bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged time to pregnancy in residents exposed to ionising radiation in cobalt-60-contaminated buildings
Authors: Lin C-M , Chang W P , Doyle P , Wang J-D , Lee L-T , Lee C L , Chen P-C 
Published: September 2009

ObjectivesRadiation-induced cytogenetic damage in somatic cells has raised concern that low-dose ionising radiation can also damage germ cells and influence gamete production and/or function, resulting in decreased fertility. Time to pregnancy (TTP) was used to investigate whether exposure to γ-radiation affected fertility among the residents of cobalt-60-contaminated buildings in Taiwan.MethodsThis was a retrospective pregnancy-based study of 357 pregnancies born to 124 exposed couples. Both the cumulative dose and the dose rate for each pregnancy was estimated based on a physical dose reconstruction programme. The comparison population consisted of 612 pregnancies born to 225 couples randomly sampled from the Taiwan general population. Information on TTP was collected by personal interviews. Fecundability ratios (FRs) were calculated with a discrete proportional hazards model.ResultsFor exposed mothers, fertility decreased significantly when unprotected intercourse began during the period of living in the radiation-contaminated buildings (FR 0.75, 95% CI 0.61 to 0.92). The effect was borderline significant for fathers (FR 0.83, 95% CI 0.68 to 1.02). There was evidence that prolonged TTP was associated with the rate of exposure for both mothers and fathers (tests for trend: female, p=0.0006; male, p=0.03), especially evident for dose rates ≥10 mSv/year (female, FR 0.60, 95% CI 0.43 to 0.84; male, FR 0.68, 95% CI 0.49 to 0.96).ConclusionsOur findings suggest that exposure to low-dose ionising radiation of cobalt-60-contaminated buildings may decrease fertility, especially in females. Fertility declined with increasing concurrent dose but not with cumulative dose.
Cross-validation and refinement of the Stoffenmanager as a first tier exposure assessment tool for REACH
Authors: Schinkel Jody , Fransman Wouter , Heussen Henri , Kromhout Hans , Marquart Hans , Tielemans Erik 
Published: September 2009

ObjectivesFor regulatory risk assessment under REACH a tiered approach is proposed in which the first tier models should provide a conservative exposure estimate that can discriminate between scenarios which are of concern and those which are not. The Stoffenmanager is mentioned as a first tier approach in the REACH guidance. In an attempt to investigate the validity of the Stoffenmanager algorithms, a cross-validation study was performed.MethodsExposure estimates using the Stoffenmanager algorithms were compared with exposure measurement results (n=254). Correlations between observed and predicted exposures, bias and precision were calculated. Stratified analyses were performed for the scenarios “handling of powders and granules” (n=82), “handling solids resulting in comminuting” (n=60), “handling of low-volatile liquids” (n=40) and “handling of volatile liquids” (n=72).ResultsThe relative bias of the four algorithms ranged between −9% and −77% with a precision of approximately 1.7. The 90th percentile estimate of one out of four algorithms was not conservative enough. Based on these statistics and analyses of residual plots the underlying algorithm was adapted. Subsequently, the calibration and the cross-validation dataset were merged into one dataset (n=952) used for calibrating the adapted Stoffenmanager algorithms. This new calibration resulted in new exposure algorithms for the four scenarios.ConclusionsThe Stoffenmanager is capable of discriminating among exposure levels mainly between scenarios in different companies. The 90th percentile estimates of the Stoffenmanager are verified to be sufficiently conservative. Therefore, the Stoffenmanager could be a useful tier 1 exposure assessment tool for REACH.
Long-term exposure to traffic-related air pollution and mortality in Shizuoka, Japan
Authors: Yorifuji Takashi , Kashima Saori , Tsuda Toshihide , Takao Soshi , Suzuki Etsuji , Doi Hiroyuki , Sugiyama Masumi , Ishikawa-Takata Kazuko , Ohta Toshiki 
Published: September 2009

ObjectivesThe number of studies investigating the health effects of long-term exposure to air pollution is increasing, however, most studies have been conducted in Western countries. The health status of Asian populations may be different to that of Western populations and may, therefore, respond differently to air pollution exposure. Therefore, we evaluated the health effects of long-term exposure to traffic-related air pollution in Shizuoka, Japan.MethodsIndividual data were extracted from participants of an ongoing cohort study. A total of 14 001 older residents, who were randomly chosen from all 74 municipalities of Shizuoka, completed questionnaires and were followed from December 1999 to March 2006. Individual nitrogen dioxide exposure data, as an index for traffic-related exposure, were modelled using a land use regression model. We assigned participants an estimated concentration of nitrogen dioxide exposure during 2000–2006. We then estimated the adjusted HR and their CI for a 10 μg/m3increase in exposure to nitrogen dioxide for all-cause or cause-specific mortality.ResultsThe adjusted HR for all-cause mortality was 1.02 (95% CI 0.96 to 1.08). Regarding cause-specific mortality, the adjusted HR for cardiopulmonary mortality was 1.16 (95% CI 1.06 to 1.26); in particular the adjusted HR for ischaemic heart disease mortality was 1.27 (95% CI 1.02 to 1.58) and for pulmonary disease mortality it was 1.19 (95% CI 1.02 to 1.38). Furthermore, among non-smokers, a 10 μg/m3increase in nitrogen dioxide was associated with a higher risk for lung cancer mortality (HR 1.30, 95% CI 0.85 to 1.93).ConclusionLong-term exposure to traffic-related air pollution, indexed by nitrogen dioxide concentration, increases the risk of cardiopulmonary mortality, even in a population with a relatively low body mass index and increases the risk of lung cancer mortality in non-smokers.
ACOUSTIC BAND GAP FORMATION IN TWO-DIMENSIONAL LOCALLY RESONANT SONIC CRYSTALS COMPRISED OF HELMHOLTZ RESONATORS
Authors: CHALMERS L. , ELFORD D. P. , KUSMARTSEV F. V. , SWALLOWE G. M. 
Published: September 2009

We present a new type of sonic crystal technology offering a novel method of achieving broad acoustic band gaps. The proposed design of a locally resonating sonic crystal (LRSC) is constructed from "C"-shaped Helmholtz resonators as opposed to traditional solid scattering units. This unique construction enables a two band gap system to be generated in which the first — a Bragg type band gap, arises due to the periodic nature of the crystal, whilst the second gap results from resonance of the air column within the resonators. The position of this secondary band gap is found to be dependent upon the dimensions of the resonating cavity. The band gap formation is investigated theoretically using finite element methods, and confirmed through experimental testing. It is noted that the resonance band gaps detected cover a much broader frequency range (in the order of kHz) than has been achieved to date. In addition the possibility of overlapping such a wide band gap with the characteristic Bragg gap generated by the structure itself could yield gaps of even greater range. A design of sonic crystal is proposed, that comprises of several resonators with differing cavity sizes. Such a structure generates multiple resonance gaps corresponding to the various resonator sizes, which may be overlapped to form yet larger band gaps. This multiple resonance gap system can occur in two configurations. Firstly a simple mixed array can be created by alternating resonator sizes in the array and secondly using a system coined the Matryoshka (Russian doll) array in which the resonators are distributed inside one another. The proposed designs of LRSC's offer a real potential for acoustic shielding using sonic crystals, as both the size and position of the band gaps generated can be controlled. This is an application which has been suggested and investigated for several years with little progress. Furthermore the frequency region attenuated by resonance is unrelated to the crystals lattice constant, providing yet more flexibility in the design of such devices.
A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Basu Hirak S. , Thompson Todd A. , Church Dawn R. , Clower Cynthia C. , Mehraein-Ghomi Farideh , Amlong Corey A. , Martin Christopher T. , Woster Patrick M. , Lindstrom Mary J. , Wilding George 
Published: September 2009

Abstract
High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression. [Cancer Res 2009;69(19):7689–95]
Comparative Analyses of Chromosome Alterations in Soft-Tissue Metastases within and across Patients with Castration-Resistant Prostate Cancer
Authors: Holcomb Ilona N. , Young Janet M. , Coleman Ilsa M. , Salari Keyan , Grove Douglas I. , Hsu Li , True Lawrence D. , Roudier Martine P. , Morrissey Colm M. , Higano Celestia S. , Nelson Peter S. , Vessella Robert L. , Trask Barbara J. 
Published: September 2009

Abstract
Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. [Cancer Res 2009;69(19):7793–802]
Epidermal Growth Factor Receptor Variant III–Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression
Authors: Micallef Johann , Taccone Michael , Mukherjee Joydeep , Croul Sidney , Busby Jennifer , Moran Michael F. , Guha Abhijit 
Published: September 2009

Abstract
Glioblastoma multiforme (GBM) is the most common and most malignant adult brain tumor. A characteristic of GBM is their highly invasive nature, making complete surgical resection impossible. The most common gain-of-function alteration in GBM is amplification, overexpression, and mutations of the epidermal growth factor receptor (EGFR). The constitutively activated mutant EGFR variant III (EGFRvIII), found in ∼20% of GBM, confers proliferative and invasive advantage. The signaling cascades downstream of aberrant EGFR activation contributing to the invasive phenotype are not completely understood. Here, we show myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. EGFRvIII-expressing or EGF-stimulated human GBM cells increased expression, phosphorylation, and cytosolic translocation of MARCKS in a protein kinase C-α–dependent manner. Down-regulation of MARCKS expression with small interfering RNA in GBM cells expressing EGFRvIII led to decreased cell adhesion, spreading, and invasion. Elucidation of mechanisms that promote EGFRvIII-mediated tumorigenesis in GBM, such as MARCKS, provides additional understanding and potential biological targets against this currently terminal human cancer. [Cancer Res 2009;69(19):7548–56]
MYC Activity Mitigates Response to Rapamycin in Prostate Cancer through Eukaryotic Initiation Factor 4E–Binding Protein 1–Mediated Inhibition of Autophagy
Authors: Balakumaran Bala S. , Porrello Alessandro , Hsu David S. , Glover Wayne , Foye Adam , Leung Janet Y. , Sullivan Beth A. , Hahn William C. , Loda Massimo , Febbo Phillip G. 
Published: September 2009

Abstract
Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E–binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy. [Cancer Res 2009;69(19):7803–10]
Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4
Authors: Caja Laia , Sancho Patricia , Bertran Esther , Iglesias-Serret Daniel , Gil Joan , Fabregat Isabel 
Published: September 2009

Abstract
Transforming growth factor-β (TGF-β) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-β in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-β–induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-β–induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-β, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-β and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-β–induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis. [Cancer Res 2009;69(19):7595–602]
Down-regulation of c-FLIP Enhances Death of Cancer Cells by Smac Mimetic Compound
Authors: Cheung Herman H. , Mahoney Douglas J. , LaCasse Eric C. , Korneluk Robert G. 
Published: September 2009

Abstract
Smac mimetic compounds (SMC) are novel small molecules being developed for cancer therapy. The mechanism of SMC-induced sensitivity in cancer cells depends on autocrine release of tumor necrosis factor α (TNFα); however, potential mechanisms of resistance remain unknown. Here, we investigated the molecular profile and cytotoxic responsiveness of a diverse panel of 51 cancer cell lines to combinations of a dimeric SMC (AEG40730), death ligand TNFα, and tumor necrosis factor-related apoptosis-inducing ligand. Synergy was seen in combination with death receptor agonists in some cells, although single-agent activity was limited to a fewsensitive lines. Unexpectedly, the majority of cell lines resistant to combinations of SMC-AEG40730 and death ligands expressed caspase-8, FADD, RIP1, and ligand receptors necessary for apoptosis execution. Furthermore, TNFα-mediated ubiquitination of RIP1 was repressed by SMC-AEG40730 treatment, leading to the formation of the proapoptosis complex II. However, in resistant cancer cells, SMC-AEG40730 repressed TNFα-mediated c-jun-NH2-kinase activation and the levels of caspase-8 inhibitor c-FLIP were persistently elevated, in contrast to SMC-responsive cancer cells. Importantly, the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand-mediated activation of caspase-8 and caspase-3 to proceed. Together, these results provide mechanistic insight into the action of SMCs, demonstrating that the deciphering of the relevant molecular signature in cancer cells leads to the prediction of cancer cell responsiveness to SMC treatment. Furthermore, a majority of resistant cancer cells were sensitized to SMC-AEG40730 and TNFα by down-regulating c-FLIP, suggesting novel approaches in the use of SMCs and c-FLIP antagonists in treating cancer. [Cancer Res 2009;69(19):7729–38]
Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters
Authors: Hu Shuiying , Chen Zhaoyuan , Franke Ryan , Orwick Shelley , Zhao Ming , Rudek Michelle A. , Sparreboom Alex , Baker Sharyn D. 
Published: September 2009

Abstract
Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.
Experimental Design: Uptake of [3H]sorafenib or [3H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.
Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.
Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. (Clin Cancer Res 2009;15(19):6062–9)
CXCL13 and CXCL12 in Central Nervous System Lymphoma Patients
Authors: Fischer Lars , Korfel Agnieszka , Pfeiffer Sebastian , Kiewe Philipp , Volk Hans-Dieter , Cakiroglu Hüsniye , Widmann Thomas , Thiel Eckhard 
Published: September 2009

Abstract
Purpose: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma.
Experimental Design: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio.
Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P &lt; 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression.
Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. (Clin Cancer Res 2009;15(19):5968–73)