region reveal a pronounced IBL throughout the data collection period. As a result, significant variability in the analyzed wind speed and direction are found across and near the coastal interface. IBL height is found to be suppressed when compared to an accepted empirical growth model, while multiple abrupt roughness transitions associated with the Cape Canaveral region contribute to a complex mean IBL structure.
Study on the possibility of increasing the maximum allowable stresses in fibre-reinforced plastics
Authors: Sánchez-Heres LF , Ringsberg JW , Johnson E
Published: July 2012

This article presents the results of a study aimed at investigating the possibility of increasing the maximum allowable stresses in fibre-reinforced plastics compared to current practice. The study consisted of a comparison between the maximum allowable stresses of a group of cross-ply laminates, determined by deterministic analyses with safety and model factors as stated in design rules, and their probabilistic responses estimated with a fracture mechanics based model that accounted for material degradation. The results suggest that for the studied cases, the maximum allowable stresses do not provide the desired reliability; thus, their increase cannot be motivated. More importantly, the investigation shows that a better understanding of the effects of matrix cracks, and therefore, the maximum allowable crack density in a composite laminate, would lead to better and safer composite structures.
Between Vichy France and Fascist Italy: Redefining Identity and the Enemy in Corsica During the Second World War
Authors: Varley Karine
Published: July 2012

This article explores how the fear of annexation by Fascist Italy meant that for Corsica the Second World War became a battle to remain French. Rather than developing a stronger French identity in opposition to Italy, however, conflicting affinities and grievances produced a stronger Corsican identity in opposition to France. Vichy France therefore found itself fighting against long-standing Corsican tensions, Italian territorial ambitions and the demands of Nazi Germany. For Fascist Italy, the struggle for Corsica exposed its inferiority complex towards Vichy France and Nazi Germany, as well as the contradictions of an irredentist foreign policy and a reluctant occupying army.
Comparing Gifted and Nongifted African American and Euro-American Students on Cognitive and Academic Variables Using Local Norms
Authors: Jordan Kelli R. , Bain Sherry K. , McCallum R. Steve , Mee Bell Sherry
Published: July 2012

A total of 47 gifted and nongifted African American and Euro-American elementary students were rated by their teachers on a multidimensional instrument developed to minimize language considerations and to rely on local norms (Universal Multiple Abilities Scales [UMAS; McCallum & Bracken, 2012a]). Results from two factorial MANOVAs revealed no significant composite mean differences between African American and Euro-American students. There was a significant difference in scores based on placement, with gifted students scoring higher on the composite mean from the three general aptitude subscales and the composite mean from the three academic aptitude subscales. There were no interaction effects for Placement × Race. A discriminant function analysis created by the six subscales of the UMAS resulted in 76.70% of participants correctly classified as gifted or nongifted. Results suggest use of multidimensional scales that minimize language and relies on local norms may be useful for identifying gifted students in traditionally underrepresented groups.
Oral Exposure to the Herbicide Simazine Induces Mouse Spleen Immunotoxicity and Immune Cell Apoptosis
Authors: Ren Rui , Sun Dian-Jun , Yan Hai , Wu Yan-Ping , Zhang Yang
Published: July 2012

The authors investigated the toxic effects of simazine on mice spleen immune cells and the underlying mechanisms. Mice were given simazine at 0, 90, 200, or 400 mg/kg by gastric gavage for 3 weeks. The authors then measured immune cell proliferation and the expressions of apoptosis-related proteins (Bcl-2, Bax, Fas, and caspase-3), spleen cell intracellular [Ca2+], cellular oxidative stress level, and immune functions. After 3 weeks, mice exposed to simazine had reduced proliferation of both spleen T and B cells. The number of spleen CD4+ T lymphocytes decreased with simazine exposure, while CD8+ T cells remained unchanged. Exposure to simazine resulted in reduced immune function, higher intracellular [Ca2+], and oxidative stress. Finally, simazine induced spleen immune cells apoptosis by reducing Bcl-2, while increasing Fas and Caspase-3 level. Overall, the immunotoxicity of simazine may involve the induction of immune cell apoptosis and alterations in the immune and physiological functions of spleen cells.
Keystroke Analysis
Authors: Baaijen Veerle M. , Galbraith David , de Glopper Kees
Published: July 2012

Although keystroke logging promises to provide a valuable tool for writing research, it can often be difficult to relate logs to underlying processes. This article describes the procedures and measures that the authors developed to analyze a sample of 80 keystroke logs, with a view to achieving a better alignment between keystroke-logging measures and underlying cognitive processes. They used these measures to analyze pauses, bursts, and revisions and found that (a) burst lengths vary depending on their initiation type as well as their termination type, suggesting that the classification system used in previous research should be elaborated; (b) mixture models fit pause duration data better than unimodal central tendency statistics; and (c) individuals who pause for longer at sentence boundaries produce shorter but more well-formed bursts. A principal components analysis identified three underlying dimensions in these data: planned text production, within-sentence revision, and revision of global text structure.
Ségrégation et fragmentation socio-spatiale – L’épreuve de la mesure
Authors: Wachsberger Jean-Michel
Published: July 2012

Segregation and Socio-spatial Fragmentation - The Ordeal of Measurement: This note is a reflection on the meaning and scope of segregation and socio-spatial fragmentation indicators and, beyond, on the role of statistics in sociological reasoning. It shows that if these indicators can be used to test theories of segregation or fragmentation, they must nevertheless themselves be put to the test of sociological reasoning. The choice of statistical indicators is actually not a purely technical exercise but is strongly linked to the meaning we give to the phenomenon. Their construction and interpretation always depend on how it was defined previously, how its causes have been pictured, and its consequences have been anticipated. In this sense, statistical indicators can only be a step in a particular argument.
Growth Management in the United States, 2000–2010
Authors: Weitz Jerry
Published: July 2012

This bibliography synthesizes literature on growth management published between 2000 and 2010 in selected planning periodicals. Scholarship on growth management during the last decade, as evidenced in the selected journals, has blossomed within six primary categories: smart growth, urban form, environment and sustainability, participation and public opinion, tools and techniques, and analysis and evaluation. This bibliography also attends to disciplinary topics that reach outside the exclusive purview of planners and which are treated more comprehensively in nonplanning journals. This synthesis of the planning periodical literature helps mark boundaries of planners’ attention to topics of growth management during the last decade.
Thermal and electrical properties of nanocomposite poly o-anisidine/metal oxides
Authors: Mansour N. A. , Mohamed M. G. , Abed M. Yahia , Mazrouaa Azza M.
Published: July 2012

Poly o-anisidine (POA) was prepared by chemical oxidation polymerization, and the nanocomposite of this polymer was mixed with different nanopowder metal oxides. The size and morphology of these synthesized POA/nanocomposites were shown using a transmission electron microscope (TEM). Fourier-transform infrared (FTIR) spectroscopy has been used to investigate the microstructure of the synthesized POA/nanocomposites. Thermal stability thermogravimetric analysis (TGA) and electrical conductivity of POA/nanocomposites were studied in the temperature range 40–120°C. It was found that the nanopowder metal oxides improve the thermal stability of POAs, except TiO2, while the POA/CuO nanocomposite has the most thermal stability. Also the thermal stability is increases when the temperature is increased. The POA/nanocomposites reveal enhanced conductivity compared to conventional bulk POA. The highest electrical conductivity is obtained when the polymer mixes with CuO.
Hysteresis compensation and high-performance tracking control of piezoelectric actuators
Authors: Lin Chi-Ying , Chen Po-Ying
Published: July 2012

This paper presents a repetitive control-based independent design method for high-performance tracking control of piezoelectric actuators. This work applies an inverse Prandtl–Ishlinskii hysteresis model as a non-linear feedforward compensator to compensate for the hysteresis effect, and validates its inverse model by open-loop compensation. To achieve precision tracking control, the current study designs and implements the feedback control using a prototype repetitive control algorithm, integrating the inverse linear plant model-based feedforward compensation and hysteresis compensation methods to further reduce tracking error. Experimental results and performance analysis demonstrate that using the control structure further improves tracking performance.
Bayesian analysis of a disability model for lung cancer survival
Authors: Armero C , Cabras S , Castellanos ME , Perra S , Quirós A , Oruezábal MJ , Sánchez-Rubio J
Published: July 2012

Bayesian reasoning, survival analysis and multi-state models are used to assess survival times for Stage IV non-small-cell lung cancer patients and the evolution of the disease over time. Bayesian estimation is done using minimum informative priors for the Weibull regression survival model, leading to an automatic inferential procedure. Markov chain Monte Carlo methods have been used for approximating posterior distributions and the Bayesian information criterion has been considered for covariate selection. In particular, the posterior distribution of the transition probabilities, resulting from the multi-state model, constitutes a very interesting tool which could be useful to help oncologists and patients make efficient and effective decisions.