bluuebunny/crossref_metadata_2025 huggingface dataset:
Régulations aminergique et cholinergique du système caudal neurosécréteur de l'omble de fontaine, Salvelinus fontinalis, en relation avec l'osmo-iono-regulation
Authors: Gauthier Laurent , Audet Céline , Chevalier Gaston
Published: January 2010

The innervation of the caudal neurosecretory system of the brook trout, Salvelinus fontinalis, was studied under light and electron microscopy in order to characterize its nature, distribution, and regulatory function over the activity of the caudal neurosecretory cells. A dual innervation of the cell bodies and axons of neurosecretory cells was disclosed. One type of axosomatic connection exhibited small lucent vesicles and large dense-cored granules. These boutons were identified as monoaminergic since they appeared depleted after reserpine treatment and they were selectively labeled with 5-OH-dopamine. In fish exposed to demineralized water, reserpine induced a condition that stimulated the synthetic activity of caudal neurosecretory cells, a clear reduction of this activity, according to morphometric (cell and nucleus diameters) and ultrastructural criteria (dimensions of the Golgi complex). By comparison, no significant variation of the synthetic activity was noted in freshwater-adapted trout treated with reserpine. A second type of innervation was also identified as cholinergic by histochemical localization of acetylcholinesterase. Electron microscopic analysis also revealed axosomatic and axoaxonic cholinergic synaptic connections with characteristic small 500-Å diameter lucent vesicles. The injection of fenitrothion, an anticholinesterase agent, enhanced discharge of neurosecretory material from axonal endings of caudal cells while the synthetic activity did not appear to be modified. Our findings suggest an important role of aminergic and cholinergic controls over the response of the caudal neurosecretory system of Salvelinus fontinalis during hyperosmotic adaptation.
Rate of arm regeneration and potential causes of arm loss in the feather star Florometra serratissima (Echinodermata: Crinoidea)
Authors: Mladenov Philip V.
Published: January 2010

Rate of arm regeneration was measured in caged specimens of the stalkless crinoid Florometra serratissima (A. H. Clark) with one, two, three, and five amputated arms. A single arm amputated at the base regenerates to a fully functional condition in under 9 months. Contrary to earlier speculation, the rate of regeneration per arm decreases slightly as the number of regenerating arms on an individual increases. However, the total rate of regeneration of new arm tissue on an individual increases with increasing number of regenerating arms. An arm amputated midway regenerates at a rate similar to that of an arm amputated near the base. In the population of F. serratissima under study, just under 80% of the individuals had at least one regenerating arm. The potential causes of arm loss are considered and some observations are presented which suggest that the sea star Pycnopodia helianthoides and the crab Oregonia gracilis will attack this feather star and cause it to autotomize arms.
DECEIVING THE V-BLOCK METHOD FOR ASSESSMENT OF DEPARTURE FROM ROUNDNESS
Authors: SANGWIN C. J.
Published: January 2010

The purpose of this paper is to construct non-circular shapes via pure geometry which are indistinguishable from a perfect circle according to the results of applying so-called V-block tests. We mean that the geometry of the curve is such that the test will, from a purely theoretical point of view, apparently show no departure from roundness whatsoever. In doing so, we call into question the theoretical basis for these practical V-block tests.
GUARDING RECTANGULAR PARTITIONS
Authors: DINITZ YEFIM , KATZ MATTHEW J. , KRAKOVSKI ROI
Published: January 2010

A rectangular partition is a partition of a rectangle into non-overlapping rectangles, such that no four rectangles meet at a common point. A vertex guard is a guard located at a vertex of the partition (i.e., at a corner of a rectangle); it guards the rectangles that meet at this vertex. An edge guard is a guard that patrols along an edge of the partition, and is thus equivalent to two adjacent vertex guards. We consider the problem of finding a minimum-cardinality guarding set for the rectangles of the partition. For vertex guards, we prove that guarding a given subset of the rectangles is NP-hard. For edge guards, we prove that guarding all rectangles, where guards are restricted to a given subset of the edges, is NP-hard. For both results we show a reduction from vertex cover in non-bipartite 3-connected cubic planar graphs of girth greater than three.

For the second NP-hardness result, we obtain a graph-theoretic result which establishes a connection between the set of faces of a plane graph of vertex degree at most three and a vertex cover for this graph. More precisely, we prove that one can assign to each internal face a distinct vertex of the cover, which lies on the face's boundary.

We show that the vertices of a rectangular partition can be colored red, green, or black, such that each rectangle has all three colors on its boundary. We conjecture that the above is also true for four colors. Finally, we obtain a worst-case upper bound on the number of edge guards that are sufficient for guarding rectangular partitions with some restrictions on their structure.
New age constraints on the evolution of the Mt Carmel structure and its implications on a Late Miocene extensional phase of the Levant continental margin
Authors: Steinberg Josh , Gvirtzman Zohar , Folkman Yehoshua
Published: January 2010

The Mt Carmel structure is one of the most prominent topographical elements along the Levant continental margin and is the surface expression of a deep tectonic structure. The use of 3D seismic data allows us to set new constraints on the uplift of the Carmel structure and define the Or Akiva fault as its southern boundary. The Or Akiva fault was created during a Late Miocene extensional phase that had also created the Carmel fault at the northern edges of Mt Carmel. The different topographic expression across these two boundary faults reflects a change in the post-Miocene activity, where activity along the Or Akiva fault ceased and its southern side began subsiding, whereas its northern side bordered by the Carmel fault continued to rise. We conclude that the Late Miocene north–south extension, previously recognized only along branches of the Dead Sea Transform in northern Israel and Lebanon, affected larger areas than previously thought and can be related to regional kinematic changes during the breakup of Arabia from Africa and its collision with Eurasia.
Turbulent Dispersed Multiphase Flow
Authors: Balachandar S. , Eaton John K.
Published: January 2010

Turbulent dispersed multiphase flows are common in many engineering and environmental applications. The stochastic nature of both the carrier-phase turbulence and the dispersed-phase distribution makes the problem of turbulent dispersed multiphase flow far more complex than its single-phase counterpart. In this article we first review the current state-of-the-art experimental and computational techniques for turbulent dispersed multiphase flows, their strengths and limitations, and opportunities for the future. The review then focuses on three important aspects of turbulent dispersed multiphase flows: the preferential concentration of particles, droplets, and bubbles; the effect of turbulence on the coupling between the dispersed and carrier phases; and modulation of carrier-phase turbulence due to the presence of particles and bubbles.
Transient outward potassium current in ICC
Authors: Parsons Sean P. , Huizinga Jan D.
Published: January 2010

Interstitial cells of Cajal (ICC) are the pacemakers of the gut, initiating slow-wave activity. Several ion channels have been identified that contribute to the depolarization phase of the slow wave. Our aim was to contribute to knowledge about the identity and role of ICC potassium channels in pacemaking. Here we describe a transient outward potassium current in cell-attached patches of ICC. This current was activated almost instantaneously at potentials positive of the resting membrane potential and inactivated as a single exponential or biexponential with time constants that varied widely from patch to patch. Averaged traces gave a biexponential inactivation with time constants of ∼40 and ∼500 ms, with no clear voltage dependence. Analysis of single-channel openings and closings indicated a channel conductance of 5 pS and permeability sequence of K+ (111) > Na+ (1) > N-methyl-d-glucamine+ (0.11). The current was completely blocked by 20 μM clotrimazole but was unaffected by 20 μM ketoconazole, 10 μM E4031, or 20 μM clofilium; 5 mM 4-aminopyridine slowed the activation of the current. The transient outward current may be important in moderating the upstroke of the pacemaker potential.
Isoflurane via TGF-β1 release increases caveolae formation and organizes sphingosine kinase signaling in renal proximal tubules
Authors: Song Joseph H. , Kim Mihwa , Park Sang Won , Chen Sean W. C. , Pitson Stuart M. , Lee H. Thomas
Published: January 2010

We previously showed that the inhalational anesthetic isoflurane protects against renal proximal tubule necrosis via isoflurane-mediated stimulation and translocation of sphingosine kinase-1 (SK1) with subsequent synthesis of sphingosine-1-phosphate (S1P) in renal proximal tubule cells (Kim M, Kim M, Kim N, D'Agati VD, Emala CW Sr, Lee HT. Am J Physiol Renal Physiol 293: F1827–F1835, 2007). We also demonstrated that the anti-necrotic and anti-inflammatory effect of isoflurane is due in part to phosphatidylserine (PS) externalization and subsequent release of transforming growth factor-β1 (TGF-β1) (Lee HT, Kim M, Kim J, Kim N, Emala CW. Am J Nephrol 27: 416–424, 2007). In this study, we tested the hypothesis that isoflurane, via TGF-β1 release, increases caveolae formation in the buoyant fraction of the cell membrane of human renal proximal tubule (HK-2) cells to organize SK1 and S1P signaling. To detect SK1 protein in the caveolae/caveolin fractions, we overexpressed human SK1 in HK-2 cells (SK1-HK-2). SK1-HK-2 cells exposed to isoflurane increased caveolae/caveolin formation in the buoyant membrane fractions which contained key signaling intermediates involved in isoflurane-mediated renal tubule protection, including S1P, SK1, ERK MAPK, and TGF-β1 receptors. Furthermore, treating SK1-HK-2 cells with recombinant TGF-β1 or PS liposome mixture increased caveolae formation, mimicking the effects of isoflurane. Conversely, TGF-β1-neutralizing antibody blocked the increase in caveolae formation induced by isoflurane in SK1-HK-2 cells. The increase in SK1 activity in the caveolae-enriched fractions from isoflurane-treated nonlentivirus-infected HK-2 cells, while smaller in magnitude, was qualitatively similar to that found in the SK1-HK-2 cell line. Finally, isoflurane also increased caveolae formation in the kidneys of TGF-β1 +/+ mice but not in TGF-β1 +/− mice (mice with reduced levels of TGF-β1). Our study demonstrates that isoflurane organizes several key cytoprotective signaling intermediates including TGF-β1 receptors, SK1 and ERK, within the caveolae fraction of the plasma membrane. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated renal protection and lead to new therapeutic applications of inhalational anesthetics during the perioperative period.
Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms
Authors: Meyer zu Schwabedissen Henriette E. , Verstuyft Celine , Kroemer Heyo K. , Becquemont Laurent , Kim Richard B.
Published: January 2010

renal elimination of a number of cationic compounds is thought to be mediated by the organic cation transporter 2 (OCT2, SLC22A2), a drug uptake transporter expressed at the basolateral domain of renal tubular cells. Recently, the key efflux transporter for the secretion organic cations was identified as an electroneutral H+/organic cation exchanger termed the multidrug and toxin extrusion (MATE)-type transporter 1 (MATE1, SLC47A1). The key goals of this study were to assess the interplay between the renal cationic transporters OCT2 and MATE1 and the functional assessment of genetic variation in human MATE1. First, the ability of various agents to interact with OCT2- or MATE1-mediated transport was determined using a recombinant vaccinia expression system. We were able to identify several drugs in clinical use with a divergent inhibitory capacity for these transporters. Subsequently, we further assessed the effect of those compounds on the cellular accumulation of shared substrates using OCT2 and MATE1 double-transfected cells. Consistent with data obtained using single transporter transfected cells, compounds that exhibited preferential inhibition of MATE1 such as rapamycin and mitoxantrone induced significant cellular accumulation of cationic substrates. We next assessed the functional relevance of MATE1 genetic polymorphisms. Significant loss of transport activity for metformin and tetraethylammonium was noted for two nonsynonymous single nucleotide polymorphisms (SNPs), c.404T>C (p.159T>M) and c.1012G>A (p.338V>A). The c.404T>C was only seen in Asian subjects with an allele frequency of 1%, and the c.1012G>A SNP was much more common, especially among those of African descent. In conclusion, we show that coordinate function of MATE1 with OCT2 likely contributes to the vectorial renal elimination of organic cationic drugs and that altered activity of MATE1, whether by drugs or polymorphisms, should be considered as an important determinant of renal cationic drug elimination.
Role of sympathetic responses on the hemodynamic consequences of rapid changes in posture in humans
Authors: Sheriff Don D. , Nådland Inger Helene , Toska Karin
Published: January 2010

Tolerance to +G z gravitational stress is reduced when +G z stress is preceded by exposure to hypogravity (fractional, 0, or negative Gz). For example, there is an exaggerated fall in eye-level arterial pressure (ELAP) early on during +G z stress (head-up tilt; HUT) when this stress is immediately preceded by −G z stress (head-down tilt; HDT), termed the “push-pull effect.” The aim of the present study was to test the hypothesis that sympathetic responses contribute to the push-pull effect. Young, healthy subjects ( n = 7 males and 3 females) were subjected to 30 s of 30° HUT from a horizontal position and to 30 s of 30° HUT when HUT was immediately preceded by 20 s of −15° HDT. Four bouts of HDT-HUT were alternated between five bouts of HUT in a counterbalanced design, and 1 min was allowed for recovery between tilts. This protocol was repeated during clonidine administration (2.5 μg/kg bolus over 30 min and then continuously at 0.36 μg·kg−1·h−1). Clonidine blunted the vasomotor responses to tilting, and this led to exaggerated changes in arterial pressure. Clonidine exerted little specific influence on the push-pull effect. Thus sympathetic responses appear neither to contribute to, nor protect against, the push-pull effect for the rate and duration of tilting imposed in the present study.
Mechanisms and Distribution of Ion Channels in Retinal Ganglion Cells: Using Temperature as an Independent Variable
Authors: Fohlmeister Jürgen F. , Cohen Ethan D. , Newman Eric A.
Published: January 2010

Trains of action potentials of rat and cat retinal ganglion cells (RGCs) were recorded intracellularly across a temperature range of 7–37°C. Phase plots of the experimental impulse trains were precision fit using multicompartment simulations of anatomically reconstructed rat and cat RGCs. Action potential excitation was simulated with a “Five-channel model” [Na, K(delayed rectifier), Ca, K(A), and K(Ca-activated) channels] and the nonspace-clamped condition of the whole cell recording was exploited to determine the channels' distribution on the dendrites, soma, and proximal axon. At each temperature, optimal phase-plot fits for RGCs occurred with the same unique channel distribution. The “waveform” of the electrotonic current was found to be temperature dependent, which reflected the shape changes in the experimental action potentials and confirmed the channel distributions. The distributions are cell-type specific and adequate for soma and dendritic excitation with a safety margin. The highest Na-channel density was found on an axonal segment some 50–130 μm distal to the soma, as determined from the temperature-dependent “initial segment–somadendritic (IS-SD) break.” The voltage dependence of the gating rate constants remains invariant between 7 and 23°C and between 30 and 37°C, but undergoes a transition between 23 and 30°C. Both gating-kinetic and ion-permeability Q10s remain virtually constant between 23 and 37°C (kinetic Q10s = 1.9–1.95; permeability Q10s = 1.49–1.64). The Q10s systematically increase for T <23°C (kinetic Q10 = 8 at T = 8°C). The Na channels were consistently “sleepy” (non-Arrhenius) for T <8°C, with a loss of spiking for T <7°C.
TD-GC-MS Analysis of Volatile Metabolites of Human Lung Cancer and Normal Cells In vitro
Authors: Filipiak Wojciech , Sponring Andreas , Filipiak Anna , Ager Clemens , Schubert Jochen , Miekisch Wolfram , Amann Anton , Troppmair Jakob
Published: January 2010

The aim of this study was to confirm the existence of volatile organic compounds (VOC) specifically released or consumed by the lung cancer cell line A549, which could be used in future screens as biomarkers for the early detection of lung cancer. For comparison, primary human bronchial epithelial cells (HBEpC) and human fibroblasts (hFB) were included. VOCs were detected in the headspace of cell cultures or medium controls following adsorption on solid sorbents, thermodesorption, and analysis by gas chromatography mass spectrometry. Using this approach, we identified VOCs that behaved similarly in normal and transformed cells. Thus, concentrations of 2-pentanone and 2,4-dimethyl-1-heptene were found to increase in the headspace of A549, HBEpC, and hFB cell cultures. In addition, the ethers methyl tert-butyl ether and ethyl tert-butyl ether could be detected at elevated levels in the case of A549 cells and one of the untransformed cell lines. However, especially branched hydrocarbons and alcohols were seen increased more frequently in untransformed than A549 cells. A big variety of predominantly aldehydes and the ester n-butyl acetate were found at decreased concentrations in the headspace of all cell lines tested compared with medium controls. Again, more different aldehydes were found to be decreased in hFB and HBEpC cells compared with A549 cells and 2-butenal was metabolized exclusively by both control cell lines. These data suggest that certain groups of VOCs may be preferentially associated with the transformed phenotype. Cancer Epidemiol Biomarkers Prev; 19(1); 182–95
Arsenic in Drinking Water and Risk of Urinary Tract Cancer: A Follow-up Study from Northeastern Taiwan
Authors: Chen Chi-Ling , Chiou Hung-Yi , Hsu Ling-I , Hsueh Yu-Mei , Wu Meei-Maan , Wang Yuan-Hung , Chen Chien-Jen
Published: January 2010

The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 μg/L), whereas studies from lower exposure areas (<100 μg/L) reported inconsistent results. A previous study conducted in northeastern Taiwan, where residents were exposed to relatively lower concentrations, reported increased risk of urinary cancer in a dose-response way. Using the same cohort with longer follow-up, we conducted analysis to elucidate the relationship between ingested arsenic and urinary cancer in lower exposure groups and assessed the influence of duration, recency, and latency of drinking arsenic-containing well water. A total of 8,086 residents from northeastern Taiwan were followed for 12 years. Incident urinary cancer was ascertained through linkage with the national cancer registry. All analysis was done by Cox proportional hazards regression models. There were 45 incidences of urinary cancer and a monotonic increased risk of urinary cancer was found with increasing arsenic concentration (P < 0.001). For the highly exposed (>100 μg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (<100 μg/L). Relative to the arsenic concentration <10 μg/L, those who drank well water with higher concentration from birth [RR, 3.69; 95% confidence interval (95% CI), 1.31-10.4], still drank at enrollment (RR, 3.50; 95% CI, 1.33-9.22), and drank for >50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher. Cancer Epidemiol Biomarkers Prev; 19(1); 101–10
Gene Methylation in Breast Ductal Fluid from BRCA1 and BRCA2 Mutation Carriers
Authors: Antill Yoland C. , Mitchell Gillian , Johnson Sandra A. , Devereux Lisa , Milner Alvin , Di Iulio Juliana , Lindeman Geoffrey J. , Kirk Judy , Phillips Kelly Anne , Campbell Ian G.
Published: January 2010

Purpose: Genomic alterations (including gene hypermethylation) are likely to precede the phenotypic changes associated with breast tumorigenesis. From a prospective collection of ductal lavage (DL) samples from women with a known mutation in BRCA1 or BRCA2, we have assessed promoter methylation with a comparison of results with several variables, including breast cancer (BC) outcome.

Experimental Design: Hypermethylation of p16, RASSF1A, twist, and RARβ was assessed using a qualitative, real-time, nested PCR assay. Associations between methylation status and variables were tested using Fisher's exact test or logistic regression. Analyses were done at three levels: a single breast, a single duct (both over time), and each DL sample in isolation.

Results: A total of 168 samples from 93 ducts in 54 breasts have been analyzed in 34 women (16 BRCA1 and 18 BRCA2 mutation carriers). A median of 2 DL was done (range, 1–5), with 7 women developing BC on study, 1 bilateral. Methylation of p16 was associated with a known BRCA1 mutation (P = 0.001, P < 0.001, and P < 0.001 for breast, duct, and sample levels, respectively) and women with a history of contralateral BC (P = 0.001 and P < 0.001 for duct and sample levels, respectively). An association was seen for women who developed BC on study and RASSF1A methylation (P = 0.001 for sample level).

Conclusions: Genetic methylation patterns could potentially be used to predict future BC risk. In addition, p16 methylation may be a predictor of BRCA1 mutation status. Further research is required to corroborate these findings. Cancer Epidemiol Biomarkers Prev; 19(1); 265–74
Influence of High-Dose Estrogen Exposure during Adolescence on Mammographic Density for Age in Adulthood
Authors: Jordan Helen L. , Hopper John L. , Thomson Russell J. , Kavanagh Anne M. , Gertig Dorota M. , Stone Jennifer , Venn Alison J.
Published: January 2010

High-dose estrogen exposure during adolescence has been hypothesized to increase a woman's breast cancer risk, possibly mediated through an increase in mammographic density, a well-established breast cancer risk factor. In 2006 to 2007, we conducted a retrospective study of women assessed for tall stature as an adolescent between 1959 and 1993. Eligible participants were ages ≥40 years and treated during adolescence with 3 mg diethylstilbestrol or 150 μg ethinyl estradiol daily or untreated. Mammograms from 167 treated and 142 untreated women were digitized. Total breast area, dense area, nondense area, and percent density were measured using a computer thresholding technique. Data on potential determinants were collected from medical records and telephone interview. Treated women had, on average, 17% lower dense area (P = 0.032). Means (95% confidence intervals) adjusted for age and body mass index for treated and untreated women were 24.5 cm2 (21.8-27.2) and 29.1 cm2 (26.0-32.4), respectively. There was no difference in adjusted means (95% confidence intervals) between treated and untreated women for nondense area [71.7 cm2 (66.2-77.7) versus 70.5 cm2 (64.7-76.9); P = 0.78], percent dense area [24.8% (22.4-27.4) versus 27.7% (24.8-30.7); P = 0.16], or total area [105.6 cm2 (100.1-111.4) versus 109.3 cm2 (103.1-115.8); P = 0.41], respectively. High-dose estrogen exposure during adolescence appears to curtail growth of mammographically dense tissue and therefore is unlikely to increase breast cancer risk through mechanisms related to mammographic density. Cancer Epidemiol Biomarkers Prev; 19(1); 121–9
Plasma 25-Hydroxyvitamin D Levels and the Risk of Colorectal Cancer: The Multiethnic Cohort Study
Authors: Woolcott Christy G. , Wilkens Lynne R. , Nomura Abraham M.Y. , Horst Ronald L. , Goodman Marc T. , Murphy Suzanne P. , Henderson Brian E. , Kolonel Laurence N. , Le Marchand Loïc
Published: January 2010

Vitamin D is obtained from the diet and synthesized in skin exposed to sunlight. Vitamin D status, assessed by circulating 25-hydroxyvitamin D [25(OH)D], has been associated with a reduced risk of colorectal cancer in previous studies. To complement existing evidence, we conducted a case-control study nested within the Multiethnic Cohort including men and women of Japanese, Latino, African-American, White, and Native Hawaiian ancestry. Using a direct competitive chemiluminescence immunoassay, 25(OH)D level was determined in plasma drawn before diagnosis from 229 cases and 434 controls matched to cases by area (Hawaii, Los Angeles), sex, ethnicity, birth year, blood draw date and time, and hours fasting. Odds ratios (OR) were estimated with conditional logistic regression. An inverse trend was observed (OR per doubling of 25(OH)D, 0.68; 95% confidence interval, 0.51-0.92; P = 0.01), but when examined in categories, relative to the first quintile (<16.8 ng/mL), the ORs in all other quintiles were quite similarly reduced between 37% and 46%. The association was not significantly heterogeneous among the four largest ethnic groups (Pheterogeneity = 0.46). In summary, this study provides evidence of an association between vitamin D status and reduced risk of colorectal cancer in an ethnically diverse population. Cancer Epidemiol Biomarkers Prev; 19(1); 130–4
Randomized Trial of a Lay Health Advisor and Computer Intervention to Increase Mammography Screening in African American Women
Authors: Russell Kathleen M. , Champion Victoria L. , Monahan Patrick O. , Millon-Underwood Sandra , Zhao Qianqian , Spacey Nicole , Rush Nathan L. , Paskett Electra D.
Published: January 2010

Background: Low-income African American women face numerous barriers to mammography screening. We tested the efficacy of a combined interactive computer program and lay health advisor intervention to increase mammography screening.

Methods: In this randomized, single blind study, participants were 181 African American female health center patients of ages 41 to 75 years, at ≤250% of poverty level, with no breast cancer history, and with no screening mammogram in the past 15 months. They were assigned to either (a) a low-dose comparison group consisting of a culturally appropriate mammography screening pamphlet or (b) interactive, tailored computer instruction at baseline and four monthly lay health advisor counseling sessions. Self-reported screening data were collected at baseline and 6 months and verified by medical record.

Results: For intent-to-treat analysis of primary outcome (medical record–verified mammography screening, available on all but two participants), the intervention group had increased screening to 51% (45 of 89) compared with 18% (16 of 90) for the comparison group at 6 months. When adjusted for employment status, disability, first-degree relatives with breast cancer, health insurance, and previous breast biopsies, the intervention group was three times more likely (adjusted relative risk, 2.7; 95% confidence interval, 1.8-3.7; P < 0.0001) to get screened than the low-dose comparison group. Similar results were found for self-reported mammography stage of screening adoption.

Conclusions: The combined intervention was efficacious in improving mammography screening in low-income African American women, with an unadjusted effect size (relative risk, 2.84) significantly higher (P < 0.05) than that in previous studies of each intervention alone. Cancer Epidemiol Biomarkers Prev; 19(1); 201–10
Cytoplasmic Localization of β-Catenin is a Marker of Poor Outcome in Breast Cancer Patients
Authors: López-Knowles Elena , Zardawi Sarah J. , McNeil Catriona M. , Millar Ewan K.A. , Crea Paul , Musgrove Elizabeth A. , Sutherland Robert L. , O'Toole Sandra A.
Published: January 2010

β-catenin is involved in cell adhesion through catenin-cadherin complexes and as a transcriptional regulator in the Wnt signaling pathway. Its deregulation is important in the genesis of a number of human malignancies, particularly colorectal cancer. A range of studies has been undertaken in breast cancer, with contradictory associations reported among β-catenin expression, clinicopathologic variables, and disease outcome. We undertook an immunohistochemical study measuring the levels and subcellular localization of β-catenin in 292 invasive ductal breast cancers with known treatment and outcome. No association with breast cancer–specific death was observed for cytoplasmic or membrane expression alone; however, a continuous score representing both locations (membrane minus cytoplasmic expression: MTC score) was associated with a worse outcome in univariate analysis (P = 0.004), and approached significance in a multivariate analysis model that included lymph node, progesterone receptor (PR), and HER2 status (P = 0.054). Therefore, the MTC score was used for further statistical analyses due to the importance of both the subcellular location and the levels of expression of β-catenin. An association was identified between high cytoplasmic expression (low MTC score), and high tumor grade (P = 0.004), positive Ki67 (P = 0.005), negative estrogen receptor (ER) (P = 0.005), positive HER2 (P = 0.04) status, and an active phosphoinositide 3-kinase pathway (P = 0.005), measured as PIK3CA mutations (P = 0.05) or PTEN loss (P = 0.05). Low cytoplasmic expression (high MTC score) was associated with the luminal A subtype (P = 0.004). In conclusion, a low β-catenin MTC score is associated with an adverse outcome in breast cancer, which may be of mechanistic significance in the disease process. Cancer Epidemiol Biomakers Prev; 19(1); 301–9
Multiple Genetic Variants in Telomere Pathway Genes and Breast Cancer Risk
Authors: Shen Jing , Gammon Marilie D. , Wu Hui-Chen , Terry Mary Beth , Wang Qiao , Bradshaw Patrick T. , Teitelbaum Susan L. , Neugut Alfred I. , Santella Regina M.
Published: January 2010

Purpose: To explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.

Methods: A population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.

Results: Seven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.

Conclusions: Four SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 219–28
Lipid Peroxidation and Etheno DNA Adducts in White Blood Cells of Liver Fluke-Infected Patients: Protection by Plasma α-Tocopherol and Praziquantel
Authors: Dechakhamphu Somkid , Pinlaor Somchai , Sitthithaworn Paiboon , Nair Jagadeesan , Bartsch Helmut , Yongvanit Puangrat
Published: January 2010

Chronic infection by the liver fluke Opisthorchis viverrini is a strong risk factor for cholangiocarcinoma. To clarify the involvement of oxidative stress and lipid peroxidation–derived DNA damage, etheno (ϵ)-DNA adducts (ϵdA, ϵdC) in WBC and plasma α-tocopherol were measured in samples collected from O. viverrini–infected Thai patients (n = 50) and healthy noninfected volunteers (n = 20). ϵdA and ϵdC levels were three to five times higher (P < 0.001) in infected patients than in controls; O. viverrini infection also increased two to three times in the plasma inflammatory indicators, 8-isoprostane, malondialdehyde, and nitrate/nitrite. Mean plasma α-tocopherol levels were two times lower in patients than in healthy controls (P < 0.001). Two months after a single dose to infected patients of the antiparasitic drug praziquantel, ϵdA and ϵdC levels in WBC were decreased to control level (P < 0.03); plasma 8-isoprostane, malondialdehyde, nitrate/nitrite, and alkaline phosphatase (ALP) were concomitantly lowered. ϵdA and ϵdC levels in WBC were positively correlated with plasma 8-isoprostane, malondialdehyde, and nitrate/nitrite levels and ALP activity, whereas plasma α-tocopherol levels showed inverse correlations. We conclude that chronic O.viverrini infection induces an accumulation of lipid peroxidation–derived DNA damage through oxidative/nitrative stress, which is lowered by the plasma α-tocopherol and by antiparasitic drug therapy. Etheno adducts in WBC and urine should be explored as a risk marker for opisthorchiasis-related cholangiocarcinoma, and to assess the efficacy of preventive and therapeutic interventions. Cancer Epidemiol Biomakers Prev; 19(1); 310–8.
Aspirin and Other Nonsteroidal Anti-inflammatory Drugs in Relation to Hodgkin Lymphoma Risk in Northern Denmark
Authors: Chang Ellen T. , Cronin-Fenton Deirdre P. , Friis Søren , Hjalgrim Henrik , Sørensen Henrik Toft , Pedersen Lars
Published: January 2010

There are few known modifiable risk factors for Hodgkin lymphoma, but the recent finding of an inverse association between routine regular-strength aspirin use and Hodgkin lymphoma risk suggests that aspirin may protect against Hodgkin lymphoma development. To further investigate this association using prospectively collected data, we conducted a population-based case-control study in northern Denmark. A total of 478 incident Hodgkin lymphoma cases were identified in nationwide health-care databases from 1991 to 2008. Ten population controls were matched to each case on age, sex, and county using risk-set sampling. Use of aspirin, selective cyclooxygenase-2 inhibitors, and other nonsteroidal anti-inflammatory drugs (NSAIDs) from 1989 to 2007 was ascertained by linkage to a population-based prescription database. Conditional logistic regression was used to estimate odds ratios for associations between medication use and risk of Hodgkin lymphoma. The odds ratio (95% confidence interval) for ever use (>2 prescriptions) compared with never/rare use (≤2 prescriptions) of low-dose aspirin was 0.7 (0.5-1.2). The association with low-dose aspirin use did not vary appreciably by recentness, duration, or intensity of use. Recent use (>2 prescriptions in the 1-2 years before the index date), short-term use (<7 years), and medium/high-intensity use (≥25% of duration of use covered by prescription) of selective cyclooxygenase-2 inhibitors or other NSAIDs was associated with increased Hodgkin lymphoma risk possibly due to prodromal symptoms among cases. In conclusion, our results provide some evidence of a protective effect of low-dose aspirin, but not other NSAIDs, against Hodgkin lymphoma development.Cancer Epidemiol Biomakers Prev; 19(1);59–64
Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival
Authors: Marcu Jahan P. , Christian Rigel T. , Lau Darryl , Zielinski Anne J. , Horowitz Maxx P. , Lee Jasmine , Pakdel Arash , Allison Juanita , Limbad Chandani , Moore Dan H. , Yount Garret L. , Desprez Pierre-Yves , McAllister Sean D.
Published: January 2010

The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist Δ9-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB1 and CB2 receptors, can modulate the actions of Δ9-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ9-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ9-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ9-THC. In the U251 and SF126 glioblastoma cell lines, Δ9-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients. Mol Cancer Ther; 9(1); 180–9
Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Authors: Wood Tabitha E. , Dalili Shadi , Simpson Craig D. , Sukhai Mahadeo A. , Hurren Rose , Anyiwe Kika , Mao Xinliang , Suarez Saiz Fernando , Gronda Marcela , Eberhard Yanina , MacLean Neil , Ketela Troy , Reed John C. , Moffat Jason , Minden Mark D. , Batey Robert A. , Schimmer Aaron D.
Published: January 2010

Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56
8-Amino-Adenosine Inhibits Multiple Mechanisms of Transcription
Authors: Frey Jennifer Ann , Gandhi Varsha
Published: January 2010

Roscovitine and flavopiridol suppress cyclin-dependent kinase 7 (CDK7) and CDK9 activity resulting in transcription inhibition, thus providing an alternative mechanism to traditional genotoxic chemotherapy. These agents have been effective in slow or nonreplicative cell types. 8-Amino-adenosine is a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. The objective of the current work was to define mechanisms of action that lead to transcription inhibition by 8-amino-adenosine. 8-Amino-adenosine is metabolized into the active triphosphate (8-amino-ATP) in cells. This accumulation resulted in a simultaneous decrease of intracellular ATP and RNA synthesis. When the effects of established ATP synthesis inhibitors and transcription inhibitors on intracellular ATP concentrations and RNA synthesis were studied, there was a strong correlation between ATP decline and RNA synthesis. This correlation substantiated the hypothesis that the loss of ATP in 8-amino-adenosine–treated cells contributes to the decrease in transcription due to the lack of substrate needed for mRNA body and polyadenylation tail synthesis. RNA polymerase II COOH terminal domain phosphorylation declined sharply in 8-amino-adenosine–treated cells, which may have been due to the lack of an ATP phosphate donor or competitive inhibition with 8-amino-ATP at CDK7 and CDK9. Furthermore, 8-amino-ATP was incorporated into nascent RNA in a dose-dependent manner at the 3′-end resulting in transcription termination. Finally, in vitro transcription assays showed that 8-amino-ATP competes with ATP for incorporation into mRNA. Collectively, we have concluded that 8-amino-adenosine elicits effects on multiple mechanisms of transcription, providing a new class of transcription inhibitors. Mol Cancer Ther; 9(1); 236–45
Notch-1 Inhibition by Withaferin-A: A Therapeutic Target against Colon Carcinogenesis
Authors: Koduru Srinivas , Kumar Raj , Srinivasan Sowmyalakshmi , Evers Mark B. , Damodaran Chendil
Published: January 2010

Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer. Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates prosurvival pathways, such as Akt/NF-κB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480, and SW-620). In addition, WA downregulated the expression of mammalian target of rapamycin signaling components, pS6K and p4E-BP1, and activated c-Jun-NH2-kinase–mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mammalian target of rapamycin signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by small interfering RNA). Our results suggest that WA inhibits Notch-mediated prosurvival signaling, which facilitates c-Jun-NH2-kinase–mediated apoptosis in colon cancer cell lines. These results underscore the anticancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer. Mol Cancer Ther; 9(1); 202–210
Sunitinib Induces Apoptosis and Growth Arrest of Medulloblastoma Tumor Cells by Inhibiting STAT3 and AKT Signaling Pathways
Authors: Yang Fan , Jove Veronica , Xin Hong , Hedvat Michael , Van Meter Timothy E. , Yu Hua
Published: January 2010

Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we show that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase and upregulation of proapoptotic genes, Bak and Bim, and inhibited the expression of survivin, an antiapoptotic protein. Sunitinib treatment also downregulated cyclin E, cyclin D2, and cyclin D3 and upregulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. Dephosphorylation of STAT3 (Tyr705) induced by sunitinib was helped by a reduction in activities of Janus-activated kinase 2 and Src. Additionally, sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of phosphorylated AKT after sunitinib treatment was accompanied by decreased phosphorylation of downstream proteins glycogen synthase kinase-3β and mammalian target of rapamycin. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor cells in vitro. These findings suggest the potential use of sunitinib for the treatment of pediatric medulloblastomas. Mol Cancer Res; 8(1); 35–45
Existence of Pink1 Antisense RNAs in Mouse and Their Localization
Authors: Chiba M. , Kiyosawa H. , Hiraiwa N. , Ohkohchi N. , Yasue H.
Published: January 2010

PTEN-induced kinase 1 (PINK1), which is identified as the gene transactivated by the tumor suppressor PTEN, has been found to be one of the causative genes in Parkinson’s disease (PD). In order to understand PD, rodent models containing affected Pink1 such as loss-of-function mutations have been exploited. Recently, natural antisense RNA of PINK1 has been demonstrated to be involved in the regulation of the PINK1 locus. However, no antisense RNAs of Pink1 except for human have been reported so far. Therefore, in the present study, while searching for the Pink1 antisense RNAs in mouse, we found that the antisense RNAs are transcribed from a mouse genomic region corresponding to the human region from which the antisense RNAs are produced. Further, we investigated the localization of the antisense RNAs in mouse brain using in situ hybridization; this demonstrated that the antisense RNAs were localized in the regions of brain where the Pink1 mRNA was found. In addition, the mRNA and antisense RNAs were found more densely in the hippocampus than in the other brain regions in newborn and 1-week-old mice, while those RNAs were found uniformly in the mouse brain regions of embryo day (E) 14, E17, and 8-weeks-old.