bluuebunny/crossref_metadata_2025 huggingface dataset:
Drosophilaprovides rapid modeling of renal development, function, and disease
Authors: Dow Julian A. T. , Romero Michael F.
Published: October 2010

The evolution of specialized excretory cells is a cornerstone of the metazoan radiation, and the basic tasks performed by Drosophila and human renal systems are similar. The development of the Drosophila renal (Malpighian) tubule is a classic example of branched tubular morphogenesis, allowing study of mesenchymal-to-epithelial transitions, stem cell-mediated regeneration, and the evolution of a glomerular kidney. Tubule function employs conserved transport proteins, such as the Na+, K+-ATPase and V-ATPase, aquaporins, inward rectifier K+channels, and organic solute transporters, regulated by cAMP, cGMP, nitric oxide, and calcium. In addition to generation and selective reabsorption of primary urine, the tubule plays roles in metabolism and excretion of xenobiotics, and in innate immunity. The gene expression resource FlyAtlas.org shows that the tubule is an ideal tissue for the modeling of renal diseases, such as nephrolithiasis and Bartter syndrome, or for inborn errors of metabolism. Studies are assisted by uniquely powerful genetic and transgenic resources, the widespread availability of mutant stocks, and low-cost, rapid deployment of new transgenics to allow manipulation of renal function in an organotypic context.
Synchrony in Normal and Focal Epileptic Brain: The Seizure Onset Zone is Functionally Disconnected
Authors: Warren Christopher P. , Hu Sanqing , Stead Matt , Brinkmann Benjamin H. , Bower Mark R. , Worrell Gregory A.
Published: October 2010

Synchronization of local and distributed neuronal assemblies is thought to underlie fundamental brain processes such as perception, learning, and cognition. In neurological disease, neuronal synchrony can be altered and in epilepsy may play an important role in the generation of seizures. Linear cross-correlation and mean phase coherence of local field potentials (LFPs) are commonly used measures of neuronal synchrony and have been studied extensively in epileptic brain. Multiple studies have reported that epileptic brain is characterized by increased neuronal synchrony except possibly prior to seizure onset when synchrony may decrease. Previous studies using intracranial electroencephalography (EEG), however, have been limited to patients with epilepsy. Here we investigate neuronal synchrony in epileptic and control brain using intracranial EEG recordings from patients with medically resistant partial epilepsy and control subjects with intractable facial pain. For both epilepsy and control patients, average LFP synchrony decreases with increasing interelectrode distance. Results in epilepsy patients show lower LFP synchrony between seizure-generating brain and other brain regions. This relative isolation of seizure-generating brain underlies the paradoxical finding that control patients without epilepsy have greater average LFP synchrony than patients with epilepsy. In conclusion, we show that in patients with focal epilepsy, the region of epileptic brain generating seizures is functionally isolated from surrounding brain regions. We further speculate that this functional isolation may contribute to spontaneous seizure generation and may represent a clinically useful electrophysiological signature for mapping epileptic brain.
Hyperexcitable Substantia Nigra Dopamine Neurons inPINK1- andHtrA2/Omi-Deficient Mice
Authors: Bishop Matthew W. , Chakraborty Subhojit , Matthews Gillian A. C. , Dougalis Antonios , Wood Nicholas W. , Festenstein Richard , Ungless Mark A.
Published: October 2010

The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca2+-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD.
Astrocytes in the Retrotrapezoid Nucleus Sense H+ by Inhibition of a Kir4.1–Kir5.1-Like Current and May Contribute to Chemoreception by a Purinergic Mechanism
Authors: Wenker Ian C. , Kréneisz Orsolya , Nishiyama Akiko , Mulkey Daniel K.
Published: October 2010

Central chemoreception is the mechanism by which CO2/pH sensors regulate breathing in response to tissue pH changes. There is compelling evidence that pH-sensitive neurons in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO2/H+-evoked adenosine 5′-triphosphate (ATP) release in the RTN, from pH-sensitive astrocytes, contributes to chemoreception. However, mechanism(s) by which RTN astrocytes sense pH is unknown and their contribution to chemoreception remains controversial. Here, we use the brain slice preparation and a combination of patch-clamp electrophysiology and immunohistochemistry to confirm that RTN astrocytes are pH sensitive and to determine mechanisms by which they sense pH. We show that pH-sensitive RTN glia are immunoreactive for aldehyde dehydrogenase 1L1, a marker of astrocytes. In HEPES buffer the pH-sensitive current expressed by RTN astrocytes reversed near EK+ (the equilibrium potential for K+) and was inhibited by Ba2+ and desipramine (blocker of Kir4.1-containing channels), characteristics most consistent with heteromeric Kir4.1–Kir5.1 channels. In bicarbonate buffer, the sodium/bicarbonate cotransporter also contributed to the CO2/H+-sensitive current in RTN astrocytes. To test the hypothesis that RTN astrocytes contribute to chemoreception by a purinergic mechanism, we used fluorocitrate to selectively depolarize astrocytes while measuring neuronal activity. We found that fluorocitrate increased baseline activity and pH sensitivity of RTN neurons by a P2-receptor–dependent mechanism, suggesting that astrocytes may release ATP to activate RTN chemoreceptors. We also found in bicarbonate but not HEPES buffer that P2-receptor antagonists decreased CO2 sensitivity of RTN neurons. We conclude that RTN astrocytes sense CO2/H+ in part by inhibition of a Kir4.1–Kir5.1-like current and may provide an excitatory purinergic drive to pH-sensitive neurons.
Sleep and Synaptic Renormalization: A Computational Study
Authors: Olcese Umberto , Esser Steve K. , Tononi Giulio
Published: October 2010

Recent evidence indicates that net synaptic strength in cortical and other networks increases during wakefulness and returns to a baseline level during sleep. These homeostatic changes in synaptic strength are accompanied by corresponding changes in sleep slow wave activity (SWA) and in neuronal firing rates and synchrony. Other evidence indicates that sleep is associated with an initial reactivation of learned firing patterns that decreases over time. Finally, sleep can enhance performance of learned tasks, aid memory consolidation, and desaturate the ability to learn. Using a large-scale model of the corticothalamic system equipped with a spike-timing dependent learning rule, in agreement with experimental results, we demonstrate a net increase in synaptic strength in the waking mode associated with an increase in neuronal firing rates and synchrony. In the sleep mode, net synaptic strength decreases accompanied by a decline in SWA. We show that the interplay of activity and plasticity changes implements a control loop yielding an exponential, self-limiting renormalization of synaptic strength. Moreover, when the model “learns” a sequence of activation during waking, the learned sequence is preferentially reactivated during sleep, and reactivation declines over time. Finally, sleep-dependent synaptic renormalization leads to increased signal-to-noise ratios, increased resistance to interference, and desaturation of learning capabilities. Although the specific mechanisms implemented in the model cannot capture the variety and complexity of biological substrates, and will need modifications in line with future evidence, the present simulations provide a unified, parsimonious account for diverse experimental findings coming from molecular, electrophysiological, and behavioral approaches.
Automatic Real-Time Generation of Floor Plans Based on Squarified Treemaps Algorithm
Authors: Marson Fernando , Musse Soraia Raupp
Published: October 2010

A novel approach to generate house floor plans with semantic information is presented. The basis of this model is the squarified treemaps algorithm. Previously, this algorithm has been used to create graphical representations based on hierarchical information, such as, directory structures and organization structures. Adapted to floor plans generation, this model allows the creation of internal house structures with information about their features and functionalities. The main contributions are related to the robustness, flexibility, and simplicity of the proposed approach to create floor plans in real-time. Results show that different and realistic floor plans can be created by adjusting a few parameters.
Large‐Angle Anomalies in the CMB
Authors: Copi Craig J. , Huterer Dragan , Schwarz Dominik J. , Starkman Glenn D.
Published: October 2010

We review the recently found large‐scale anomalies in the maps of temperature anisotropies in the
cosmic microwave background. These include alignments of the largest modes of CMB anisotropy
with each other and with geometry and direction of motion of the solar ssystem, and the unusually
low power at these largest scales. We discuss these findings in relation to expectation from standard
inflationary cosmology, their statistical significance, the tools to study them, and the various
attempts to explain them.
A Geometric Approach for Robotic Arm Kinematics with Hardware Design, Electrical Design, and Implementation
Authors: Clothier Kurt E. , Shang Ying
Published: October 2010

This paper presents a geometric approach to solve the unknown joint angles required for the autonomous positioning of a robotic arm. A plethora of complex mathematical processes is reduced using basic trigonometric in the modeling of the robotic arm. This modeling and analysis approach is tested using a five-degree-of-freedom arm with a gripper style end effector mounted to an iRobot Create mobile platform. The geometric method is easily modifiable for similar robotic system architectures and provides the capability of local autonomy to a system which is very difficult to manually control.
Oncogene-Driven Intrinsic Inflammation Induces Leukocyte Production of Tumor Necrosis Factor That Critically Contributes to Mammary Carcinogenesis
Authors: Sangaletti Sabina , Tripodo Claudio , Ratti Chiara , Piconese Silvia , Porcasi Rossana , Salcedo Rosalba , Trinchieri Giorgio , Colombo Mario P. , Chiodoni Claudia
Published: October 2010

Oncogene activation promotes an intrinsic inflammatory pathway that is crucial for cancer development. Here, we have investigated the actual effect of the inflammatory cytokine tumor necrosis factor (TNF) on the natural history of spontaneous mammary cancer in the HER2/neuT (NeuT) transgenic mouse model. Bone marrow transplantation from TNF knockout mice into NeuT recipients significantly impaired tumor growth, indicating that the source of TNF fostering tumor development was of bone marrow origin. We show that the absence of leukocyte-derived TNF disarranged the tumor vasculature, which lacked pericyte coverage and structural integrity, leading to diffuse vascular hemorrhage and stromal necrosis. In addition, tumor-associated Tie2–expressing monocytes were reduced and cytokine expression skewed from Th2 to Th1 type. Treatment of NeuT mice with anti-TNF antibody partially phenocopied the antitumor effect of TNF-deficient bone marrow cell transplantation, providing a strong preclinical background and rationale for the introduction of TNF antagonists in the treatment of human breast cancer, including basal-like samples for which consolidated targeted therapies do not exist. Cancer Res; 70(20); 7764–75. ©2010 AACR.
Microtentacles Tip the Balance of Cytoskeletal Forces in Circulating Tumor Cells
Authors: Matrone Michael A. , Whipple Rebecca A. , Balzer Eric M. , Martin Stuart S.
Published: October 2010

Detection of circulating tumor cells (CTC) is advancing as an effective predictor of patient outcome and therapeutic response. Unfortunately, our knowledge of CTC biology remains limited, and the impact of drug treatments on CTC metastatic potential is currently unclear. Improved CTC imaging in vivo and analysis of free-floating tumor cells now show that cytoskeletal regulation in CTCs contrasts starkly with tumor cells attached to extracellular matrix. In this review, we examine how persistent microtubule stabilization promotes the formation of microtentacles on the surface of detached breast tumor cells and enhances metastatic potential. Cancer Res; 70(20); 7737–41. ©2010 AACR.
Expression of the Transcriptional Repressor Gfi-1 Is Regulated by C/EBPα and Is Involved in Its Proliferation and Colony Formation–Inhibitory Effects in p210BCR/ABL-Expressing Cells
Authors: Lidonnici Maria Rosa , Audia Alessandra , Soliera Angela Rachele , Prisco Marco , Ferrari-Amorotti Giovanna , Waldron Todd , Donato Nick , Zhang Ying , Martinez Robert V. , Holyoake Tessa L. , Calabretta Bruno
Published: October 2010

Ectopic expression of CAAT/enhancer binding protein α (C/EBPα) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPα-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPα in a DNA binding–dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5′-flanking region and enhances the promoter activity of Gfi-1. Moreover, in K562 cells, RNA interference–mediated downregulation of Gfi-1 expression partially rescued the proliferation-inhibitory but not the differentiation-inducing effect of C/EBPα. Ectopic expression of wild-type Gfi-1, but not of a transcriptional repressor mutant (Gfi-1P2A), inhibited proliferation and markedly suppressed colony formation but did not induce granulocytic differentiation of BCR/ABL-expressing cells. By contrast, Gfi-1 short hairpin RNA–tranduced CD34+ chronic myeloid leukemia cells were markedly more clonogenic than the scramble-transduced counterpart. Together, these studies indicate that Gfi-1 is a direct target of C/EBPα required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells. Cancer Res; 70(20); 7949–59. ©2010 AACR.
Method of Detection and Breast Cancer Survival Disparities in Hispanic Women
Authors: Hill Deirdre A. , Nibbe Andrea , Royce Melanie E. , Wallace Anne Marie , Kang Huining , Wiggins Charles L. , Rosenberg Robert D.
Published: October 2010

Background: Hispanic women in New Mexico (NM) are more likely than non-Hispanic women to die of breast cancer–related causes. We determined whether survival differences between Hispanic and non-Hispanic women might be attributable to the method of detection, an independent breast cancer prognostic factor in previous studies.

Methods: White women diagnosed with invasive breast cancer from 1995 through 2004 were identified from NM Surveillance Epidemiology End Results (SEER) files (n = 5,067) and matched to NM Mammography Project records. Method of cancer detection was categorized as “symptomatic” or “screen-detected.” The proportion of Hispanic survival disparity accounted for by included variables was assessed using Cox models.

Results: In the median follow-up of 87 months, 490 breast cancer deaths occurred. Symptomatic versus screen-detection was classifiable for 3,891 women (76.8%), and was independently related to breast cancer-specific survival [hazard ratio (HR), 1.6; 95% confidence interval (95% CI), 1.3-2.0]. Hispanic women had a 1.5-fold increased risk of breast cancer–related death, relative to non-Hispanic women (95% CI, 1.2-1.8). After adjustment for detection method, the Hispanic HR declined from 1.50 to 1.45 (10%), but after inclusion of other prognostic indicators the Hispanic HR equaled 1.23 (95% CI, 1.01-1.48).

Conclusions: Although the Hispanic HR declined 50% after adjustment, the decrease was largely due to adverse tumor prognostic characteristics.

Impact: Reduction of disparate survival in Hispanic women may rely not only on increased detection of tumors when asymptomatic but on the development of greater understanding of biological factors that predispose to poor prognosis tumors. Cancer Epidemiol Biomarkers Prev; 19(10); 2453–60. ©2010 AACR.
Association of Insurance and Race/Ethnicity with Disease Severity among Men Diagnosed with Prostate Cancer, National Cancer Database 2004-2006
Authors: Fedewa Stacey A. , Etzioni Ruth , Flanders W. Dana , Jemal Ahmedin , Ward Elizabeth M.
Published: October 2010

Background: Previous studies documenting variations in severity of prostate cancer at diagnosis by race/ethnicity and insurance status have been limited to small sample sizes and patients ≥65 years of age. This study examines disease severity among patients ages 18 to 99 from the National Cancer Database (NCDB).

Methods: Patients diagnosed between 2004 and 2006 with prostate cancer were selected from the NCDB (n = 312,339). We evaluated the association among three disease severity measures: prostate specific antigen (PSA) level, Gleason score 8 to 10, and clinical T-stage 3/4, by race/ethnicity and insurance while adjusting for sociodemographic and clinical factors.

Results: Uninsured and Medicaid-insured patients had elevated PSA levels, higher odds of advanced Gleason score [uninsured odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.82-2.12; Medicaid OR, 1.67; 95% CI, 1.55-1.79], and advanced clinical T stage (uninsured OR, 1.85; 95% CI, 1.69-2.03; Medicaid OR, 1.49; 95% CI, 1.35-1.63) compared with privately insured patients. Black (OR, 1.19; 95% CI, 1.15-1.23), Hispanic (OR, 1.16; 95% CI, 1.10-1.23), and Asian patients (OR, 1.22; 95% CI, 1.24-1.43) had higher odds of advanced Gleason score and similar odds of advanced stage of disease relative to whites.

Conclusion: Insurance status is strongly associated with disease severity among prostate cancer patients.

Impact: Strong associations between insurance and disease severity may be related to lack of access to preventive services such as PSA screening and barriers to medical evaluation. Although the risks and benefits of PSA screening have not been fully elucidated, it is important that all men have the opportunity to be informed about this option and preventative medical services. Cancer Epidemiol Biomarkers Prev; 19(10); 2437–44. ©2010 AACR.
Five-Year and Lifetime Risk of Breast Cancer among U.S. Subpopulations: Implications for Magnetic Resonance Imaging Screening
Authors: Graubard Barry I. , Freedman Andrew N. , Gail Mitchell H.
Published: October 2010

Background: Guidelines from the American Cancer Society recommend annual breast magnetic resonance imaging (MRI) screening for women with a projected lifetime risk of ≥20% based on risk models that use family history. Because MRI screening is costly and has limited specificity, estimates of the numbers of U.S. women with ≥20% breast cancer risk would be useful.

Methods: We used data from the 2000 and 2005 National Health Interview Survey and the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool (i.e., Gail model 2 with a revision for African Americans) to calculate estimates of U.S. women by age and race/ethnicity categories with a lifetime absolute breast cancer risk of ≥20%. Distributions of 5-year and lifetime absolute risk of breast cancer were compared across demographic groups.

Results: We estimated that 1.09% (95% confidence interval, 0.95-1.24%) of women age 30 to 84 years have a lifetime absolute breast cancer risk of ≥20%, which translates to 880,063 U.S. women eligible for MRI screening. The 5-year risks are highest for white non-Hispanics and lowest for Hispanics. The lifetime risks decrease with age and are generally highest for white non-Hispanics, lower for African American non-Hispanic, and lowest for Hispanics.

Conclusion: We provide national estimates of the number of U.S. women who would be eligible for MRI breast screening and distributions of 5-year and lifetime risks of breast cancer using the NCI Breast Cancer Risk Assessment Tool.

Impact: These estimates inform the potential resources and public health demand for MRI screening and chemopreventive interventions that might be required for U.S. women. Cancer Epidemiol Biomarkers Prev; 19(10); 2430–6. ©2010 AACR.
Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Authors: Lu Tzu-Pin , Tsai Mong-Hsun , Lee Jang-Ming , Hsu Chung-Ping , Chen Pei-Chun , Lin Chung-Wu , Shih Jin-Yuan , Yang Pan-Chyr , Hsiao Chuhsing Kate , Lai Liang-Chuan , Chuang Eric Y.
Published: October 2010

Background: Although cigarette smoking is the major risk factor for lung cancer, only 7% of female lung cancer patients in Taiwan have a history of smoking. The genetic mechanisms of carcinogenesis in nonsmokers are unclear, but semaphorins have been suggested to play a role as lung tumor suppressors. This report is a comprehensive analysis of the molecular signature of nonsmoking female lung cancer patients in Taiwan, with a particular focus on the semaphorin gene family.

Methods: Sixty pairs of tumor and adjacent normal lung tissue specimens were analyzed by using Affymetrix U133plus2.0 expression arrays. Differentially expressed genes in tumor tissues were identified by a paired t test and validated by reverse transcriptase-PCR and immunohistochemistry. Functional analysis was conducted by using Ingenuity Pathway Analysis as well as gene set enrichment analysis and sigPathway algorithms. Kaplan-Meier survival analyses were used to evaluate the association of SEMA5A expression and clinical outcome.

Results: We identified 687 differentially expressed genes in non–small cell lung carcinoma (NSCLC). Many of these genes, most notably the semaphorin family, were participants in the axon guidance signaling pathway. The downregulation of SEMA5A in tumor tissue, both at the transcriptional and translational levels, was associated with poor survival among nonsmoking women with NSCLC.

Conclusions: In summary, several semaphorin gene family members were identified as potential therapeutic targets, and SEMA5A may be useful as a prognostic biomarker for NSCLC, which may also be gender specific in Taiwanese patients.

Impact: A novel biomarker for NSCLC is identified. Cancer Epidemiol Biomarkers Prev; 19(10); 2590–7. ©2010 AACR.
Carbamazepine but Not Valproate Induces CYP2A6 Activity in Smokers with Mental Illness
Authors: Williams Jill M. , Gandhi Kunal K. , Benowitz Neal L.
Published: October 2010

Background: Antiepileptic drugs (AED) are being increasingly used in the management of serious mental illness, but their effects on nicotine metabolism have not been studied.

Methods: This study investigated the effects of three AEDs (carbamazepine, oxcarbazepine, and valproic acid) on nicotine and nicotine metabolite levels in 149 smokers with schizophrenia and bipolar disorder who participated in an afternoon blood draw for nicotine, cotinine, and 3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine was calculated as a marker of CYP2A6 metabolic activity. Among the participants, 8 smokers were taking carbamazepine, 6 were taking oxcarbazepine, and 40 were taking valproic acid.

Results: The 3HC/cotinine ratio was significantly higher in individuals taking carbamazepine or oxcarbazepine (combined, n = 14) versus those not taking either (mean 0.993 versus 0.503; P < 0.001). The cotinine/cigarette per day ratio was significantly lower in individuals taking carbamazepine or oxcarbazepine. The 3HC/cotinine ratios were also significantly higher in the subgroup of individuals taking carbamazepine (n = 8) versus those not taking it. There were no significant differences in nicotine or cotinine levels or 3HC/cotinine ratios in individuals taking valproic acid versus those not taking it. We conducted backward stepwise linear regression models to identify predictors of the log transformed 3HC/cotinine ratios. Taking carbamazepine and number of cigarettes smoked per day were significant determinants of log 3HC/cotinine.

Conclusions: Carbamazepine likely induces hepatic metabolism via CYP2A6 and is associated with increased 3HC/cotinine ratios.

Impact: Increased nicotine metabolism in individuals using AED has implications for increased smoking behavior and exposure to more tobacco toxins, which warrants further study. Cancer Epidemiol Biomarkers Prev; 19(10); 2582–9. ©2010 AACR.
Plasma Vitamins B2, B6, and B12, and Related Genetic Variants as Predictors of Colorectal Cancer Risk
Authors: Eussen Simone J.P.M. , Vollset Stein Emil , Hustad Steinar , Midttun Øivind , Meyer Klaus , Fredriksen Åse , Ueland Per Magne , Jenab Mazda , Slimani Nadia , Boffetta Paolo , Overvad Kim , Thorlacius-Ussing Ole , Tjønneland Anne , Olsen Anja , Clavel-Chapelon Françoise , Boutron-Ruault Marie-Christine , Morois Sophie , Weikert Cornelia , Pischon Tobias , Linseisen Jakob , Kaaks Rudolf , Trichopoulou Antonia , Zilis Demosthenes , Katsoulis Michael , Palli Domenico , Pala Valeria , Vineis Paolo , Tumino Rosario , Panico Salvatore , Peeters Petra H.M. , Bueno-de-Mesquita H. Bas , van Duijnhoven Fränzel J.B. , Skeie Guri , Muñoz Xavier , Martínez Carmen , Dorronsoro Miren , Ardanaz Eva , Navarro Carmen , Rodríguez Laudina , VanGuelpen Bethany , Palmqvist Richard , Manjer Jonas , Ericson Ulrika , Bingham Sheila , Khaw Kay-Tee , Norat Teresa , Riboli Elio
Published: October 2010

Background: B-vitamins are essential for one-carbon metabolism and have been linked to colorectal cancer. Although associations with folate have frequently been studied, studies on other plasma vitamins B2, B6, and B12 and colorectal cancer are scarce or inconclusive.

Methods: We carried out a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, including 1,365 incident colorectal cancer cases and 2,319 controls matched for study center, age, and sex. We measured the sum of B2 species riboflavin and flavin mononucleotide, and the sum of B6 species pyridoxal 5′-phosphate, pyridoxal, and 4-pyridoxic acid as indicators for vitamin B2 and B6 status, as well as vitamin B12 in plasma samples collected at baseline. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for colorectal cancer were estimated using conditional logistic regression, adjusted for smoking, education, physical activity, body mass index, alcohol consumption, and intakes of fiber and red and processed meat.

Results: The relative risks comparing highest to lowest quintile were 0.71 [95% confidence interval (95% CI), 0.56-0.91; Ptrend = 0.02] for vitamin B2, 0.68 (95% CI, 0.53-0.87; Ptrend <0.001) for vitamin B6, and 1.02 (95% CI, 0.80-1.29; Ptrend = 0.19) for vitamin B12. The associations for vitamin B6 were stronger in males who consumed ≥30 g alcohol/day. The polymorphisms were not associated with colorectal cancer.

Conclusions: Higher plasma concentrations of vitamins B2 and B6 are associated with a lower colorectal cancer risk.

Impact: This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 19(10); 2549–61. ©2010 AACR.
Complement Factor H Is Elevated in Bronchoalveolar Lavage Fluid and Sputum from Patients with Lung Cancer
Authors: Pio Ruben , Garcia Javier , Corrales Leticia , Ajona Daniel , Fleischhacker Michael , Pajares Maria J. , Cardenal Felipe , Seijo Luis , Zulueta Javier J. , Nadal Ernest , Witt Christian , Lozano Maria D. , Schmidt Bernd , Montuenga Luis M.
Published: October 2010

Background: Cytologic examination of specimens obtained from the respiratory tract is a lung cancer diagnostic procedure with high specificity but moderate sensitivity. The use of molecular biomarkers may enhance the sensitivity of cytologic examination in the detection of lung cancer.

Methods: Complement factor H, a protein secreted by lung cancer cells, was quantified in a series of bronchoalveolar lavage supernatants from lung cancer patients and patients with nonmalignant respiratory diseases. Albumin, total protein content, and hemoglobin were also analyzed. Results were validated in independent sets of bronchoalveolar lavage and sputum supernatants.

Results: There was a significantly higher concentration of factor H in bronchoalveolar lavage samples from lung cancer patients. The sensitivity and specificity of the factor H test was 82% and 77%, respectively. These results were validated in an independent set of patients with nearly identical results. Furthermore, 70% and 45% of bronchoalveolar lavage fluids from central and peripheral tumors, respectively, reported as cytologically negative, were classified as positive using this marker. Finally, the test was evaluated in a series of sputum supernatants from lung cancer patients and controls. The sensitivity and specificity of the factor H test in this series was 80% and 88%, respectively.

Conclusion: Factor H is elevated in bronchoalveolar lavage and sputum from lung cancer patients.

Impact: Measurement of molecular biomarkers, such as complement factor H, may be used in the future as an adjunct to cytology in the diagnosis of malignant pulmonary diseases. Cancer Epidemiol Biomarkers Prev; 19(10); 2665–72. ©2010 AACR.
Alcohol-Folate Interactions in the Risk of Oral Cancer in Women: A Prospective Cohort Study
Authors: Shanmugham Jayapriyaa R. , Zavras Athanasios I. , Rosner Bernard A. , Giovannucci Edward L.
Published: October 2010

Background: The aim of this cohort study was to quantify the effect of alcohol on the risk of oral cancer in different strata of folate intake, controlling for known confounders.

Methods: A cohort of 87,621 women in the Nurses' Health Study was followed up from 1980 to 2006, and 147 incident oral cancer cases were reported and confirmed. Data on alcohol intake and diet were obtained through self-reported food frequency questionnaires every 4 years. Cox proportional regression analysis was conducted to estimate the adjusted risk ratios (RR) and 95% confidence intervals (95% CI).

Results: When compared with nondrinkers, the adjusted RRs (95% CIs) for alcohol intake were 0.59 (0.39-0.87) for 0.1-14.9 g/d, 1.15 (0.67-1.97) for 15-29.9 g/d, and 1.92 (1.08-3.40) for ≥30 g/d. We observed a significant interaction between alcohol and folate intakes (P = 0.02). The cancer risk for subjects with high alcohol (≥30 g/d) and low folate (<350 μg/d) intakes was significantly elevated (RR, 3.36; 95% CI, 1.57-7.20) as compared with nondrinkers with low folate intake. The risk associated with high alcohol intake (≥30 g/d) was reduced to 0.98 (0.35-2.70) in the high-folate (≥350 μg/d) group as compared with nondrinkers with high folate intake.

Conclusions: High alcohol intake is associated with significantly increased oral cancer risk, especially in women with low folate intake.

Impact: A significant interaction between alcohol and folate intakes seems to affect oral cancer risk in women, a finding with potential public health utility. Cancer Epidemiol Biomarkers Prev; 19(10); 2516–24. ©2010 AACR.
Influence of Obesity on the Serum Carcinoembryonic Antigen Value in Patients with Colorectal Cancer
Authors: Park Jun Seok , Choi Gyu-Seog , Jang You Seok , Jun Soo Han , Kang Hyun
Published: October 2010

Background: Prior studies suggest that obesity is inversely associated with tumor marker concentration and may reduce diagnostic precision. This study was undertaken to evaluate the association between body mass index (BMI) and serum carcinoembryonic antigen (CEA) concentrations in colorectal cancer patients.

Methods: We analyzed the association between BMI and CEA concentration in a group of 2,845 patients who underwent surgical treatment for colorectal adenocarcinoma from 1995 to 2009. Multivariate linear regression analysis was applied to adjust for clinicopathologic confounding factors to analyze main outcome measures. The association of BMI with plasma volume, CEA concentration, and total circulating CEA mass was assessed by determining P values for trends. We also developed a regression formula to calculate the effect of obesity on the serum CEA levels.

Results: Increased BMI was linearly correlated with higher plasma volume (P < 0.001 for trend) and lower adjusted CEA concentrations after controlling for potentially confounding factors (P ≤ 0.005 for trend in stage II and III tumors). Our theoretical model suggests that a CEA value of 7.0 ng/mL in patients of normal weight corresponds to 6.1 ng/mL in obese patients.

Conclusions: The hemodilution effect from increased plasma volume may account for the decreased CEA concentrations observed in patients with higher BMI.

Impact: Obesity might be one of the factors that affect CEA value, leading to loss of sensitivity and diagnostic accuracy in the CEA test. The BMI status of patients should be taken into account during assessment of serum CEA during the surveillance of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 19(10); 2461–8. ©2010 AACR.
Do Steroid Hormones Play a Role in the Etiology of Glioma?
Authors: Kabat Geoffrey C. , Etgen Anne M. , Rohan Thomas E.
Published: October 2010

Gliomas are the most common type of primary malignant brain tumor and have a very poor prognosis. Little is known, however, about the etiology of these tumors. Evidence from a number of sources suggests that endogenous steroid hormones may play a role in the development of gliomas. First, the descriptive epidemiology of glioma suggests a relative protection of females compared with males, particularly during the premenopausal years. Second, some gliomas and glioblastomas express estrogen receptors (ER), especially ERβ, as well as aromatase, the enzyme responsible for the conversion of testosterone to estradiol, and possibly other steroid hormone receptors. Third, experimental studies indicate that glioblastomas transplanted into animals grow at a slower rate in females compared with males. Finally, experimental studies show that estradiol, 2-methoxyestradiol, and a number of selective estrogen receptor modulators inhibit proliferation of gliomas and induce cell death. These hormonal agonists and antagonists may act either through classical steroid hormone receptors or independently of such receptors. In view of these findings, further clinical, experimental, and epidemiologic studies are needed to elucidate the role of steroid hormone agonists and antagonists in the development and proliferation of glioma. If hormonal pathways are involved in gliomagenesis, this could eventually lead to the design of preventive strategies. Cancer Epidemiol Biomarkers Prev; 19(10); 2421–7. ©2010 AACR.
Expression of the Tumor Suppressor Krüppel-Like Factor 4 as a Prognostic Predictor for Colon Cancer
Authors: Patel Nilesh V. , Ghaleb Amr M. , Nandan Mandayam O. , Yang Vincent W.
Published: October 2010

Background: The zinc finger transcription factor Krüppel-like factor 4 (KLF4) regulates numerous physiologic processes, including proliferation, differentiation, and development. Studies also showed that KLF4 is involved in tumorigenesis and somatic cell reprogramming. Here, we aimed to assess whether KLF4 is a prognostic indicator for colon cancer.

Methods: Levels of KLF4 were measured by immunohistochemical analysis of a tissue microarray containing 367 independent colon cancer sections. Univariate data analysis was done in addition to construction of multivariate models with several clinicopathologic factors to evaluate KLF4 as an independent predictor of survival and cancer recurrence (disease-free survival).

Results: Colon cancer tissues had significantly overall lower KLF4 levels compared with noncancer tissues (P < 0.0001). Using logistic regression, a trend was noted for decreased odds of KLF4 expression in higher stages of tumors. In univariate and multivariate analyses, KLF4 was a significant predictor of survival and recurrence.

Conclusions: KLF4 expression is significantly downregulated in colon cancer, and loss of KLF4 is an independent predictor of survival and recurrence.

Impact: These findings suggest that KLF4 may serve as a prognostic biomarker for colon cancer. Cancer Epidemiol Biomarkers Prev; 19(10); 2631–8. ©2010 AACR.
Oral Contraceptive Use and Breast Cancer: A Prospective Study of Young Women
Authors: Hunter David J. , Colditz Graham A. , Hankinson Susan E. , Malspeis Susan , Spiegelman Donna , Chen Wendy , Stampfer Meir J. , Willett Walter C.
Published: October 2010

Background: Previous studies convincingly showed an increase in risk of breast cancer associated with current or recent use of oral contraceptives from the 1960s to 1980s. The relation of contemporary oral contraceptive formulations to breast cancer risk is less clear.

Methods: We assessed lifetime oral contraceptive use and the specific formulations used among 116,608 female nurses ages 25 to 42 years at enrollment in 1989, and subsequently updated this information every 2 years. We related this information to risk of breast cancer up to June 1, 2001.

Results: During 1,246,967 person-years of follow-up, 1,344 cases of invasive breast cancer were diagnosed. Past use of any oral contraceptive was not related to breast cancer risk [multivariate relative risk (RR), 1.12; 95% confidence interval 0.95-1.33]. Current use of any oral contraceptive was related to a marginally significant higher risk (multivariate RR, 1.33; 95% CI, 1.03-1.73). One specific formulation substantially accounted for the excess risk: the RR for current use of triphasic preparations with levonorgestrel as the progestin was 3.05 (95% CI, 2.00-4.66; P < 0.0001).

Conclusions: Current use of oral contraceptives carries an excess risk of breast cancer. Levonorgestrel used in triphasic preparations may account for much of this elevation in risk.

Impact: Different oral contraceptive formulations might convey different risks of breast cancer; ongoing monitoring of these associations is necessary as oral contraceptive formulations change. Cancer Epidemiol Biomarkers Prev; 19(10); 2496–502. ©2010 AACR.
Development of a Validated Immunofluorescence Assay for γH2AX as a Pharmacodynamic Marker of Topoisomerase I Inhibitor Activity
Authors: Kinders Robert J. , Hollingshead Melinda , Lawrence Scott , Ji Jiuping , Tabb Brian , Bonner William M. , Pommier Yves , Rubinstein Larry , Evrard Yvonne A. , Parchment Ralph E. , Tomaszewski Joseph , Doroshow James H.
Published: October 2010

Purpose: Phosphorylated histone H2AX (γH2AX) serves as a biomarker for formation of DNA double-strand break repair complexes. A quantitative pharmacodynamic immunofluorescence assay for γH2AX was developed, validated, and tested in human tumor xenograft models with the use of clinically relevant procedures.

Experimental Design: The γH2AX immunofluorescence assay uses a novel data quantitation and image processing algorithm to determine the extent of nuclear-specific γH2AX staining in tumor needle biopsies and hair follicles collected from mice bearing topotecan-responsive A375 xenografts. After method validation with the topoisomerase I (Top1) inhibitor topotecan, the assay was used to compare pharmacodynamic properties of three structurally related indenoisoquinoline Top1 inhibitors.

Results: γH2AX response to topotecan was quantified over a 60-fold dose range (0.016-1.0 times the murine single-dose maximum tolerated dose), and significant pharmacodynamic response was measured at the mouse equivalent of the 1.5 mg/m2 clinical dose as well as the lowest dose tested. Responses were within a time window amenable for biopsy collection in clinical trials. These studies enabled characterization of dose and time responses for three indenoisoquinolines, resulting in selection of two for clinical evaluation. γH2AX response to Top1 inhibitors in hair follicles was also observable above a minimal dose threshold.

Conclusions: Our γH2AX assay is sufficiently accurate and sensitive to quantify γH2AX in tumor samples and will be used in correlative studies of two indenoisoquinolines in a phase I clinical trial at the National Cancer Institute. Data suggest that hair follicles may potentially serve as a surrogate tissue to evaluate tumor γH2AX response to Top1 inhibitors. Clin Cancer Res; 16(22); 5447–57. ©2010 AACR.
REO-10: A Phase I Study of Intravenous Reovirus and Docetaxel in Patients with Advanced Cancer
Authors: Comins Charles , Spicer James , Protheroe Andrew , Roulstone Victoria , Twigger Katie , White Christine M. , Vile Richard , Melcher Alan , Coffey Matt C. , Mettinger Karl L. , Nuovo Gerard , Cohn David E. , Phelps Mitch , Harrington Kevin J. , Pandha Hardev S.
Published: October 2010

Purpose: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer.

Experimental Design: Patients received 75 mg/m2 docetaxel (day 1) and escalating doses of reovirus up to 3 × 1010 TCID50 (days 1-5) every 3 weeks.

Results: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients.

Conclusion: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m2, three times weekly) and reovirus (3 × 1010 TCID50, days 1-5, every 3 weeks). Clin Cancer Res; 16(22); 5564–72. ©2010 AACR.
Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer
Authors: Buck Elizabeth , Gokhale Prafulla C. , Koujak Susan , Brown Eric , Eyzaguirre Alexandra , Tao Nianjun , Rosenfeld-Franklin Maryland , Lerner Lorena , Chiu M. Isabel , Wild Robert , Epstein David , Pachter Jonathan A. , Miglarese Mark R.
Published: October 2010

Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase–AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti–IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti–IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. Mol Cancer Ther; 9(10); 2652–64. ©2010 AACR.
Visual Bias in Time’s “The Great Divide”: A Semiotic Analysis of Clinton and Obama Photographs
Authors: Goodnow Trischa
Published: October 2010

In the 2008 Democratic presidential campaign Hillary Clinton was pitted against Barack Obama for the nomination. On February 18, 2008 Time magazine published a behind-the-scenes photo essay of each candidate titled “The Great Divide.” As has been well established, news photographs can have an influence on the electorate. Using a close semiotic analysis this article considers the images found in the photo essays to discover any underlying visual bias. The results of the analysis show that the two candidates are portrayed differently. However, those differences may be a reflection of how the public and the media already perceived each candidate.
Results From a Clinical Multidisciplinary Weight Management Program
Authors: Woolford Susan J. , Sallinen Bethany J. , Clark Sarah J. , Freed Gary L.
Published: October 2010

Background/Objective: Published data regarding outcomes of pediatric behavioral weight management are mainly from research interventions. The authors wished to explore outcomes from a clinical program. Methods: A retrospective analysis of data from obese adolescents enrolled in the Michigan Pediatric Outpatient Weight Evaluation and Reduction program (April 2007 to June 2008). The multidisciplinary program included group sessions, individual visits, and exercise classes. Linear regression was used to explore associations between change in body mass index (BMI) and age, sex, race, and insurance. Results: N = 67. Mean age was 14.5 years; 71% female, 50% Medicaid enrollees, and 30% African American. Mean initial BMI was 40. Mean change in BMI was -2.3 for those completing the 24-week program (n = 48; P < .01). Reduction in BMI was not associated with participants’ demographic characteristics. Conclusions: A clinical multidisciplinary weight loss program for adolescents can lead to decreases in BMI after 24 weeks. Further work is needed to assess long-term outcomes.